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GLP-1 Agonists and Cardiovascular Health

GLP-1 Agonists and Cardiovascular Health. Alan Mathis PharmD Candidate 2013. Overview. GLP-1 agonists have shown to help patients lose weight Mechanism of GLP-1 agonists Cardioprotective effects of GLP-1 agonists GLP-1 agonists and cardiovascular outcomes. Introduction.

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GLP-1 Agonists and Cardiovascular Health

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  1. GLP-1 Agonists and Cardiovascular Health Alan Mathis PharmD Candidate 2013

  2. Overview • GLP-1 agonists have shown to help patients lose weight • Mechanism of GLP-1 agonists • Cardioprotective effects of GLP-1 agonists • GLP-1 agonists and cardiovascular outcomes

  3. Introduction • Obesity is a common problem especially with Type-2 diabetics • Obesity leads to several physiologic effects including cardiovascular disease and increased mortality • Cardiovascular disease is responsible for 65% of deaths in people with type-2 diabetes Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Diabetes Public Health Resource. Statistics: Diabetes Surveillance, 1999. Accessed August, 2003 at: www.cdc.gov/diabetes/statistics/survl99/chap5/figure1.htm.

  4. 3.0 2.6 2.2 1.8 1.4 1.0 0.6 Overweight and Obesity Increase the Risk of CV Disease Mortality Men Women Relative Risk of Cardiovascular Disease Mortality Normal weight Overweight Obese >18 25 30 >40 BMI, kg/m2 Data are from 1 million men and women (average age, 57 years) followed for 16 years who never smoked and had no history of disease at enrollment. Calle EE, et al. N Engl J Med. 1999;341:1097-1105.

  5. Weight Loss Reduces Cardiometabolic Risk Factors in Patients With Type 2 Diabetes Intensified Lifestyle Intervention, 8.6% Weight Loss Diabetes Support and Education, 0.7% Weight Loss 4 0 * 3 -0.2 Δ HDL Cholesterol (mg/dL) Δ A1C (%) -0.4 2 -0.6 1 * -0.8 0 Systolic Diastolic 0 0 -10 -2.5 Δ Triglycerides(mg/dL) Δ Blood Pressure(mm Hg) * -20 -5.0 -30 * -7.5 * -40 Randomized, controlled trial; n = 5145; Patients with type 2 diabetes, age >18 y; Mean ± SEIntensified lifestyle intervention (n = 2496) vs diabetes support and education (n = 2463) therapy; *P<0.001 between groups Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383

  6. Exenatide Continued to Reduce Weight in 3-Year Completers (n=217)

  7. Effect of Exenatide on Body Weight

  8. Mechanism of Incretins Incretin Mimetic Glucose dependent Insulin (GLP-1andGIP) Glucose uptake by peripheral tissue Ingestion of food Pancreas Release of active incretins GLP-1 and GIP Beta cells Alpha cells GI tract  Blood glucose in fasting and postprandial states Glucose- dependent X DPP-4 enzyme DPP-4 inhibitor Hepatic glucose production Glucagon (GLP-1) Inactive GLP-1 Inactive GIP • Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels  in response to a meal. • Incretin Mimetics are resistant to DPP-4 inactivation Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging the actions of these hormones. GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

  9. Change in Weight by Quartile at 82 Weeks

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

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

  12. 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.

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

  14. Exenatide Treatment: 3.5-Year Follow-up

  15. 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.

  16. 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

  17. Exentide 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

  18. 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.

  19. 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.

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