Avances en Insulinoterapia Dr Paz 2014

JOSE LUIS PAZ IBARRA ENDOCRINOLOGO UNMSM – HNERM

24 Feb 2014

XII Congreso Internacional “TERAPÉUTICA MÉDICA Y QUIRÚRGICA” Cuerpo Médico del Hospital Nacional “Dos de Mayo” 140 Natalicio del Dr. Guillermo Gastañeta Espinoza

24, 25 y 26 Febrero 2014

¿Por Qué debemos Prevenir/Tratar la DM2 ?

Prevención de Complicaciones Micro Vasculares • Retinopatía - Nefropatía - Neuropatía

Prevención de Complicaciones Macro Vasculares • Cardiopatía (Enfermedad Coronaria, IC) • ACV y EVP

Cambiar la Historia Natural de la Diabetes y ECV • Reducir la Resistencia a la Insulina • Mejorar la función de los islotes/Preservar una adecuada masa de las celulas β • Tratar las Co-morbilidades

Mejorar la calidad de vida y prolongarla • Control de síntomas •Disminuir la carga económica de la Diabetes • Disminuir la polifarmacia • Reducir la Mortalidad ¿? Pre-diabetes: Clinical Relevance and Therapeutic Approach

Pratley R, et al / Br J Diabetes Vasc Dis 2007; 7 (3): 120

Impacto de la Terapia Intensiva para DM: Estudios Clínicos

Estudio Microvasculars CVD Mortalidad

UKPDS

DCCT / EDIC*

ACCORD

ADVANCE

VADT

Long Term Follow-up

Initial Trial

* in T1DM

Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024)

A medida que la enfermedad progresa resulta más desafiante lograr que los pacientes alcancen la meta

Lebovitz HE. Med Clin N Am. 2004;88:847–863; Turner RC y cols. JAMA. 1999;281:2005–2012; UKPDS 16. Diabetes. 1995;44:1249–1258; Warren RE. Diabetes Res Clin Pract. 2004;65:S3–S8; Resnick HE y cols. Diabetes Care. 2006;29:531–537; Koro CE y cols. Diabetes Care. 2004;27:17–20.

100

0

Funció

n d

e las c

élu

las β

(%)

-10 0

Diagnóstico de diabetes

Esquema basado en

Insulina

Requieren insulina

Fracaso de la monoterapia

Combinación

con Múltiples Fármacos

+/– Insulina

Tiempo aproximado (años)

Esquema

Dos Fármacos

Monoterapia

80

60

40

20 Prediabetes Diabetes

10–20

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

(Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

ADA / EASD 2012


Esquema Basal Bolo (Adicionar Insulina Prandial antes de las comidas)

Esquema Basal Plus (Adicionar Insulina Prandial en la Comida Principal)

Esquema Basal (Adicionar Insulina Basal y Titular)

Cambios de los Estilos de Vida + MTF (± otros agentes)

Optimizando la Insulinoterapia para Mantener el Control Glicémico cuando la Basal No es Suficiente

Basal + Inhibidores DPP4

o

Análogos de GLP1

Inhibidores SGLT2

Hitos en el desarrollo de la Insulina

Withdrawn.

Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Blackwell Science: Malden, MA; 2003:1.1-1.22;

Drugs@ FDA; Bailey CJ, Barnett AH. BMJ. 2007;335:1156.

1920 1930 1940 1960 1970 1980 2000 2010 1990 1950

Insulin discovered (1921)

First human treatment with bovine insulin (1922)

Protamine and protamine zinc insulins developed (1936)

NPH insulin developed (1946)

Lente (zinc) insulins developed (1952)

Recombinant human insulin developed (1979)

Insulin pump developed (≈ 1978)

Insulin pen developed (1981)

Insulin lispro approved in US (1996)

Insulin aspart and insulin glargine approved in US (2000)

Insulin glulisine approved in US (2004)

Insulin detemir approved in US (2005)

Inhaled insulin developed (2006)

Tipos de Insulina

•Insulinas Humanas:

•Neutral protamine Hagedorn (NPH)

•Regular

•Pre-mezclas

•Análogos de Insulina

•Análogos Basales (glargina, detemir)

•Análogos ultra-rapidos (lispro, aspart, glulisina)

•Pre-mezclas


Formulaciones de Insulina Basales en Investigación

Farmacocinética de Insulina Glargina U-300a en Voluntarios Saludables

a U-300 insulin glargine is not FDA approved for clinical use. Becker R, et al. European Patent EP 2 387 989 A2. 2011.

U-100 0.4 U/kg (n = 24)

U-300 0.4 U/kg (n = 23)

35

30

25

20

15

10

5

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Co

nce

ntr

atio

n (

uIV

/mL)

Time

Nueva Formulación de Insulina GLAR-300a vs. GLAR-100 en Pacientes en Insulina

Basal Plus Mealtime

Noninferior A1C change for GLAR-300 vs GLAR-100 (both groups, -0.83%)

No between-group differences in adverse events

Significantly fewer with nocturnal hypoglycemia (≥ 1 severe or confirmedb) with GLAR-300 (graph)

45.5

36.1

0

20

40

60

80

100

Seve

re o

r co

nfi

rme

d

no

ctu

rnal

hyp

ogl

yce

mia

, %

GLAR, glargine. a GLAR-300 is not FDA approved for clinical use. b Confirmed hypoglycemia, ≤ 70 mg/dL. Riddle M, et al. ADA 73rd Scientific Sessions. 2013;43-LB.

GLAR-100 (n = 403)

GLAR-300 (n = 404)

RR 0.79 (CI, 0.67-0.94) P = .0070

Insulina Lispro PEGylada

• Delayed insulin absorption • Reduced clearance

Análogos de Insulina Basales en Investigación

a Polyethylene glycol (PEG)

group may be attached at any of 3 points.

Jonassen I, et al. Pharm Res. 2012;29:2104-2114.

Beals JM, et al. US Patent 2011/0105392 A1. May 5, 2011.

N6

O

CO2H

H HN O

HO2C

PEGa

PEGa

PEGa

Insulina Degludec • Dihexamers form soluble multihexamers after injection

• Multihexamers disassemble slowly

• Monomers are released rapidly after hexamers disassemble

Insulin association state

Rapid absorption Slow absorption

Insulin

Molecular size

Absorption

Zn2+

Capillary membrane

Subcutaneous tissue

36 kDa 6 kDa

Zn2+

Zn2+

72 kDa >5000 kDa

Absorption rate

Brange et al. Diabetes Care 1990;13:923–54

High molecular weight forms

http://www.sciencephoto.com/images/download_wm_image.html/P206223-Blood_vessels-SPL.jpg?id=802060223

Insulin degludec

injected

Long multi-hexamers assemble

Phenol Zn2+

As phenol from the vehicle diffuses degludec hexamers link up via single

side-chain contacts

Insulin degludec

multi-hexamers

Zinc diffuses slowly causing individual hexamers to disassemble, releasing

monomers

Subcutaneous depot Zn2+

Monomers are absorbed from the depot into the circulation

Media Armónica

(hs)

CV

(%)

Vida ½ Terminal (estado estable)

Degludec 24.5 23

Glargina 12.2 56

Relative serum IDeg trough concentrations during initiation of once-daily (0.4 U/kg) dosing in patients with T1DM

0 1 2 3 4 5 6 7 8 9 10 0

10

20

30

40

50

60

70

80

90

100

110

120

Days since first dose

Seru

m I

Deg c

oncentr

ation

Pro

port

ion o

f D

ay 1

0 level (%

)

Values are estimated ratios and 95% CI relative to day 10

Heise T et al. IDF 2011 21st World Congress Abstract Book. IDF: Dubai, 2011; Poster 1453

Absorción desde el depósito SC Activación del Receptor &

Depuración de insulina

Perfiles Farmacodinámicos Glargina vs Degludec

Clamp studies of patients with T1DM.

Curves shown are at steady state.

FDA Endocrinologic and Metabolic Drugs Advisory Committee Meeting.

FDA briefing document. UCM327015. November 8, 2012.

Glargine Degludec

• Peak effects earlier and slightly larger for glargine than degludec • Peak effects for glargine and degludec are dose-dependent

GIR

, mg/

kg/m

in

0

4

5

6

3

16 0 4 8 12 20 24

Time, h

2

1 GIR

, mg/

kg/m

in

0

4

5

6

3

16 4 8 12 20 24

Time, h

2

1

0

0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg

IDeg OD + metformin ± DPP-4 (n=773)

IGlar OD + metformin ± DPP-4 (n=257)

Insulin-naïve patients with type 2 diabetes

(n=1030)

0 52 weeks Inclusion criteria

• Type 2 diabetes ≥6 months

• Insulin naïve treated with metformin ± SU, DPP-4 or acarbose for ≥3 months

• HbA1c 7.0–10.0%

• BMI ≤40 kg/m2

• Age ≥18 years

Randomised 3:1 (IDeg OD:IGlar OD) Open label

DPP-4, dipeptidyl peptidase-4 inhibitor SU, sulphonylurea OD, once daily Data on file: NN1250-3579; Accepted for presentation at ADA 2012

Degludec QDa vs Glargina QD en Pacientes con DM2 Insulin-Naïve en 1 año

Similar A1C and weight changes -1.1% vs -1.2% (P = .40)

2.4 kg vs 2.1 kg (P = .28)

Similar overall hypoglycemia b 1.5 vs 1.9 events/y (NS)

Lower nocturnal hypoglycemiab with degludec QD (graph)

0.3

0.003

0.4

0.023

0.0

0.5

1.0

Nocturnal Severe

Hyp

ogl

yce

mia

, eve

nts

/y

DEG, insulin degludec; GLAR, insulin glargine; QD, once daily. a Insulin degludec is not FDA approved for clinical use. b Hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition; nocturnal, occurring between 0100 h and 0559 h. Zinman B, et al. Diabetes Care. 2012;35:2464-2471.

DEG QD (n = 773; 0.59 U/kg)

GLAR QD (n = 257; 0.60 U/kg)

All P < .05

Degludec QD ó 3 veces/semana vs. Glargine QD en Adultos con DM2: Eficacia e Hipoglicemia en 16 ssa

Efficacy

-1.5 -1.3 -1.3

-1.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

ΔA

1C

(%

)

Hypoglycemia

2.3

0.2

0.1

0.6

0.1

0 0

.9

0.1

0

1.1

0

0

0

5

10

15

Confirmed Overall

Nocturnal Severe

Eve

nt

Rat

e (

EPY

)

a N = 245 (DEG 3TW, n = 62; DEG QD A, n = 60; DEG QD B, n = 61; GLAR

QD, n = 62); all patients treated with metformin (1500-2000 mg/d).

Hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition. Zinman B, et al. Lancet. 2011;377:924-931.

8.6

%

8.7

%

8.7

%

8.8

%

BL

A

1C

DEG 3TW (3.4 U/kg) DEG QD A (3.1 U/kg)

DEG QD B (4.5 U/kg) GLAR QD (3.3 U/kg)

Patients with type 2 diabetes

(n=687)

0 26 weeks

Inclusion criteria

• Type 2 diabetes ≥6 months

• Previously treated with OADs and/or basal insulin

• HbA1c:

OADs only 7–11% Basal insulin ± OADs 7–10%

• BMI ≤40 kg/m2

• Age ≥18 years

Open label

Glargine OD ±OADs (n=230)

(metformin/SU/pioglitazone)

Degludec OD Fixed ±OADs (n=228)


Degludec OD Flexible ±OADs (n=229)


Birkeland et al. IDF 2011:P-1443; Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423; Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668)

morning

Mon Tue Wed Thu Fri Sat Sun

morning morning

evening evening evening evening

40h 40h 40h

8h 8h

24h

8-12 AND 36-40 hours between insulin administration

Degludec QD Dosis Flexible vs Fija en Adultos con DM2:Eficacia e Hipoglicemia en 26 ssa

Efficacy

-1.3 -1.1

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

ΔA

1C

(%

)

Hypoglycemia

3.6

0.6

2

3.6

0.6

2

0

5

10

15

Confirmed Overall

Nocturnal Severe (episodes)

Eve

nt

Rat

e (

EPY

)

a N = 457; DEG OADs (not specified). FIXED, administered with evening meal daily; FLEX, administered 8-40 hours apart; hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition. Birkeland KI, et al. EASD 2011. Abstract 1041.

8.4% 8.5% BL A1C:

FLEX QD (n = 229) FIXED QD (n = 228)

= 20-40 kDa PEG

PEG

PEG

0

1

2

3

4

5

0 2 4 6 8 10 12 14 16 18 20 22 24

Me

an

GIR

, m

g/m

in/k

g

0.33 U/kg 0.50 U/kg

0.67 U/kg 1.00 U/kg

a PEGylated insulin lispro is not FDA-approved for clinical use. Heise T, et al. Diabetes. 2012;61(suppl 1):A256 [abstract 1000-P].

Time, h

PEGLisproa vs. Glargine en Adultos con DM2 en 12 ss Patients with T2DM, 12 weeks

After adjusting for baseline rates, nocturnal hypoglycemia was 48% lower in the pegylated lispro group (P = .021)

EPY, events/patient-year; GLAR, insulin glargine; PEGL, pegylated

insulin lispro; QD, once daily.

2-period, phase 2 randomized trial. a PEGylated insulin lispro is not FDA approved for clinical use.

Hypoglycemia, plasma glucose ≤ 70 mg/dL or severe per ADA

definition. Bergenstal RM, et al. Diabetes Care. 2012;35:2140-2147.

Outcome PEGL QD

(n = 195; 0.59 U/kg) GLAR QD

(n = 93; 0.60 U/kg) P Value

∆A1C, % ‒0.7 ‒0.7 NS

∆Weight, kg ‒0.6 0.3 .001

Overall hypoglycemia, EPY 1.3 1.5 .804

Nocturnal hypoglycemia, EPY 0.3 0.4 .178

Severe hypoglycemia, no. of episodes

0 0

Contribución de la Glicemia de Ayuno vs. PP a la A1C: Antes & después de Insulina basal

Fasting hyperglycemia

Post-prandial hyperglycemia

Antes

Insulina Basal

Riddle, et al. Diabetes Care 2011; 34 (12): 2508-2514

Insulinas Prandiales en Investigación

Adición de Hialuronidasa a Insulina Acelera su absorción SC

Hyaluronidase is a naturally occurring enzyme

Temporarily degrades hyaluronan, a naturally

occurring space-filling gel-like substance that is a major

component of soft connective tissue such as skin

Facilitates penetration of drugs at the injection site

Natural and synthetic hyaluronidase formulations

are available

FDA-approved as adjuvants to increase the dispersion and

absorption of injected drugs

Transient locally acting permeation enhancers

Girish KS, Kemparaju K. Life Sci. 2007;80:1921-1943;

Drugs@FDA. Hyaluronidase.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021859s006lbl.pdf.

Efectos de la adición de Hialuronidasa Recombinante Humana en la farmacodinámica de Lispro

T1DM, 60 g CHO, n = 221,a T2DM, 80 g CHO, n = 212,b

Profiles obtained in liquid meal tests. a Identical insulin doses; b LIS, 0.275 units/kg; LIS + RHH, 0.254

units/kg + 5 mcg/mL; RHI + RHH, 0.288 units/kg + 5 mcg/mL.

1. Hompesch M, et al. Diabetes Care. 2011;34:666-668.

2. Hompesch M, et al. Diabetes Technol Ther. 2012;14:218-224.

RHH: bigger early peak effect, similar tail

Me

an B

loo

d

Glu

cose

, mg/

mL

SEM

80

140

160

120

240 0 60 120 180 420 480

Time from Injection, minutes

100

300 360

LIS

LIS + RHH

Me

an B

loo

d

Glu

cose

, mg/

mL

SEM

80

140

180

120

240 0 60 120 180 420 480

Time from Injection, minutes

100

300 360

160

RHH: slightly earlier peak, less tail

LIS

LIS + RHH

RHI + RHH

Hialuronidasa Recombinante Humanaa en Combinación con un análogo reduce GPP en DM1

a RHH is not approved for chronic administration with insulin.

Two-period, 12-week, double-blind, randomized crossover trial.

N = 117, all using BBT; solid lines, means; dashed lines, SEM. Hirsch IB, et al. Diabetes. 2012;61(suppl 1):A92 [abstract 353-OR].

Breakfast Lunch Dinner

40

0

-20

1 2 3

Time, h

Mea

l Exc

urs

ion

, m

g/d

L S

EM 20

4 0

40

0

-20

1 2 3

Time, h

Mea

l Exc

urs

ion

, m

g/d

L S

EM

-40

20

4 0

40

0

-20

1 2 3

Time, h

Mea

l Exc

urs

ion

, m

g/d

L S

EM

-40

20

4 0

LIS or ASP + RHH LIS Alone



Hialuronidasa Recombinante Humanaa en Combinación con un análogo reduce GPP en DM2

a RHH is not approved for chronic administration with insulin.

Two-period, 12-week, double-blind, randomized crossover trial.

N = 121, all using BBT; solid lines, means; dashed lines, SEM.

Bergenstal RM, et al. Diabetes. 2012;61(suppl 1):

A224 [abstract 882-P].

140

130

12 18 24

Time of Day

Blo

od

Glu

cose

, m

g/d

L S

EM

150

26 6

120

160

170

LIS or ASP + RHH

LIS Alone

Degludec-Asparta BID vs. Aspart Bifásico BID en DM2

a Degludec and degludec-aspart are not approved in the US. b Significantly different between groups. Niskanen L, et al. Eur J Endocrinol. 2012;167:287-294.

-1.8 -1.8

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

ΔA

1C

(%

)

2.9

0.4 0

7.3

1.1 0

0

5

10

15

Eve

nt

Rat

e (

EPY

)

BL A1C: 8.5% 8.6%

DEG 70/ASP 30 (0.57 U/kg) (n = 61) BIASP 70/30 (0.66 U/kg) (n = 62)

Hypoglycemia

b

Efficacy

DEG 70/ASP 30 vs BIASP 70/30 • A1C < 7% without hypoglycemia: 67% vs 40%b • Weight gain: 1.1 kg vs 1.4 kg

Degludec + Aspart BBT vs. Glargine + Aspart BBT en Adultos con DM2: Eficacia e Hipoglicemia Nocturna en 1 añoa

Efficacy

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

0 20 40 60

A1C

(%)

Time (Weeks)

DEG + ASP BBT (n = 744)

GLAR + ASP BBT (n = 248)

Nocturnal Hypoglycemia

0.0

0.5

1.0

1.5

2.0

0 20 40 60

Cu

mu

lati

ve N

oct

urn

al

Hy

po

gly

cem

ia (

EP

Y)

Time (Weeks)

DEG + ASP BBT (n = 753)

GLAR + ASP BBT (n = 251)

Nocturnal hypoglycemia, BG < 56 mg/dL from 12:00 AM to 5:59 AM.

Garber A, et al. Diabetes. 2011;60(suppl 1):A20 [abstr 74-OR].

Hollander PA, et al. EASD 2011. Abstract 1035.

P = .04

Adicionar Exenatide a Insulin Glargine mejora control en DM2

Buse, et al. Ann Intern Med. 2011;154:103-112. Rosenstock, et al. Diabetes Care 2012; 35(5):955-8. Epub 2012 Mar 19.

A1C 8.3-8.5%

Insulin 0.5 u/kg

BMI 33-34

-1.0% +20u +1.0kg

-1.7% +13u -1.8kg

Minor hypoglycemia 25% (EXE) vs 29% (PLB)

Longer diabetes duration and lower BMI had greater A1C reductions. Longer diabetes

duration also lost the most weight.

The use of IDegLira, a fixed-ratio combination of Liraglutide (Victoza) and insulin Degludec (Tresiba) in a single-injection delivery device (1 unit of insulin degludec is combined with 0.036 mg of liraglutide. The maximum doses available for the combination would include 50 units of degludec with 1.8 mg of liraglutide), in T2D patients inadequately controlled on basal insulin led to improved overall glycemic control, with significant weight loss, in the phase 3 DUAL II trial reported at the World Diabetes Congress 2013.

Importantly, there was no increased risk for hypoglycemia among those patients who received IDegLira compared with those who were randomized to insulin degludec alone, despite the former group having a significantly lower HbA1c level.

And the rate of nausea observed in those receiving IDegLira was low, at around 7%, vs. 4% among the insulin-only patients.

Conclusiones

Los Algoritmos ADA/EASD y AACE recomiendan el uso de Insulina si el objetivo glicémico no es alcanzado dentro del 1° año de Tto.

Los pacientes pueden auto-titular satisfactoriamente la insulina basal

La insulina basal es titulada hasta alcanzar una GPA objetivo

Los análogos de insulina basal proveen un perfil más fisiológico (tiempo-acción) que insulina NPH.

Insulina puede ser usada en combinación con otros agentes.

Considerar detener titulación de insulina basal si dosis es > 0.5 IU /kg/day o hay incremento de riesgo de hipoglicemia

Análogos emergentes tienen el potencial de mejorar la insulinoterapia por proveer perfiles (tiempo-acción) relativamente con menos picos y menores tasas de hipoglicemia

Conclusiones…

Análogos basales con duración de acción > 24 hs están en desarrollo.

Insulinas Degludec y PEGLispro demuestran perfiles farmacocinéticos relativamente sin picos

Datos disponibles para Degludec en pacientes con DM2 demuestran: Ninguna diferencia estadísticamente significativa en eficacia o

hipoglicemia con intervalos de dosis de 8-40 hs Menos variabilidad que Glargina Menor riesgo de hipoglicemia que Glargina cuando es usada como

componente del regimen BBT con aspart.

Datos disponibles para Degludec plus en pacientes con DM2 demuestra eficacia equivalente a, y menos hipoglicemia que aspart bifásica con dosis BID.

Uso combinado de análogos basales con análogos de GLP1 prometen un mejor control glicémico sin ganancia ponderal con esquemas simples.

Insulinas prandiales deben considerarse cuando los objetivos glicémicos no son alcanzados con la insulina basal.

Algunos pacientes pueden requerir insulina prandial solamente con su comida principal

Los regímenes Basal-bolo, basal plus 1, y pre-mezclas son efectivos

Los esquemas con pre-mezclas y basal bolo tienen mayores tasas de hipoglicemia.

El uso de hialuronidasa podrían permitir un control más efectivo de la GPP con menor tasa de hipoglicemia,

Conclusiones…

Gracias por su Atención

[email protected]

Avances en Insulinoterapia Dr Paz 2014

Health & Medicine

Transcript of Avances en Insulinoterapia Dr Paz 2014