Lipèmia/Glucèmia postprandrial i risc CV.CV, cardiovascular; CVD, cardiovascular disease; PPG,...

Lipemia/Glucemia postprandrial i risc CV.

Antonio Ceriello

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain and IRCCS MultiMedica, Milan, Italy

Agenda

PPG, postprandial plasma glucose

PPG

Assessment of PPG

Addressing PPG

Agenda


PPG

Definition of PPG

PPG homeostasis

Pathophysiology of PPG regulation in diabetes

Overall glucose exposure is the sum of physiological, basal and postprandial exposures

Schematic representation. Adapted from Monnier & Colette. Diabetes Metab 2015;41:179–82

Breakfast Lunch Dinner

Glycaemia (mmol/L; mg/dL)

Basal hyperglycaemia

Prep

ran

dia

l g

lycaem

ia F

PG

Postprandial glycaemia

Diabetes

Normal

4 h 4 h 4 h

Prep

ran

dia

l g

lycaem

ia

Prep

ran

dia

l g

lycaem

ia

Physiological exposure

Additional overall glucose in people with diabetes • Basal hyperglycaemia • Postprandial

hyperglycaemia

Postprandial hyperglycaemia

PPG increment: PPG peak–preprandial glycaemia

Agenda


PPG

Definition of PPG

PPG homeostasis


Complementary roles of insulin and glucagon

EGP, endogenous glucose production; PPG, postprandial plasma glucose

Adapted from Aronoff et al. Diabetes Spectr 2004;17:183–90

EGP is primarily derived from the liver under the direction of glucagon

Rate of glucose

appearance

Liver

Gut

Pancreas Rate of glucose

disappearance

Plasma glucose

Insulin

Glucagon

Preprandial state

Low-level insulin secretion controls glucose disposal and has a minimal role in suppressing EGP

Postprandial state

Rate of glucose

appearance

Glucose is primarily derived from the gut

Insulin suppresses glucagon secretion and hepatic EGP and promotes glucose disposal in the periphery

Liver

Gut

Pancreas Rate of glucose

disappearance

Plasma glucose

Insulin

Glucagon

Fat Muscle

+ -

-

+

+

-

-

+

Promoted signal

+

-

Stimulatory

Inhibitory

Suppressed signal

Tissues

Fat Muscle

Tissues

Agenda


PPG

Definition of PPG

PPG homeostasis


In subjects with diabetes:

• Both preprandial and postprandial hyperglycaemia can occur1

• PPG excursions are greater and of longer duration2

• HGP suppression is suboptimal1

• Impaired HGP suppression occurs early in the evolution of diabetes3

• Time to post-meal peak insulin concentration: ~2 h (vs. ~45 min in individuals without diabetes)2

• Appropriately timed exposure of the liver to insulin has a great impact on PPG3

PPG and insulin profile in diabetes

HGP, hepatic glucose production; PPG, postprandial plasma glucose

1. Firth et al. J Clin Invest 1986;77:1525–32; 2. Basu et al. J Clin Invest 1996;97:2351–61; 3. Rizza. Diabetes 2010;59:2697–707

240

Insulin c

oncentr

ation (

pm

ol/

L)

300

Time (min)

200

100

0

400

500

0

Postprandial insulin profile

Meal

180 120 60

No diabetes Type 2 diabetes

Endogenous glucose production accounts for a significant part of postprandial hyperglycaemia in type 2 diabetes


Woerle et al. Am J Physiol Endocrinol Metab 2006;290:E67–77

59 61

15

27 4

10

0

20

40

60

80

100

Healthy Type 2 diabetes

Glycogenolysis

Gluconeogenesis

Meal

PPG

rele

ase o

ver

6 h

(g)

(75%)

(20%)

(5%)

(62%)

(28%)

(10%)

p<0.001

p=0.007

Time after meal ingestions (min)

–60 0 60 120 180 240 300 360

Pla

sm

a g

lucose (

mM

)

4

20

12

Type 2 diabetes (n=26) Healthy (n=15)

p<0.001

• Endogenous glucose in subjects with type 2 diabetes started out higher and did not decrease after meal ingestion

• Early changes in insulin and glucagon secretion are important determinants of overall PPG

Summary of PPG


Meal size and content, pancreatic hormones and gastric emptying are the most important regulators of PPG

Postprandial hyperglycaemia occurs early in the development of diabetes

The delay in the insulin response to a meal cannot appropriately suppress the hepatic glucose production, and is responsible for postprandial hyperglycaemia

Agenda


PPG

Assessment of PPG

Addressing PPG

Agenda


Assessment of PPG

Self monitored blood glucose (SMBG)

1,5-AG, 1,5-anhydroglucitol; CGM, continuous glucose monitoring; FGM, flash glucose monitoring; IDF, International Diabetes Federation; PPG, postprandial plasma glucose; SMBG, self-monitored blood glucose

Heinemann & Freckmann. J Diabetes Sci Technol 2015;9:947–50; IDF. 2011 Guideline for Management of Postmeal Glucose in Diabetes. www.idf.org; IDF. Self-Monitoring of Blood Glucose in Non-Insulin Treated Type 2 Diabetes. 2009. www.idf.org; National Diabetes Information Clearinghouse. http://diabetes.niddk.nih.gov

SMBG

Pre- Post- Pre- Post- Pre- Post- Bedtime

5-point profile

7-point profile

IDF guidelines:

• SMBG – optimal method for assessing PPG

• Emerging technologies: CGM, FGM, 1,5-AG

• SMBG – integral part of diabetes management

• The timing and frequency of SMBG must be individualised

• Breakfast post-meal glucose excursions

• Larger AUC1–4h vs. lunch or dinner

• Smaller intra- and inter-variability of post-meal peaks vs. lunch or dinner

• Time to peak

• ~90 min for all meals

Post-meal peaks during CGM

CGM, continuous glucose monitoring Cichosz et al. Diabetes Technol Ther 2013;15:78–83

24-h glycaemic profile (mean and SD)

10

Glu

cose (

mm

ol/

L)

8

6

4

0 10 20

Time (h)

Retrospective study of CGM in 86 newly diagnosed insulin-naïve patients with type 2 diabetes

• Meals used for calculation: breakfast (5–11 am), lunch (11 am–3 pm) and dinner (5–9 pm)

Flash Glucose Monitoring (FGM)

*A finger-prick test using a blood glucose meter is required during times of rapidly changing glucose levels when interstitial fluid glucose levels may not accurately reflect blood glucose levels, or if hypoglycaemia or impending hypoglycaemia is reported or the symptoms do not match the system readings

CGM, continuous glucose monitoring; FGM, flash glucose monitoring; PPG, postprandial plasma glucose; SMBG, self-monitored blood glucose

1. Bailey et al. Diabetes Technol Ther 2015;17:787–94.; 2. Abbott. www.freestylelibre.co.uk; 3. Heinemann & Freckmann. J Diabetes Sci Technol 2015;9:947–50

• FGM measures interstitial glucose1

• Handheld device used to scan sensor for current blood glucose level2

• One scan also records glucose data for the last 8 h2

• One sensor last for up to 14 days and is factory-calibrated; no calibration with finger pricks is needed*2

• Lower cost than CGM, similar price to SMBG (if testing 6–8 times per day)3

http://www.freestylelibre.co.uk/

Meal tests

*p<0.05 differences vs. NGT subjects. Dashed lines indicate glucose tolerance levels: normal (<140 mg/dL); impaired (140–199 mg/dL); and diabetic (≥200 mg/dL)

ADA, American Diabetes Assocation; IGT, impaired glucose tolerance; MTT, mixed meal tolerance test; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; SMBG, self-monitored blood glucose; WHO, World Health Organization

Meier et al. Diabetes Obes Metab 2009;11:213–22

Glu

cose (

mg/d

L)

300

Time (min)

200

150

0

350

–30

Test meal

240 90 60

250

100

50

30 0 120 150 210 180

Mixed test meal (820 kcal)

* * *

* *

* *

* *

*

*

* * *

Glu

cose (

mg/d

L)

300

Time (min)

200

150

0

350

–30

75g oral glucose

240 90 60

250

100

50

30 0 120 150 210 180

NGT IGT Type 2 diabetes

Oral glucose (75 g)

* *

*

*

*

*

*

*

*

*

* *

*

*

*

*

• WHO, ADA: OGTT – recommended test for diagnosis of diabetes or IGT

• Unicentric study, n=60 type 2 diabetes, IGT or NGT

• OGTT vs. MTT (continental breakfast) vs. SMBG

Close correlation, OGTT and MTT

2-h PPG (r2=0.78, p<0.0001)

Summary of PPG assessment

SMBG is the recommended method for assessing PPG. The timing and frequency of SMBG must be individualised

CGM is recommended as adjunct to SMBG and FGM alone or as complement to SMBG, for treatment decision.

There is a close correlation between the OGTT and the meal tolerance test

Agenda


PPG

Assessment of PPG

Addressing PPG

Agenda


Addressing PPG

Contribution to overall glucose control (HbA1c)

Short-term effects of postprandial hyperglycaemia

Long-term diabetes-related complications

Targeting PPG

Relative contribution of PPG to HbA1c

BF, breakfast; FPG, fasting plasma glucose; L, lunch; PPG, postprandial plasma glucose

Monnier et al. Diabetes Care 2003;26:881–5

6.1 mmol/L 110 mg/dL

6.1

PPG

8 11 2 5

am pm

BF L

FPG

• 290 non-insulin-treated patients with type 2 diabetes

• 4-point profile: FPG (8 am) vs. PPG (11 am, 2 pm, 5 pm)

• Relative contribution to the average diurnal hyperglycaemia

70%

50% 45% 40% 30%

0%

20%

40%

60%

80%

100%

<7.3% 7.3–8.4% 8.5–9.2% 9.3–10.2% >10.2%

PPG

FPG

Rela

tive c

ontr

ibution (

%)

HbA1c

100

80

60

40

20

0

Relative contribution of PPG in relatively ‘well-controlled’ patients

FPG, fasting plasma glucose; NPH, neutral protamine Hagedorn; PPG, postprandial plasma glucose; RCT, randomised controlled trial

Riddle et al. Diabetes Care 2011;34:2508–14

300

08:00

250

200

150

100

50

0

10:00 12:30 14:30 18:00 20:00 23:00 Day 2 08:00

Self-m

onitore

d

glu

cose (

mg/d

L)

• Pooled analysis

• Six RCTs

• 1261 patients with type 2 diabetes receiving basal insulin (insulin glargine or NPH insulin)

• 7-point profiles

• FPG: AUCFPG-100 mg/dL 24 h

• PPG: AUCPPG-FPG 24 h

21%

66%

0%

20%

40%

60%

80%

100%

Before basal insulin (HbA1c

8.7%)

After basal insulin (HbA1c

7%)

PPG

FPG

Before basal insulin (HbA1c 8.7%)

After basal insulin (HbA1c 7.0%)

Relative contribution of PPG

100

80

60

40

20

0

Summary of PPG contribution to HbA1c

SMBG profiles and CGM allow estimation of the relative contribution of PPG (as AUC) to HbA1c

The relative contribution of PPG to overall hyperglycaemia (HbA1c) is significant in relatively well-controlled patients with diabetes

Glycaemic control is still suboptimal. Achieving the HbA1c targets requires correcting both the FPG and PPG values

Agenda


Addressing PPG




Targeting PPG

Hyperglycaemia

Ceriello A. Annual Meeting Italian Society of Diabetology, 1998

Ceriello A. Diabetologia 2003; 46 Suppl 1:M9-16

LDL oxidation

Antioxidant consumption

F VIIa

Endothelium

Endothelial dysfunction

Atherosclerosis

Hypertriglyceridemia

Oxidative stress

Study Start Location No. of

patients Duration (years)

Chicago Peoples Gas Company Study 1992 US 873 19

Oslo Study 1995 US 873 19

Diabetes Intervention Study 1996 Germany 1139 11

Chicago Heart Association Detection Project 1997 US 12220 22

Paris Prospective and Helsinki Policemen Studies 1998 – 7260 20

Rancho Bernardo Study 1998 US 1858 7

Funagata Diabetes Study 1999 Japan 2534 6

Honolulu Heart Program 1999 Hawaii 8006 23

Hoorn Study 1999 The Netherlands 2363 8

Mauritius-Fiji-Nauru Study 1999 – 9179 8–12

Epidemiological data correlating PPG with CVD 1/2

CV, cardiovascular; CVD, cardiovascular disease; PPG, postprandial plasma glucose

Standl et al. Diabetes Care 2011;34(Suppl. 2):120–7; Bergman et al. Diabet Med 2016;33:1060–6

Epidemiological data correlating PPG with CVD 2/2

CV, cardiovascular; CVD, cardiovascular disease; PPG, postprandial plasma glucose

Standl et al. Diabetes Care 2011;34(Suppl. 2):120–7; Bergman et al. Diabet Med 2016;33:1060–6

Study Start Location No. of

patients Duration (years)

DECODE 1999 EU 22514 8.8

Saydah, Diabetes Care 2001 US 3092 16

Framingham Offspring Study 2002 US 3370 4

Cardiovascular Health Study 2002 US 4014 8.5

Qiao, Eur Heart J 2002 Finland 6766 7–10

DECODA 2004 Asia 6817 5

San Luigi Gonzaga Study 2006 Italy 529 5

Whitehall Study 2006 UK 17869 33

AusDiab Study 2009 Australia 10026 7

Israel Study of Glucose Intolerance, Obesity and Hypertension

2016 Israel 2138 33

Consistent observation Significant correlation between postprandial hyperglycaemia and CV mortality or CV events

Study (publication year)

Intervention, sample, follow-up

Results on CV endpoints

Observations

STOP-NIDDM (2003)1

• Acarbose vs. placebo • IGT, n=1429

• 3.3 years

• Major CV events • HR: 0.51

(95% CI 0.28–0.95)

• Secondary endpoint (hypothesis-generating)

• Very small difference in PPG

HEART2D (2009)2

• Prandial vs. basal insulin • Type 2 diabetes and

AMI, n=1115 • 2.6 years

• Major CV events • HR: 0.98

(95% CI 0.80–1.21)

• 47% achieved PPG target (<7.5 mmol/L)

• PPG difference: 0.8 mmol/L

NAVIGATOR (2010)3

• Nateglinide vs. placebo • IGT, n=9518

• 6.4 years

• Extended CV outcomes • HR: 0.93

(95% CI 0.83–1.03)

PPG is not lower in nateglinide arm

Less supportive evidence from RCTs

AMI, acute myocardial infarction; CV, cardiovascular; HR, hazard ratio; IGT, impaired glucose tolerance; MACE, major adverse cardiovascular events; PPG, postprandial plasma glucose; RCT, randomised controlled trial

1. Chiasson et al. JAMA 2003;290:486–94; 2. Raz et al. Diabetes Care 2009;32:381–6; 3. NAVIGATOR study group. N Engl J Med 2010;362:1463–76

Five-point Primary Outcome (ITT analysis)

Acarbose: 14.4% (470), 3·33 per 100 person-years Placebo: 14.7% (479), 3·41 per 100 person-years

Acarbose Placebo

Mean Two-hour Plasma Glucose Levels Over Six Years

Overall least-squares mean difference −0.24 mmol/L 95% CI −0.16 to −0.32 p<0.0001

0.0

2 H

r P

lasm

a G

luco

se (

mm

ol/

L)

Acarbose Placebo

Pathophysiology of postprandial state due to excessive hyperglycaemia

Ceriello. Nutr Metab Cardiovasc Dis 2008;18:S17–33

Excessive postprandial hyperglycaemia

High density lipoprotein Cholesterol catabolism

Triglycerides rich lipoprotein and low density lipoprotein

removal

Glucose auto-oxidation

Fibrinolysis

Free fatty acids Insulin resistance Early phase insulin

secretion

Endothelial function disturbed (nitric oxide

release )

Plaque stability

Blood coagulation

Agenda


Addressing PPG




Targeting PPG

PPG

Is it time for a paradigm switch in diabetes

management?

Why should we target 1-hour post-meal glucose ?

?

Coronary heart disease and peak glucose levels

Honolulu heart study, N= 6394; p< 0.001 comparing quintiles 1 and 5, p<0.01 comparing quintiles 1 and 5. Donahue RP et al. Diabetes 1987; 36:689-92

0

10

20

30

40

50

60

40-114

mg/dL

115-133

mg/dL

134-156

mg/dL

157-189

mg/dL

190-532

mg/dL R

ate

* p

er 1

00

0

Fatal coronary heart disease

Total coronary heart disease

Glucose levels one hour after 50 gm glucose load

One hour PPG control

“Diabetes and mortality risk is associated with elevated 1-hour glucose

level. The risk was independent of traditional CV risk factors, and it was

accentuated when combined with BMI. The obvious need is to compare

1-hour glucose with fasting and 2-hour postload glucose levels as

well as Hb A1c in a similar setting and in various populations”.


This large longitudinal study provides evidence that 1-hour postload plasma glucose in the absence of clinical diabetes at

baseline apparently is an independent risk factor for fatal coronary heart disease and stroke in middle-aged and older nondiabetic men

and women, and also for CVD and for all cause mortality.

• Oxidative stress:

• higher at higher levels of glycaemia

• induces endothelial dysfunction

• Endothelial dysfunction

• is directly correlated to the level of glycaemia reached during OGTT and “glucose spike”

• is a stronger predictor of CIMT.

• is worse at 1h than at 2h (OGTT and meals).

• Inflammation and thrombosis activation, follow the same pattern of endothelial dysfunction as during acute hyperglycaemia.

Deleterious mechanisms of 1h hyperglycaemia OGTT/PP: possible mechanisms

1. Ceriello A et al, Nutr Metab Cardiovasc Dis 2016,26: 285-92; 2. Giacco F et al, Diabetes 2015; 64: 3273–84; 3. Ceriello A, et al. Diabetes Res Clin Pract 2008,82: 262–7; 4. Ceriello A et al. Diabetes 1995,44:924–8.

CIMT, carotid intima-media thickness, OGTT, oral glucose tolerance test

Endothelial Dysfunction and Oxidative Stress Worsen as Glycaemia Increases During an OGTT

* P<0.05 versus fasting, † P<0.01 versus one hour, ‡ P<0.01

1. Endothelial vasodilation in response to 75 g oral glucose load (N=58)

2. Assessed by plasma level of thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxide

Kawano H et al. J Am Coll Cardiol 1999;34:146-154.

Arterial function1

12

10

8

6

4

2

0

-2

FMD of brachial artery (%)

400

Plasma glucose levels (mg/dL)

0 100 200 300

n=174

r=-0.61

P<0.01

8

6

4

2

0

FMD of brachial artery (%)

Fasting 1h 2h

‡

‡ ‡

* †

NGT

IGT

DM

Plasma TBARS levels (nmol/mL)

Oxidative stress2

Fasting 1h 2h 1

2

3

‡ ‡

‡

* †

NGT

IGT

DM

Changes of glycaemia, GLP-1, FMD, plasma nitrotyrosine, 8-iso-

PGF2a, and insulin during the meal and the OGTT in normal

healthy control patients and T2D patients.

Protective role of glucagon-like peptide 1 on endothelium during the meal

Data are expressed as mean ± SE

Ceriello A et al. Diabetes Care 2011; 34: 697–702

△ meal test controls ▲OGTT controls ○ meal test T2D ● OGTT T2D

• 1h glucose might be more dangerous than that at 2h simply because glycaemia is higher at 1h, during an OGTT and post-meal – common sense, but

• There are data showing that the glycaemic peak usually appears 1h after the start of meal.1-3

Why 1h postmeal hyperglycaemia is more deleterious than that of 2h?

1. Polonsky KS et al. J Clin Invest 1988; 81: 442–448. 2. Mazze RS et al. Diabetes Technol Ther 2008; 10: 149–59. 3. Tsujino D et al. Diabetes Technol Ther 2009; 11: 457–60

Pathways of hyperglycaemia-induced vascular damage

NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; GFAT, glutamine fructose phosphate amidotransferase Brownlee M. Nature 2001;414:813–20

2011 PPG guidelines from IDF

IDF, International Diabetes Federation; PPG, postprandial plasma glucose

IDF. 2011 Guideline for Management of Postmeal Glucose in Diabetes. www.idf.org

Treatment recommendations

• Post-meal hyperglycaemia is harmful and should be addressed

• Implement treatment strategies to lower PPG in people with post-meal hyperglycaemia

• A variety of both non-pharmacological and pharmacological therapies should be considered to target PPG

• PPG should be measured 1–2 h post-meal

• The target for PPG is 9.0 mmol/L (160 mg/dL) as long as hypoglycaemia is avoided

• Self-monitoring of blood glucose should be considered because it is currently the most practical method for monitoring PPG

http://www.idf.org/

Glycaemic control recommendations ADA/EASD, AACE and IDF guidelines

*No comorbidities, long life expectancy; †depending on disease duration, life expectancy, important comorbidities, patient attitudes and resource or support targets can be set more or less stringent

AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; IDF, International Diabetes Federation; PPG, postprandial plasma glucose

1. Chiang et al. Diabetes Care 2014;37:2034–54; 2. Inzucchi et al. Diabetologia 2015;58:429–42; 3. ADA. Diabetes Care 2015;38(S1):33–40; 4. Garber et al. Endocr Pract 2016;22;84–113; 5. IDF. 2011 Guideline for Management of Postmeal Glucose in Diabetes. www.idf.org

Age group Type 1

diabetes1

Type 2 diabetes2

Young (<18 years) <7.5% 7.0%

Adult <7.0% 7.0%

Older adults Healthy* Complex/intermediate Very complex/poor health

<7.5% <8.0% <8.5%

7.0%†

Association PPG target

(1–2 h postmeal)

ADA/EASD2,3 <10 mmol/L <180 mg/dL

AACE4 <7.8 mmol/L <140 mg/dL

IDF5 <9 mmol/L <160 mg/dL

HbA1c recommendations (ADA/EASD) PPG recommendations

http://www.idf.org/

Conclusions – already accepted

Glycaemic control is dependent on adequate regulation of FPG and PPG levels

Postprandial hyperglycaemia is associated with • Oxidative stress (e.g. atherosclerosis) • CVD • CV mortality

Reducing PPG levels may lower CV risk

Guidelines recognise the importance of addressing PPG at every stage of diabetes treatment

Conclusions – paradigm switch

Current ADA and the IDF guidelines suggest targeting PPG at 1h and between 1h and 1.5 h after the start of meals, respectively.

Paradigm switch in diabetes management

Introduce 1hOGTT for prediabetes and T2D diagnosis and 1hPPG for diabetes control

New ultra fast acting insulins and non-invasive technologies for blood

glucose monitoring

Lipèmia/Glucèmia postprandrial i risc CV.CV, cardiovascular; CVD, cardiovascular disease; PPG,...

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Transcript of Lipèmia/Glucèmia postprandrial i risc CV.CV, cardiovascular; CVD, cardiovascular disease; PPG,...