Management? Sanjay Rajagopalan, MD FACC FAHA Herman Hellerstein - PowerPoint PPT Presentation

Are New Incretin Agent Outcome trials Changing the Fundamentals of Diabetes Management? Sanjay Rajagopalan, MD FACC FAHA Herman Hellerstein Professor of CV Research Chief, Cardiovascular Medicine, University Hospitals Director, Cardiovascular Research Institute (CVRI) Harrington Heart and Vascular Institute Case Western Reserve School of Medicine Cleveland, OH

Clinical Case • A 65 year old man with a history of hypertension, and obesity is hospitalized with NSTEMI • Cardiac cath revealed 3 vessel disease, LVEF 40%. • During his stay, he was noted to have symptoms of heart failure. He was placed on IV insulin for persistently elevated glucoses Laboratory Data Other Clinical Data Hemoglobin A1c = 8.9% Weight 213 lb BUN = 23 Height 70.5 inches Creatinine = 1.8 BMI = 30.19 Glucose = 115 LDL=120 mg/dl eGFR = 40 TG=365 mg/dl HDL=25 mg/dl

Diabetes and ACS: Implications for Mortality N=62,036 patients with ACS, 11 TIMI trials N=9,492 patients with ACS in Europe Adapted from JAMA 2007; 298; 765-75 Am J Cardiol. 2016 Aug 1;118(3):345-52 3

Effects of Intensive Lifestyle Intervention on CV Events A. Weight E 20 Control % 100 st Control of 16 i 98 P m at 12 Intervention 96 at ie e 94 nt 8 d Intervention s M 92 w 4 e Main effect, -4 (95% CI, -5 to -3) it 90 P < 0.001 a h 0 0 n 0 2 4 6 8 10 0 1 2 3 4 5 6 7 8 9 10 E (k Years v Year g) No. at Risk e Control 2575 2425 2296 2156 2019 688 D. Glycated Hemoglobin nt Intervention 2570 2447 2326 2192 2049 505 s Control E 7.4 st i 7.2 Intervention The primary outcome was composite of death m at from CV causes, nonfatal MI, nonfatal CVA, or 7.0 e hospitalization for angina. d 6.8 M Main effect, -0.22 (95% CI, -0.28 to -0.16) e 6.6 P < 0.001 a 0.0 n 0 1 2 3 4 5 6 7 8 9 10 (k Year g) LOOK-AHEAD. N Engl J Med . 2013 Jul 11;369(2):145-54. 4 4

A Brief Overview of GLP-1 Peptide Biology NEP 24.11 DPP-IV GLP-1 (7-36) GLP-1 (28-36) GLP-1 (9-36) ?Receptor GLP-1R GLP-1R Mediated Effects GLP-1R Independent Effects

Rationale for DPP-4 Inhibition PHYSIOLOGIC SUBSTRATES GLP-1 SDF-1 SUBTANCE P GIP GLP-2 PYY PHARMACOLOGIC SUBSTRATES BNP EOTAXIN NPY EPO GLUCAGON GM-CSF GRP IP-10 MIG RANTES Zhong J and Rajagopalan S, et al. Circ Res 2015;116(8):1491-504.

GLP-1 (7-36)Amide His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Amide 7 10 15 20 25 30 35 36 Proteolytic attack (DPP-4) Exenatide (exendin-4), Amylin/Eli Lilly & Co./Bristol-Myers Squibb) Amide His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lixisenatide* (Sanofi) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Lys Lys Lys Lys Lys Lys Ser Liraglutide (Novo Nordisk) His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly Glu Albumin C-16 Free fatty acid (noncovalent binding to albumin) Semaglutide* (Novo Nordisk) AIB: Alpha Amino Isobutyric acid His AIB Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly C-18 Free fatty acid (noncovalent binding to albumin) Taspoglutide* (Roche) His AIB Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys AIB Arg Amide 7 7 10 15 20 25 30 35 36 *Not FDA approved.

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

GLP-1 Agonists Lower Blood Pressure: Results of a Meta-regression Analysis 31 trials; >1500 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 −2.00) Increase in HR of 1.30 bpm (95% CI = 0.26 – 2.33 Katout and Rajagopalan S. Am J Hypertens 2014;27:130-139

Concentrations of GLP-1 Achieved With DPP4 Inhibition and Comparison With GLP-1 Agonists GLP-1 receptor agonist 90 90 GLP-1 (pmol/L) GLP-1 (pmol/L) 60 60 DPP4 inhibitor 30 30 0 0 8 12 16 20 24 8 12 16 20 24 Time (h) Time (h) No blood pressure lowering or weight loss effects? Adapted from Nauck MA, et al. Am J Med . 2011;124(1 suppl):s3-s18.

Differences Between GLP-1 Analogues? Waldrop G, Rajagopalan S et al. J Am Coll Cardiol. 2016 Mar 29;67(12):1488-96

Completed trials with CV Outcomes 2016 2013 EXAMINE 1 SAVOR-TIMI 2 TECOS 3 ELIXA 4 SUSTAIN-6 5 LEADER 6 Alogliptin Saxagliptin Sitagliptin Lixisenatide Semaglutide Liraglutide Time to first Time to first Time to first Time to first Time to first Time to first MACE event: eMACE eMACE MACE event: MACE event: MACE event: event: event: • CV death • CV death • CV death • CV death • non-fatal MI • CV death • CV death • non-fatal MI • non-fatal MI • non-fatal MI • non-fatal • non-fatal MI • non-fatal MI • non-fatal • non-fatal • non-fatal • non-fatal • non-fatal stroke stroke ischaemic stroke • Hospitalizati ischaemic stroke stroke • Hospitalisati stroke on for on for angina angina DPP-4 Inhibitors GLP-1 Agonists EMPA-REG 7 Empagliflozin Time to first MACE event: • CV Death • non-fatal MI or stroke SGLT-2 Inhibitors 1. White WB, et al . N Engl J Med 2013;369:1327 – 35; 2. Scirica BM, et al . N Engl J Med 2013;369:1317 – 26; 3. Green JB, et al . N Engl J Med 2015;373: 232 – 42. 4. Pfeffer MA, et al . N Engl J Med. 2015 Dec 3;373(23):2247-57 ; 5.Marso S et al. N Engl J Med. 2016 Sep 15 ; 6. Marso P et al. N Engl J Med. 2016 Jul 28;375(4):311-22 ;. Zinman B, et al . N Engl J Med. 2015 Nov 26;373(22):2117-28

Baseline Characteristics of Trials ELIXA 5 EXAMINE 1 SAVOR-TIMI 2 TECOS 3,4 Randomized Alogliptin Saxagliptin Sitagliptin population (n=2,701) (n=8,280) (n=7,332) (N=6,068) Mean age (years) 61.0 65.1 65.4 60.3 Median/mean duration 7.1 10.3 11.6 9.3 of diabetes (years) Median/mean weight (kg) 80.2 87.7 NA NA Median or mean BMI 28.7 31.1 30.2 30.2 (kg/m 2 ) Average/mean HbA1c 8.0 8.0 7.2 7.7 CV history/risk factors Prior MI (%) 88.4 38 42.7 22 Prior stroke (%) 7.2 NA 17.7 5.2 Heart failure (%) 28.0 12.8 17.8 12.4 Hypertension (%) 82.5 81.2 NA 75.5 PAD (%) 9.7 11.9* 16.6 6.0 77 † Dyslipidemia (%) 27.1 71.2 NA Coronary revascularization (%) 62.5 43.1 38.9 16.5 13

EXAMINE: study design International, multicenter, randomized, double-blind phase 3 study of alogliptin versus placebo in post-ACS patients with T2D receiving standard antihyperglycemic and CV drug therapy Inclusion criteria • T2D patients Alogliptin* OD + standard of care † (n=2,701) • HbA 1c 6.5% 11.0% • High CV risk – Treatment period (4.5 years) diagnosed with ACS 15 90 days before Placebo OD + standard of care † (n=2,679) randomization Days – 14 Day 1 Month 1 Month 12 End of study 2-week to – 1 follow-up Visits every 4 months Visits at months 3, 6, and 9 Median duration of exposure to alogliptin: 18 months Screening visit Baseline/ randomisation * At randomization, patients were assigned to receive 25, 12.5, or 6.25mg OD based on renal function. After randomization, dose adjustments were allowed on the basis of changes in renal function. † Investigators were permitted to adjust any antidiabetic therapy in alogliptin and placebo arms if required (with the exception of the addition of a DPP-4 inhibitor or GLP-1 analogue). White WB, et al . N Engl J Med 2013;369:1327 – 35. 14

Primary End Point by Components – EXAMINE Alogliptin Placebo HR Ratio (N=2701) (N=2679) (95% CI) Primary end point: CV death, 0.96 nonfatal MI, or 305 (11.3) 316 (11.8) (≤1.16)* nonfatal stroke, No. (%) 0.79 CV death 89 (3.3) 111 (4.1) (0.60, 1.04) 1.08 Nonfatal MI 187 (6.9) 173 (6.5) (0.88, 1.33) Nonfatal 0.91 29 (1.1) 32 (1.2) stroke (0.55, 1.50) * 99% one-sided confidence interval, p<0.001 for non-inferiority; p=0.32 for superiority 15 White WB, et al. N Engl J Med 2013;369(14):1327-1335.

Composite Endpoint of HHF and CV Death for Patients With and Without History of Heart Failure Cumulative Incidence of Events (%) 25 Alogliptin Placebo 20 History of Heart Failure Prior to Randomization Hazard ratio, 0.90 (95% Cl, 0.70 – 1.17) Events, No. (%) 15 Placebo: 120 (15.7%) No History of Heart Failure Prior to Randomization 10 Hazard ratio, 1.14 (95% Cl, 0.85, 1.54) Events, No. (%) Placebo: 81 (4.2%) 5 0 0 6 12 18 24 30 Months Zannad F, et al. Lancet. 2015;385:2067-76.