GLP-1 Agonists and Cardiovascular Health

1. GLP-1 Agonists and Cardiovascular Health Alan Mathis PharmD Candidate 2013 www.DIABETESINCONTROL.COM Part 2 of 2

2. Change in Weight by Quartile at 82 Weeks

3. Change in A1C as a Function of Change in Weight at 82 Weeks

4. Change in Triglycerides and HDL-C as Function of Weight-Change Quartile at 82 Weeks

5. Effects of GLP-1 agonists on inflammatory markers • GLP-1 agonists have been shown to reduce several inflammatory markers including plasminogen activa­tor inhibitor-1 (PAI-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) • E-selectin was not significantly reduced • C-reactive protein has also been associated with increased cardiovascular disease • Patients treated with exenatide showed marked decrease in c-reactive protein levels after an 82-week study (from 3.21mg/dL to 1.35 mg/dL) Kendall DM, Bhole D, Guan X, et al.: Exenatide treatment for 82 weeks reduced C-reactive protein, HbAlc, and body weight in patients with type 2 diabetes mellitus. Presented at 42nd Congress of EASD.Copenhagen, Denmark; September 14-17, 2006.

6. Change in Blood Pressure as Function of Weight-Change Quartile at 82 Weeks

7. Exenatide Treatment: 3.5-Year Follow-up

8. Adding Exenatide to Glucose-Lowering regimen reduces heart failure risk • 50,330 patients taking exenatide with insulin and another antidiabetic treatment were 57% less likely to develop heart failure compared to those that took insulin, antidiabetic treatment, but no exenatide (OR 0.43; 95% CI 0.35-0.53) • 53,446 patients who received exenatide and other noninsulin therapies were 31% less likely to develop heart failure compared to those that took a noninsulin therapy and no exenatide (OR 0.69; 95% CI 0.44-1.07) • After combining data, patients who took exenatide were 54% less likely to develop heart failure than those that were not (OR 0.46; 95% CI 0.38-0.56) Best JH, Maggs D, Little W, et al. The risk of heart failure among patients receiving exenatide twice daily versus other glucose-lowering medications for diabetes: a matched retrospective analysis of the GE Healthcare EMR data. Diabetologia 2011; 54(Suppl. 1): S1–S542.

9. Cardiac Actions of GLP-1 • ↑ Cardiac output, ↓ LV end diastolic pressure, and ↑ myocardial glucose uptake in animal (rodent and dog) models of CHF and myocardial injury • ↓Infarct size in ischemic animal models • ↑ LVEF and ↑ wall motion in humans with MI and EF <40% • GLP-1 (9-36)amide ↑ myocardial contractility (dp/dt) and glucose uptake in dogs with cardiomyopathy

10. Exenatide and CV outcomes- 430,000 patients-near 40,000 on exenatide Risk of Cardiovascular Disease Events in Patients With Type 2 Diabetes Prescribed the Glucagon-Like Peptide 1 (GLP-1) Receptor Agonist Exenatide Twice Daily orOther Glucose-Lowering Therapies A retrospective analysis of the LifeLink database JENNIE H. BEST, PHD, Diabetes Care 34:90–95, 2011 1

11. Summary of PharmacologicIncretin Actions on Different Target Tissues Heart Brain Neuroprotection Stomach Appetite Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver GI Tract Insulin Secretion β-Cell Neogenesis β-Cell Apoptosis Glucagon Secretion Glucose Production + Glucose Uptake Muscle Drucker DJ, Cell Metab. 2006;3:153-165.

12. Summary • GLP-1 agonists not only help reduce plasma glucose levels in type-2 diabetics, but also help improve markers of cardiovascular function including blood pressure, cholesterol, and weight loss. • GLP-1 agonists are shown to have positive effects on cardiovascular outcomes and reduce the risk for heart failure • These benefits to cardiovascular health are independent of GLP-1 agonists’ effect on glucose control and add important cardiocascular effects for type-2 diabetics.