Understanding the science of incretin biology and implications on cardiovascular risk and diabetes

Sanjay Rajagopalan, MD FACC FAHA Melvin Sharoky Professorship in Medicine Chief, Division of Cardiovascular Medicine The University of Maryland School of Medicine Baltimore, MD

Slides prepared and presented during CDMC in Almaty, Kazakhstan on Saturday April 12 , 2014

Adapted from Monnier L. Eur J Clin Invest. 2000;30(suppl 2):3-11.

Patients With Type 2 Diabetes May Spend

12 Hours Per Day in the Postprandial State

Postprandial Postabsorptive Fasting

Duration of Postprandial State

Breakfast Lunch Dinner Midnight 4AM Breakfast

8 AM 11 AM 2 PM 5 PM

Relationship Between Post-Prandial State

and CV Disease

• CM and CM remnants induce

atherosclerosis (1)

• RLP-C correlates with CIMT (2)

• Higher fasting RLP-C predicts CAD

events (Honolulu Heart Study) (3)

• RLP-C predicts CAD incidence

independent of TC/HDL-C/LDL-C

(Honolulu HS) (4)

• RLP-C strongest causal predictor of

CV events in Copenhagen Heart

Study

• DECODE reported that 2 h glucose

concentrations after OGTT are better

predictors of CV events and all-cause

mortality than fasting blood glucose

The Framingham Offspring Study, 2-h

blood glucose predicted CV events

better than A1C

• A meta-analysis of 38 prospective

studies in non-diabetics confirmed a

strong association between 2-h blood

glucose with fatal and nonfatal

cardiovascular events

3

Post-Prandial Lipemia

1. Zilversmit DB. Atherosclerosis a Post-Prandial Phenomenon. Circulation. 1979

Sep;60(3):473-85.

2. Karpe et al. RLPs are related to IMT of carotid artery independent of LDL-C and plasma

TG. J Lipid Res 2001; 42; 17-21

3. Kugiyama et al Remnant Lipoprotein Levels in Fasting Serum Predict Coronary Events in

patients with CAD. Circulation 1999; 99; 2858-60

4. Imke C and Rodriguez et al. Honolulu Heart Study. Arterioscl Thromb Vasc Biol 2005; 25;

1718-1722

5. Varbo A et al. Circulation. 2013 Sep 17;128(12):1298-30

Post-Prandial Hyperglycemia

1. DECODE Study Group. Glucose tolerance and CV mortality: comparison of fasting

and 2-hour criteria. Arch Intern Med 2001;161:397–405

2. Meigs JB,et al. Framingham Offspring Study. Fasting and postchallenge glycemia

and cardiovascular risk: the Framingham Offspring Study. Diabetes Care

2002;25:1845–1850

3. Levitan EB et al. Is nondiabetic hyperglycemia a risk factor for cardiovascular

disease? A meta-analysis of prospective studies. Arch Intern Med 2004;164:2147–

2155 .

0

10

20

30

40

50

60

70

80

NGT T2DMC

ontr

ibutions o

f In

cre

tin F

acto

rs (

%)

Oral glucose load

Intravenous glucose infusion

Time (min)

Insulin

(m

U/l)

80

60

40

20

0

180 60 120 0

Incretin

effect

Control subjects (n=8) People with Type 2 diabetes (n=14)

Insulin

(m

U/l)

Time (min)

80

60

40

20

0

180 60 120 0

Nauck M, et al. Diabetologia. 1986;29(1):46-52. Kreymann B, et al. Lancet. 1987;2(8571):1300-1304.

1964: Plasma insulin higher with oral than IV glucose

1969: A factor from porcine intestine by Brown et al termed GIP

1. Brown J, Dryburgh JR 1971 A gastric inhibitory polypeptide. The complete sequence. Can J Biochem 49:867-72.

2. Dupre J, Ross SA, Brown JC 1973 Stimulation of insulin secretion by GIP in man. JCEM 37:826–828

GLP-1 and GIP Are the Two

Major Incretins ProGIP

GIP[1-42]

K-cell

GLP-1 GIP

• Produced by L cells in distal gut • Produced by K cells in the proximal gut

• Half life 1 minute • Half life 10 minutes

• Suppresses glucagon secretion • Stimulates glucagon secretion

• Inhibition of gastric emptying • Minimal effect on gastric emptying;

• Reduces Apo 48, CM and VLDL Production • Increases Lipoprotein Production

• Insulinotropic Activity in DM Preserved • Insulinotropic Activity in DM/IR Attenuated

GLP, glucagon-like peptide; GIP, glucose-dependent insulinotropic polypeptide.

GIP

[1-42]

GIP

[3-42]

INACTIVE

DPP-IV

GLP-1

[7-36NH2]

DPP-IV GLP-1

[9-36NH2]

INACTIVE

Proglucagon

GLP-1[1-37]

GLP-1[1-36NH2]

L-cell

GLP-1[7-36NH2]

5

Complexity of GLP-1 Peptide Biology

7

GLP-1 (7-36)

DPP-IV

GLP-1R

GLP-1 (28-36)

NEP 24.11

GLP-1R Mediated Effects GLP-1R Independent Effects

?Receptor

GLP-1 (9-36)

SDF-1 (1-68) GLP-1 (7-36) BNP(1-32) SP (1-11) NPY (1-36) PYY (1-36) GLP-2 (1-33) GIP (1-42)

BNP (3-32) GLP-1 (9-36) NPY (3-36) PYY (3-36)

Progenitor

cell Blood vessel

Kidney

Heart

Brain

DPP-4

Adipose tissue

Ussher JR, and Drucker DJ. Endocrine Reviews 2012;33:187-215

Diversity of DPP4 Substrates

9

Summary of Pharmacological Incretin action

on Different Target Tissues

Pancreas

GI tract

Insulin biosynthesis

Glucagon Release

Beta-cell proliferation

Beta-cell apoptosis

INCRETINS

Brain Neuroprotection

Appetite

Insulin secretion

Glucagon secretion

Gastric emptying

Stomach

Cardioprotection

Cardiac output

Liver

Insulin sensitivity Glucose production

VLDL Production

Muscle

Apo 48 production

CM Production

Heart

Inflammation

Vasodilation

Endothelial function

Vasculature

10

Location and Impact of GLP-1/Receptors in

the Cardiovascular System

• Atrial Tissue in the heart

• Endocardium

• Endothelium

• Smooth Muscle Cells

• T Lymphocytes/Macrophages

Koska J, et al. Diabetes Care. 2010;33(5):1028-30.

Basu A, et al. Am J Physiol Endocrinol Metab 2007;293(5);1289-1296.

Zhao T, et al. J Pharmacol Exp Ther. 2006;317(3):1106–1113.

Nikolaidis, et al. Circulation. 2004;110(8):955–961.

Nikolaidis LA, et al. Am J Physiol Heart Circ Physiol. 2005;289(6):H2401–H2408.

Nikolaidis LA, et al. Circulation. 2004;109(8):962–965.

Sokos GG, et al. J Card Fail. 2006;12(9):694–699.

Watts GF, Chan DC. Diabetes 2013;62(2);336-338.

• GLP-1 agonists improve endothelial function

• GLP-1 agonists reduce BP

• Improve function in post-MI LV dysfunction and CHF

12

GLP-1 Agonists Lower Blood Pressure: Results

of a Meta-regression Analysis

Using Random effect models

−3.42 mm Hg decrease in SBP (95% CI −3.54 to −3.31)

−2.56 kg loss of weight (95% CI = −3.12 to −2.00)

Increase in HR of 1.30 bpm (95% CI = 0.26–2.33

31 trials; >1500 patients;

Random-Effects Meta-analysis

and Meta-regression analysis

Am J Hypertens 2014;27:130-139

Mechanisms of GLP-1 Induced Reduction in

Blood Pressure and Natriuresis

14 Kim M et al. Nat Med. 2013 May;19(5):567-75. doi: 10.1038/nm.3128. Epub 2013 Mar 31.

Increased expression of DPP4 (CD26) in Acute

Coronary Syndrome

CD26 CD40L CD69

30

20

10

0

* * *

*

Group 1: Stable angina

Group 2: USA on treatment

Group 3: Refractory USA

Group 4: Acute MI

Hosono M, et al. Atherosclerosis. 2003;168 :73-80. 16

Sell H et al. Dia Care 2013;36:4083-4090

DPP4 Expression and Activity is Increased in

Obesity/IR

Effect of DPP4 Inhibition in Atherosclerosis

• Alogliptin reduces atherosclerosis and

Adipose inflammation in High-Fat Fed

Insulin Resistant LDLR–/–

• PKF275-055 reduces

atherosclerosis in ApoE–/–

NV

ND

HV

HD

70,000

60,000

50,000

40,000

30,000

20,000

10,000

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c a

rea (

μm

2)

NV ND HV HD

^^

##

**

Shah Z, et al. Circulation. 2011;124(21):2338-2349. Terasaki M, et al. Metabolism. 2012;61(7):974-977.

NV=Normal diet vehicle

ND=Normal diet Alogliptin

HV=High fat diet Vehicle

HD=High fat diet Alogliptin

Visceral Adipose Aortic Plaque

Lipid Accumulation

20

Alogliptin Reduces Plaque Inflammation and

Improves Vascular Function

Plaque Inflammation/Fibrosis Vascular Function

CD

11

b c

ell

s in

%

75

50

25

0

**

#

CD

11

b/C

D2

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lls

in

%

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/80

+ c

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oll

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pla

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Rela

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% o

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re-c

on

str

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-8 -7 -6 -5

Log [Ach]

-8 -7 -6 -5

Log [PE]

Co

ns

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n (

% o

f K

Cl1

20

)

500

400

300

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200

NV=Normal diet vehicle

ND=Normal diet Alogliptin

HV=High fat diet Vehicle

HD=High fat diet Alogliptin Shah Z, et al. Circulation. 2011;124(21):2338-2349. 21

Liver

↑ GLP-1R

signaling in Gut

Adipocytes

↓ Lipolysis

Pancreas

↓ Plasma FFAs

↓ Competition for

CM Clearance?

Effects of GLP-1R Signaling on Lipoprotein Metabolism

Direct

Sympathetic enteric neurons?

↓ Gastric

emptying?

↓ TG

absorption

Enterocytes

↑ Insulin

↓ Apo B100

↑ FA β-oxidation

↓ Apo48

↓ CM Biogenesis

↓ Plasma

FFAs

↓ VLDL

DECREASED POST-PRANDIAL

TG, VLDL AND CM REMNANTS 22

* *

**

**

** ** *

*

**

*** *** ***

***

***

*** *** ***

*** *** ***

*** **

Alogliptin Reduces Post-Prandial Lipoproteins

5

4

0

Tri

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(mm

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l)

–1 0 1 2 3 4 5 6 7 8

Time (h)

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-48

(mg

/l)

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Time (h)

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Time (h)

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8 (

mg

/l)

0 2 4 6 8

Time (h)

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10

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1

3

***

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*** *** ***

***

Eliasson B et al. Diabetologia. 2012;55(4):915-925.

Alogliptin

*p<0.5

**p<0.01

***p<0.001

16 week double-blind placebo controlled trial in Type II DM

Mixed Meal Challenge at end of treatment (n=71)

VLDL Apo B100 ↓ with Alo but not Alo/Pio 23

Communication Between Heart and

Bone Marrow Signals in Repair

SDF-1

Bone Bone marrow

MI

Zaruba M, et al. Cell Stem Cell. 2009;4(4):313–323.

Zhang D, et al. Am J Physiol Heart Circ Physiol. 2010;299(5):H1339–H1347.

Theiss HD, et al. Int J Cardiol. 2010;145(2):282–284.

DPP4

DPP4

In Peri-MI tissue Degradation

of SDF-1 Homing of CXCR4

Progenitor Cells Healing of MI

DPP4 Inhibitor

CXCR4

DPP4i

Stem/progenitor cell

GLP-1 Reduces MI Size in Patients with STEMI

n Exenatide n Placebo P-value

Salvage index 0.71 ± 0.13 51 0.62 ± 0.16 0.003

Infarct size (g)/area at risk (g) 0.30 ± 0.15 51 0.39 ± 0.15 0.003

Lønborg J et al. Eur Heart J. 2012;33(12):1491-1499.

Double-blind placebo controlled trial of Exenatide (25 mg) vs. Placebo in STEMI with

TIMI 0/1 Flow (n=172) Infarct Size and Salvage Index at 90 days by CMR

No change in 30-day clinical outcomes or LV function 25

A suggested working model.

Shigeta T et al. Circulation 2012;126:1838-1851

Copyright © American Heart Association

A Role for DPP-4 in LV Remodeling:

Implications for Diabetic Cardiomyopathy

26 Shigeta T, Murohara T et al. Circulation. 2012 Oct 9;126(15):1838-51

Incretin Based Therapies: Summary

• Incretins such as GLP-1 have complex and

pleiotropic effects on the cardiovascular system

beyond glycemic control

• DPP-4 (CD26) is up regulated in tissues such as the

vessel wall, visceral adipose and inflammatory cells

• Enzymatic inhibition of DPP-4 reduces

inflammation, atherosclerosis, chylomicron/VLDL

biosynthesis and LV remodeling and may be

cardioprotective

27