SB Solerte
Universitagrave di Pavia
brunosolerteunipvit
TERAPIA CON ANALOGHI DEL GLP-1
SB Solerte
Universitagrave di Pavia
brunosolerteunipvit
TERAPIA CON ANALOGHI DEL GLP-1
40
SB Solerte
Universitagrave di Pavia
brunosolerteunipvit
TERAPIA CON ANALOGHI DEL GLP-1
40 Protezione CV e renale
Uso negli anziani + 75 anni
Uso fino a GFR 15 mlmin
In sostituzione del BasalBolus
insulinico
Neuroprotezione
Recupero della massa magra
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA Binomio
GLICEMIAINSULINA
RISCHIO ANGIOMETABOLICO SISTEMICO
Il binomio glicemiainsulina
egrave superato
helliphellipdagli anni rsquo70
ma non ce ne siamo accorti
Grimelius L Capella C Buffa R PolakJM Pearse AG Solcia E
Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic-type glucagon cells of
gastrointestinal tract
Virchows Arch Cell Pathol 20217-2281976
Ohneda A Horigome K Kay Y Habashi H Ishii S Yagamata S
Purification of canine gut glucagon-like immunoreactivity (GLI) and its insulin releasing activity
Horm Metab Res 8170-1741976
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System PREMORBILITArsquo
COMORBILITArsquo
COMPLICANZA
Holst JJ Physiol Rev 87 1409ndash1439 2007
The physiology of Glucagon-like Peptide 1
Prohormone convertase 2
Prohormone convertase 13
Epithelial cell regeneration
(barrier function in intestine)
Satiety
bull Satiety (15 min max 40 ndash 90 min)
bull GI transient reduction
bull Insulin secretion INSL5 colonic L-cells
upregulated by CR and in germ-free mice
orexogenic hormone hepatic glucose production
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
SB Solerte
Universitagrave di Pavia
brunosolerteunipvit
TERAPIA CON ANALOGHI DEL GLP-1
40
SB Solerte
Universitagrave di Pavia
brunosolerteunipvit
TERAPIA CON ANALOGHI DEL GLP-1
40 Protezione CV e renale
Uso negli anziani + 75 anni
Uso fino a GFR 15 mlmin
In sostituzione del BasalBolus
insulinico
Neuroprotezione
Recupero della massa magra
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA Binomio
GLICEMIAINSULINA
RISCHIO ANGIOMETABOLICO SISTEMICO
Il binomio glicemiainsulina
egrave superato
helliphellipdagli anni rsquo70
ma non ce ne siamo accorti
Grimelius L Capella C Buffa R PolakJM Pearse AG Solcia E
Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic-type glucagon cells of
gastrointestinal tract
Virchows Arch Cell Pathol 20217-2281976
Ohneda A Horigome K Kay Y Habashi H Ishii S Yagamata S
Purification of canine gut glucagon-like immunoreactivity (GLI) and its insulin releasing activity
Horm Metab Res 8170-1741976
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System PREMORBILITArsquo
COMORBILITArsquo
COMPLICANZA
Holst JJ Physiol Rev 87 1409ndash1439 2007
The physiology of Glucagon-like Peptide 1
Prohormone convertase 2
Prohormone convertase 13
Epithelial cell regeneration
(barrier function in intestine)
Satiety
bull Satiety (15 min max 40 ndash 90 min)
bull GI transient reduction
bull Insulin secretion INSL5 colonic L-cells
upregulated by CR and in germ-free mice
orexogenic hormone hepatic glucose production
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
SB Solerte
Universitagrave di Pavia
brunosolerteunipvit
TERAPIA CON ANALOGHI DEL GLP-1
40 Protezione CV e renale
Uso negli anziani + 75 anni
Uso fino a GFR 15 mlmin
In sostituzione del BasalBolus
insulinico
Neuroprotezione
Recupero della massa magra
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA Binomio
GLICEMIAINSULINA
RISCHIO ANGIOMETABOLICO SISTEMICO
Il binomio glicemiainsulina
egrave superato
helliphellipdagli anni rsquo70
ma non ce ne siamo accorti
Grimelius L Capella C Buffa R PolakJM Pearse AG Solcia E
Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic-type glucagon cells of
gastrointestinal tract
Virchows Arch Cell Pathol 20217-2281976
Ohneda A Horigome K Kay Y Habashi H Ishii S Yagamata S
Purification of canine gut glucagon-like immunoreactivity (GLI) and its insulin releasing activity
Horm Metab Res 8170-1741976
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System PREMORBILITArsquo
COMORBILITArsquo
COMPLICANZA
Holst JJ Physiol Rev 87 1409ndash1439 2007
The physiology of Glucagon-like Peptide 1
Prohormone convertase 2
Prohormone convertase 13
Epithelial cell regeneration
(barrier function in intestine)
Satiety
bull Satiety (15 min max 40 ndash 90 min)
bull GI transient reduction
bull Insulin secretion INSL5 colonic L-cells
upregulated by CR and in germ-free mice
orexogenic hormone hepatic glucose production
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA Binomio
GLICEMIAINSULINA
RISCHIO ANGIOMETABOLICO SISTEMICO
Il binomio glicemiainsulina
egrave superato
helliphellipdagli anni rsquo70
ma non ce ne siamo accorti
Grimelius L Capella C Buffa R PolakJM Pearse AG Solcia E
Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic-type glucagon cells of
gastrointestinal tract
Virchows Arch Cell Pathol 20217-2281976
Ohneda A Horigome K Kay Y Habashi H Ishii S Yagamata S
Purification of canine gut glucagon-like immunoreactivity (GLI) and its insulin releasing activity
Horm Metab Res 8170-1741976
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System PREMORBILITArsquo
COMORBILITArsquo
COMPLICANZA
Holst JJ Physiol Rev 87 1409ndash1439 2007
The physiology of Glucagon-like Peptide 1
Prohormone convertase 2
Prohormone convertase 13
Epithelial cell regeneration
(barrier function in intestine)
Satiety
bull Satiety (15 min max 40 ndash 90 min)
bull GI transient reduction
bull Insulin secretion INSL5 colonic L-cells
upregulated by CR and in germ-free mice
orexogenic hormone hepatic glucose production
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Il binomio glicemiainsulina
egrave superato
helliphellipdagli anni rsquo70
ma non ce ne siamo accorti
Grimelius L Capella C Buffa R PolakJM Pearse AG Solcia E
Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic-type glucagon cells of
gastrointestinal tract
Virchows Arch Cell Pathol 20217-2281976
Ohneda A Horigome K Kay Y Habashi H Ishii S Yagamata S
Purification of canine gut glucagon-like immunoreactivity (GLI) and its insulin releasing activity
Horm Metab Res 8170-1741976
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System PREMORBILITArsquo
COMORBILITArsquo
COMPLICANZA
Holst JJ Physiol Rev 87 1409ndash1439 2007
The physiology of Glucagon-like Peptide 1
Prohormone convertase 2
Prohormone convertase 13
Epithelial cell regeneration
(barrier function in intestine)
Satiety
bull Satiety (15 min max 40 ndash 90 min)
bull GI transient reduction
bull Insulin secretion INSL5 colonic L-cells
upregulated by CR and in germ-free mice
orexogenic hormone hepatic glucose production
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System PREMORBILITArsquo
COMORBILITArsquo
COMPLICANZA
Holst JJ Physiol Rev 87 1409ndash1439 2007
The physiology of Glucagon-like Peptide 1
Prohormone convertase 2
Prohormone convertase 13
Epithelial cell regeneration
(barrier function in intestine)
Satiety
bull Satiety (15 min max 40 ndash 90 min)
bull GI transient reduction
bull Insulin secretion INSL5 colonic L-cells
upregulated by CR and in germ-free mice
orexogenic hormone hepatic glucose production
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
RISCHIO ANGIOMETABOLICO SISTEMICO
PREVENZIONE PRIMORDIALE
PREVENZIONE PRIMARIA
PREVENZIONE SECONDARIA
PREVENZIONE TERZIARIA
Gut Brain Pancreas
System PREMORBILITArsquo
COMORBILITArsquo
COMPLICANZA
Holst JJ Physiol Rev 87 1409ndash1439 2007
The physiology of Glucagon-like Peptide 1
Prohormone convertase 2
Prohormone convertase 13
Epithelial cell regeneration
(barrier function in intestine)
Satiety
bull Satiety (15 min max 40 ndash 90 min)
bull GI transient reduction
bull Insulin secretion INSL5 colonic L-cells
upregulated by CR and in germ-free mice
orexogenic hormone hepatic glucose production
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Holst JJ Physiol Rev 87 1409ndash1439 2007
The physiology of Glucagon-like Peptide 1
Prohormone convertase 2
Prohormone convertase 13
Epithelial cell regeneration
(barrier function in intestine)
Satiety
bull Satiety (15 min max 40 ndash 90 min)
bull GI transient reduction
bull Insulin secretion INSL5 colonic L-cells
upregulated by CR and in germ-free mice
orexogenic hormone hepatic glucose production
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS
Miocardiocytes Endocardium Endothelium + VSMC
Ban K Circulation 1172340 2008
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Potential indirect cardiovascular effects of GLP-1R agonists
Ussher JR et al Circ Res 1141788-1803 2014
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]
TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait
Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and
Aging L Vanvitelli University Naples Italy
The drugs used to reduce glucose levels in patients with
type 2 diabetes seem important for the ultimate
cardiovascular outcome the combination of intensive
glycemic control when safely attainable with newer
diabetes drugs (empagliflozin canagliflozin liraglutide
and semaglutide) may decrease the incidence of MACE
nephropathy and retinopathy Moreover depending on the
drug used CV mortality and heart failure may also be
reduced
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Date
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224
Healthy individuals (n=6)
Inta
ct
GL
P-1
(p
mo
ll)
500
1000
tfrac12 = 15ndash21 minutes
(iv bolus 25ndash250
nmoll)
Enzymatic cleavage
High clearance (4ndash9 lmin)
NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE
Human ileum
GLP-1 producing
L-cells
Capillaries
Di-Peptidyl
Peptidase-IV
(DPP-IV)
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
His Gly Thr Thr Ser Phe Glu Gly Asp
Leu
Ser
Lys Gln Met Glu Glu Ala Val Glu Arg
Phe
Leu
Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys
bull 50 amino acid homology to human GLP-1
bull T12 27ndash43 hours
Lixisenatide1
GLP-1 glucagon-like peptide-1
1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513
bull 97 amino acid homology to human GLP-1
bull T12 13 hours
Liraglutide23
His Ala Thr Thr Ser Phe Glu Gly Asp
Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
Glu
Arg
C-16
Fatty acid
7
37
9
Lys
DPP-IV
His Ala Thr Thr Ser Phe Glu Gly Asp Val
Ser
Ser Tyr Leu Glu Gly Ala Ala Gln Lys
Phe
Glu
Ile Ala Trp Leu Gly Val Gly Arg
GLP1 nativo
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1
Insulin secretion (glucose-dependent) and β-cell sensitivity
Insulin synthesis
Glucagon secretion (glucose-dependent)
Pancreas2ndash4
Liver4
Hepatic glucose output
Brain56
Satiety
Energy intake
Cardiovascular system78
Systolic blood pressure
Heart rate
1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5
Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev
Endocrinol 20128728ndash742
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Marso SP et al N Engl J Med 2016375311ndash322
Presented at ADA June 13 2016 Published in NEJM June 13 2016
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Baseline characteristics (mean plusmn SD unless stated)
Heart failure includes New York Heart Association class I II and III
BMI body mass index HbA1c glycated hemoglobin SD standard deviation
Marso SP et al N Engl J Med 2016375311ndash322
ANZIANI eo FRAGILI
Chhetri JK et Al
The prevalence and incidence of frailty in pre-
diabetic and diabetic community-dwelling older
population
BMC Geriatr 17472017
20 di diabetici anziani sono fragili
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Heterogeneity in health status among patients with diabetes based on data from the Health
and Retirement Study of people over age 50 People with known diabetes were assigned to
one of four mutually exclusive categories
A Very Healthy group with no comorbidities A Healthy Intermediate group with
comorbidities constrained to osteoarthritis and hypertension and with no functional
impairments A group for whom intensive diabetes management would be Difficult to
Implement andor any one of the following mild cognitive impairment poor vision two or
more minor functional due to multiple comorbidities impairments and a group with
Uncertain Benefit from intensive diabetes management due to having the poorest health
status with one or more of the following moderate-to-severe cognitive impairment two or
more major functional dependencies andor residence in a long-term nursing facility
As the Health and Retirement Study is a US population-based survey the y-axis estimates the
total number of people in the US over age 50 with diabetes in each category
JB Halter et Al
Diabetes 2014 Aug 63(8) 2578ndash2589
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
N Engl J Med 2016 Jul 28375(4)311-22
LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M
Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)
BACKGROUND
The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes
remains unknown
METHODS
In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial
infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were
performed for the prespecified exploratory outcomes
RESULTS
A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer
patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95
confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the
liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of
death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95
CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly
lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were
gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group
CONCLUSIONS
In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or
nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Severe hypoglycemia over time
Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a
negative binomial regression model using a log link and the logarithm of the observation time (100 years)
as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at
baseline included as covariates
CI confidence interval
Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke
The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard
ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at
54 months because less than 10 of the patients had an observation time beyond 54 months
CI confidence interval CV cardiovascular HR hazard ratio
Marso SP et al N Engl J Med 2016375311ndash322
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Marso SP et al N Engl J Med 2016375311ndash322
liraglutide liraglutide
liraglutide
liraglutide
liraglutide
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Mann JFE et al N Eng J Med 2017 August 377839-848
- 22 - 26
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Mann JFE et al N Eng J Med 2017 August 377839-848
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
JAMA 2017 Oct 17318(15)1460-1470
Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on
Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial
Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES
BRAIN
PANCREAS
GI TRACT
LIVER
ADIPOSE TISSUE
SKELETAL MUSCLE
Decreased energy intake
Increased satiety
GLP-1 RA
Glucose-dependent insulin
and glucagon secretion
Insulin synthesis
GLP-1 RA
Inhibits gastric emptying GLP-1 RA
Inhibition of hepatic
glucose production
GLP-1 RA
Insulin receptor
activation
Basal insulin
Increased glucose disposal Basal insulin
Basal insulin Inhibition of hepatic
glucose production
GLP-1 RA glucagon-like peptide-1 receptor agonist
1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
IDegLira puograve consentire di
ottimizzare al meglio il regime insulinico basale nellrsquoanziano
Risultati dal Protocollo DUAL V
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
DUAL V HBA1C OVER TIME
55
60
65
70
75
80
85
90
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
71
66 HbA
1c (
)
Time (weeks)
IDegLira (n=278)
IGlar (n=279)
EOT
Treatment
difference
ndash059
plt0001
∆HbA1C
ndash181
ndash113
00
Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data
Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF
---ADAEASD HbA1c target lt70 AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes
Lingvay et al JAMA 2016315(9)898ndash907
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (weeks)
Dose (
units)
At EOT approximately 40 of subjects
on IDegLira received the maximum 50
dose steps of which 68 achieved
HbA1c lt7
Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose
capped at 50 dose steps there was no maximum dose for IGlar
ETD was estimated from an ANCOVA analysis based on FAS
ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin
IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set
Lingvay et al JAMA 2016315(9)898ndash907
41 U
66 U
ETD ndash2547 U
[ndash2890 ndash2205]95 CI
plt0001
DUAL V DAILY INSULIN DOSE
IDegLira (n=278)
IGlar (n=279)
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
00
01
02
03
04
05
06
07
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Treatment ratio 017
plt0001
Num
ber
of epis
odes p
er
subje
ct
Time (weeks)
Mean cumulative function based on SAS
Treatment ratio is estimated from a negative binomial model based on FAS
Nocturnal was defined as the time from 0001ndash0559 (both inclusive)
FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set
Lingvay et al JAMA 2016315898ndash907
DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME
IDegLira (n=278)
IGlar (n=279) IDegLira IGlar
HbA1c at week 26 66 71
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
IDegLira puograve consentire di
sostituire il regime insulinico basal bolus (4 iniezioni)
nellrsquoanziano
Risultati dal Protocollo DUAL VII
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
CHANGE IN HBA1C OVER TIME DUAL VII
55
60
65
70
75
80
85
0 2 4 6 8 10 12 14 16 18 20 22 24 26
67
67 HbA
1c (
)
Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from
full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65
AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European
Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination
ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean
ETD
-002 [-016 012]95 CI
plt00001 for test for non-inferiority by 03
IDegLira (n=252)
IGlar U100 + IAsp (n=254)
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII
404 units
841 units
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26
ETD
-4450 units
[-4830 -4071]95 CI
plt00001
Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data
using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates
ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart
IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Time (weeks)
Dose (
units)
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME
DUAL VII
00
05
10
15
20
25
30
35
40
45
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Num
ber
of
epis
odes
per
subje
ct
Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA
classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia
ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide
combination IGlar U100 insulin glargine 100 unitsmL
Treatment ratio
011
[008 017]95CI
plt00001
Time (weeks)
IDegLira (n=252)
IGlar U100 + IAsp (n=253)
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Diabetes Technol Ther 2017 19(4)255-264
A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND
BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES
KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5
BACKGROUND
Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic
fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of
insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone
METHODS
We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients
with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess
glycemic fluctuation and day-to-day variability
RESULTS
Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-
90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also
resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira
provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)
compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all
pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside
the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)
CONCLUSIONS
Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than
either IDeg or liraglutide alone
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Variabile Mediana
A1c () - 08
BMI (Kgm2) - 078
Waist circumference (cm) - 2
Body weight (g) - 2000
Fat mass (g) - 1498
Free Fat Mass (g) + 9
SMI (Kgm2) + 003
PASE score (point) - 1164
9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450
Aging Clin Exp Res 2016
hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
ANALOGO GLP1 LIRAGLUTIDE
effetti su
CARDIOTOSSICITArsquo
ATEROGENESI
NEUROGENERAZIONE ALZHEIMER
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
- 29 + 1 - 36 - 4
Obesity 2017
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16
SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC
ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D
Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R
Abstract
The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic
patients is unknown We evaluated SIRT6 expression and the effect
of incretin-based therapies in carotid plaques of asymptomatic diabetic
and nondiabetic patients Plaques were obtained from 52 type 2
diabetic and 30 nondiabetic patients undergoing carotid endarterectomy
Twenty-two diabetic patients were treated with drugs that work on the
incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4
inhibitors for 26 plusmn 8 months before undergoing the endarterectomy
Compared with nondiabetic plaques diabetic plaques had more inflammation
and oxidative stress along with a lesser SIRT6 expression and collagen
content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy
-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress
indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial
progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in
the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression
compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory
pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is
associated with morphological and compositional characteristics of a potential stable plaque phenotype
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Expert Rev Neurother 2017 Jan17(1)59-75
MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH
IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E
Clinical studies suggest a link between peripheral insulin resistance and
cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)
subjects revealed insulin resistance in the brain suggesting a role of this
condition in cognitive deficits observed in AD In this review we focus on the
glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain
is collecting increasing attention because of its association with insulin
signaling activation Areas covered The role of GLP-1-mediated effects in the
brain and how they are affected along the progression of AD pathology is
discussed Furthermore we provide a comprehensive discussion about the use
of GLP-1 mimetics drugs which have been developed as a treatment for T2DM
but seem to possess a number of other physiological properties including
neuroprotective and anti-inflammatory effects that may be useful to slow AD
progression Expert commentary The repurposing of antidiabetic drugs for
the modulation of brain insulin resistance in AD appears to be of great interest
The beneficial effects on synaptogenesis neurogenesis and cell repair as well
as the reduction of the chronic inflammatory response and most importantly
the reduction of amyloid plaques in the brain indicate that these drugs have
promise as novel treatments for AD
Aumento neurogenesi
Ridotta insulino
resistenza
Ridotta
Neuroinfiammazione
Decremento placche
Abeta
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Neuronal IRIGF-1R and GLP-1R mediated
intracellular signaling transduction
pathways show several overlapping
downstream targets Activation of these
pathways may mediate several biological
responses in the central nervous system
such as control of cell metabolism and
energy homeostasis inhibition of
apoptosis reduction of inflammatory
responses modulation of synaptic
neurotransmission regulation of gene
transcription cell growth synapse growth
cell repair and regeneration facilitation of
long-term potentiation and memory
formation
World J Diabetes 2015 Jun 256(6)807-27
GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE
Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28
COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A
COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
Busch RS Kane MP
Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany
College of Pharmacy and Health Sciences Albany NY USA
Associazione INCRETINE E GLICOSURICI
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
EMPAGLIFLOZIN AND LIRAGLUTIDE
CV cardiovascular HR hazard ratio MI myocardial infarction
1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827
0 6 12 18 30 24 42 36 48
20
10
5
0
15
Pa
tie
nts
wit
h a
n e
ve
nt
()
Time from randomisation (months)
Placebo
Empagliflozin
Patients at risk
Empagliflozin
Placebo
4687
2333
4455
2194
4328
2112
3851
1875
2821
1380
2359
1161
1534
741
370
166
4580
2256
HR 086
9502 CI (074 ndash 099)
Pa
tie
nts
wit
h a
n e
ve
nt
()
Patients at risk
Liraglutide
Placebo
4668
4672
4593
4588
4496
4473
4400
4352
4280
4237
4172
4123
4072
4010
3982
3914
1562
1543
424
407
0 6 12 18 24 30 36 42 48 54
0
5
10
15
20
Placebo
Liraglutide
HR 087
95 CI (078 ndash 097)
EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke
plt0001 for non-inferiority
p=001 for superiority
plt0001 for non-inferiority
p=004 for superiority
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
SACCO RL STROKE 2007
Strategic Group
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
2000 1960
lsquoEnteroinsular
axisrsquo named
Incretin
defined
Discovered as
proglucagon
gene product
Receptor
cloned
1930 1980 1970 1990
Normalisation
of BG in type 2
diabetes
GLP1 mimetics and
analogues
(exenatide
liraglutide)
Insulinotropic
action of
incretins
confirmed Incretin and
enteroinsular
axis further
defined
HISTORY OF GLP-1-RA PREHISTORY OF GLP-1
2010
Prevention of
CV risk and
death in type 2
diabetes
Liraglutid
e
LEADER
2020 2030
PubMe
d
Semaglutid
eSUSTAIN
Primary
prevention of
type 2 diabetes
and CV global risk
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia
Dalla diabetologia dellrsquoaging al paradosso di
Waterloo
Contrastare
lrsquoipoglicemia iperglicemia