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

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1 Understanding the science of incretin biology and implications on cardiovascular risk and diabetes Slides prepared and presented during CDMC in Almaty, Kazakhstan on Saturday April 12, 214 Sanjay Rajagopalan, MD FACC FAHA Melvin Sharoky Professorship in Medicine Chief, Division of Cardiovascular Medicine The University of Maryland School of Medicine Baltimore, MD

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

Relationship Between Post-Prandial State and CV Disease Post-Prandial Lipemia CM and CM remnants induce atherosclerosis (1) RLP-C correlates with CIMT (2) Higher fasting RLP-C predicts CAD events

Hyperglycemia 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

3 Relationship Between Post-Prandial State and CV Disease Post-Prandial Lipemia 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 Post-Prandial Hyperglycemia 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 1. Zilversmit DB. Atherosclerosis a Post-Prandial Phenomenon. Circulation Sep;6(3): Karpe et al. RLPs are related to IMT of carotid artery independent of LDL-C and plasma TG. J Lipid Res 21; 42; Kugiyama et al Remnant Lipoprotein Levels in Fasting Serum Predict Coronary Events in patients with CAD. Circulation 1999; 99; Imke C and Rodriguez et al. Honolulu Heart Study. Arterioscl Thromb Vasc Biol 25; 25; Varbo A et al. Circulation. 213 Sep 17;128(12): DECODE Study Group. Glucose tolerance and CV mortality: comparison of fasting and 2-hour criteria. Arch Intern Med 21;161: Meigs JB,et al. Framingham Offspring Study. Fasting and postchallenge glycemia and cardiovascular risk: the Framingham Offspring Study. Diabetes Care 22;25: Levitan EB et al. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies. Arch Intern Med 24;164:

4 Insulin (mu/l) 1. Brown J, Dryburgh JR 1971 A gastric inhibitory polypeptide. The complete sequence. Can J Biochem 49: Dupre J, Ross SA, Brown JC 1973 Stimulation of insulin secretion by GIP in man. JCEM 37: Insulin (mu/l) Contributions of Incretin Factors (%) 1964: Plasma insulin higher with oral than IV glucose 1969: A factor from porcine intestine by Brown et al termed GIP 8 Control subjects (n=8) People with Type 2 diabetes (n=14) Incretin effect Time (min) 18 Oral glucose load Intravenous glucose infusion Time (min) NGT T2DM 18 Nauck M, et al. Diabetologia. 1986;29(1): Kreymann B, et al. Lancet. 1987;2(8571):

GIP [1-42] DPP-IV GIP [3-42] INACTIVE GLP-1 Produced by L cells in distal gut Half life 1 minute Suppresses glucagon secretion Inhibition of gastric emptying Reduces Apo 48, CM

5 L-cell Proglucagon GLP-1[1-37] GLP-1[1-36NH 2 ] GLP-1 and GIP Are the Two Major Incretins K-cell ProGIP GIP[1-42] GLP-1[7-36NH 2 ] GLP-1 [7-36NH 2 ] DPP-IV GLP-1 [9-36NH 2 ] INACTIVE GLP, glucagon-like peptide; GIP, glucose-dependent insulinotropic polypeptide. GIP [1-42] DPP-IV GIP [3-42] INACTIVE GLP-1 Produced by L cells in distal gut Half life 1 minute Suppresses glucagon secretion Inhibition of gastric emptying Reduces Apo 48, CM and VLDL Production Insulinotropic Activity in DM Preserved GIP Produced by K cells in the proximal gut Half life 1 minutes Stimulates glucagon secretion Minimal effect on gastric emptying; Increases Lipoprotein Production Insulinotropic Activity in DM/IR Attenuated 5

Complexity of GLP-1 Peptide Biology DPP-IV NEP 24.

6 Complexity of GLP-1 Peptide Biology DPP-IV NEP GLP-1 (7-36) GLP-1 (9-36) GLP-1 (28-36) GLP-1R?Receptor GLP-1R Mediated Effects GLP-1R Independent Effects 7

Kidney Heart Brain DPP-4 Adipose tissue BNP (3-32) GLP-1 (9-36) NPY (3-36)

7 Diversity of DPP4 Substrates 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) Progenitor cell Blood vessel Kidney Heart Brain DPP-4 Adipose tissue BNP (3-32) GLP-1 (9-36) NPY (3-36) PYY (3-36) Ussher JR, and Drucker DJ. Endocrine Reviews 212;33:

Summary of Pharmacological Incretin action on Different

Neuroprotection Appetite Gastric emptying Vasculature

48 production CM Production Liver Glucose production VLDL

Pancreas Insulin secretion Glucagon secretion Insulin

8 Summary of Pharmacological Incretin action on Different Target Tissues Cardioprotection Cardiac output Heart Brain Neuroprotection Appetite Gastric emptying Vasculature Stomach Inflammation Vasodilation Endothelial function Apo 48 production CM Production Liver Glucose production VLDL Production GI tract Insulin sensitivity Muscle INCRETINS Pancreas Insulin secretion Glucagon secretion Insulin biosynthesis Glucagon Release Beta-cell proliferation Beta-cell apoptosis 1

Location and Impact of GLP-1/Receptors in the Cardiovascular System Atrial Tissue in the heart Endocardium Endothelium Smooth Muscle Cells T Lymphocytes/Macrophages GLP-1 agonists improve endothelial

9 Location and Impact of GLP-1/Receptors in the Cardiovascular System Atrial Tissue in the heart Endocardium Endothelium Smooth Muscle Cells T Lymphocytes/Macrophages GLP-1 agonists improve endothelial function GLP-1 agonists reduce BP Improve function in post-mi LV dysfunction and CHF Koska J, et al. Diabetes Care. 21;33(5): Basu A, et al. Am J Physiol Endocrinol Metab 27;293(5); Zhao T, et al. J Pharmacol Exp Ther. 26;317(3): Nikolaidis, et al. Circulation. 24;11(8): Nikolaidis LA, et al. Am J Physiol Heart Circ Physiol. 25;289(6):H241 H248. Nikolaidis LA, et al. Circulation. 24;19(8): Sokos GG, et al. J Card Fail. 26;12(9): Watts GF, Chan DC. Diabetes 213;62(2);

GLP-1 Agonists Lower Blood Pressure: Results of a Meta-regression Analysis 31 trials; >15 patients; Random-Effects Meta-analysis and Meta-regression analysis Using Random

10 GLP-1 Agonists Lower Blood Pressure: Results of a Meta-regression Analysis 31 trials; >15 patients; Random-Effects Meta-analysis and 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.) Increase in HR of 1.3 bpm (95% CI = Am J Hypertens 214;27:13-139

11 Mechanisms of GLP-1 Induced Reduction in Blood Pressure and Natriuresis Kim M et al. Nat Med. 213 May;19(5): doi: 1.138/nm Epub 213 Mar

$3: Refractory$ Acute MI * * * *

12 Increased expression of DPP4 (CD26) in Acute Coronary Syndrome 3 Group 1: Stable angina Group 2: USA on treatment Group 3: Refractory USA Group 4: Acute MI * * * * 2 1 CD26 CD4L CD69 Hosono M, et al. Atherosclerosis. 23;168 :

13 DPP4 Expression and Activity is Increased in Obesity/IR Sell H et al. Dia Care 213;36:483-49

Atherosclerotic area (μm 2 ) Effect of DPP4 Inhibition in Atherosclerosis 7, 6, 5, 4,

HV HD NV=Normal diet vehicle ND=Normal diet Alogliptin HV=High fat diet Vehicle HD=High

High-Fat Fed Insulin Resistant LDLR / PKF275-55 reduces atherosclerosis in ApoE / Shah

14 Atherosclerotic area (μm 2 ) Effect of DPP4 Inhibition in Atherosclerosis 7, 6, 5, 4, 3, 2, 1, NV ND ** ^^ ## NV ND HV HD Visceral Adipose Aortic Plaque Lipid Accumulation HV HD NV=Normal diet vehicle ND=Normal diet Alogliptin HV=High fat diet Vehicle HD=High fat diet Alogliptin Alogliptin reduces atherosclerosis and Adipose inflammation in High-Fat Fed Insulin Resistant LDLR / PKF reduces atherosclerosis in ApoE / Shah Z, et al. Circulation. 211;124(21): Terasaki M, et al. Metabolism. 212;61(7):

15 CD11b cells in % F4/8 + cells Alogliptin Reduces Plaque Inflammation and Improves Vascular Function CD11b/CD26 cells in % % Collagen of plaque Relaxation (% of pre-construction) Constriction (% of KCl12) Plaque Inflammation/Fibrosis Vascular Function * # ** 75 ** ^^ ## Log [Ach] 5 # NV=Normal diet vehicle ND=Normal diet Alogliptin HV=High fat diet Vehicle Log [PE] HD=High fat diet Alogliptin Shah Z, et al. Circulation. 211;124(21):

16 Effects of GLP-1R Signaling on Lipoprotein Metabolism Insulin Pancreas Plasma FFAs GLP-1R signaling in Gut Lipolysis Adipocytes Direct Gastric emptying? Sympathetic enteric neurons? Plasma FFAs TG absorption Enterocytes Apo48 CM Biogenesis Liver Apo B1 FA β-oxidation VLDL Competition for CM Clearance? DECREASED POST-PRANDIAL TG, VLDL AND CM REMNANTS 22

17 Chylomicron ApoB-48 (mg/l) VLDL1 ApoB-48 (mg/l) Triacylglycerols (mmol/l) Chylomicron triacylglycerols (mmol/l) Alogliptin Reduces Post-Prandial Lipoproteins 16 week double-blind placebo controlled trial in Type II DM Mixed Meal Challenge at end of treatment (n=71) 5 16 Alogliptin ** Time (h) ** * Time (h) ** *p<.5 **p<.1 p<.1 * ** ** Time (h) Eliasson B et al. Diabetologia. 212;55(4): * * * ** ** ** Time (h) VLDL Apo B1 with Alo but not Alo/Pio 23 *

Communication Between Heart and Bone Marrow Signals in Repair MI DPP4 In Peri-MI tissue DPP4 Inhibitor Degradation of SDF-1 Homing of CXCR4 Progenitor Cells Healing of MI SDF-1 DPP4 DPP4i CXCR4

18 Communication Between Heart and Bone Marrow Signals in Repair MI DPP4 In Peri-MI tissue DPP4 Inhibitor Degradation of SDF-1 Homing of CXCR4 Progenitor Cells Healing of MI SDF-1 DPP4 DPP4i CXCR4 Stem/progenitor cell Bone marrow Bone Zaruba M, et al. Cell Stem Cell. 29;4(4): Zhang D, et al. Am J Physiol Heart Circ Physiol. 21;299(5):H1339 H1347. Theiss HD, et al. Int J Cardiol. 21;145(2):

19 GLP-1 Reduces MI Size in Patients with STEMI Double-blind placebo controlled trial of Exenatide (25 mg) vs. Placebo in STEMI with TIMI /1 Flow (n=172) Infarct Size and Salvage Index at 9 days by CMR n Exenatide n Placebo P-value Salvage index.71 ± ±.16.3 Infarct size (g)/area at risk (g).3 ± ±.15.3 No change in 3-day clinical outcomes or LV function Lønborg J et al. Eur Heart J. 212;33(12):

20 A Role for DPP-4 in LV Remodeling: A suggested working model. Implications for Diabetic Cardiomyopathy Shigeta T et al. Circulation 212;126: Shigeta T, Murohara T et al. Circulation. 212 Oct 9;126(15): Copyright American Heart Association 26

21 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

Scope. History. History. Incretins. Incretin-based Therapy and DPP-4 Inhibitors

Scope. History. History. Incretins. Incretin-based Therapy and DPP-4 Inhibitors Plasma Glucose (mg/dl) Plasma Insulin (pmol/l) Incretin-based Therapy and Inhibitors Scope Mechanism of action ผศ.ดร.นพ.ว ระเดช พ ศประเสร ฐ สาขาว ชาโภชนว ทยาคล น ก ภาคว ชาอาย รศาสตร คณะแพทยศาสตร มหาว ทยาล