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 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.

Overweight and Obesity Increase the Risk of CV Disease Mortality 0.6 3.0 2.6 2.2 1.8 1.4 1.0 Men Women Relative Risk of Cardiovascular Disease Mortality These data are from the Cancer Prevention Study II, a prospective study of mortality in more than 1 million men and women in the United States. The risk of cardiovascular death was lowest at a BMI between 23.5 and 24.9 kg/m2 and was used as the reference BMI category. The mortality curves represent a continuum that begins to increase at a BMI of 26.5 kg/m2 in men and 25 kg/m2 in women. The risk of death from all causes was lowest at a BMI between 23.5 and 24.9 kg/m2 in men and 22.0 and 23.4 kg/m2 in women. A BMI between 23.5 and 24.9 kg/m2 was used as the reference BMI category for calculating relative risk. The mortality curves represent a continuum that begins to increase significantly at a BMI of 26.4 kg/m2 in men and 25 kg/m2 in women. 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. Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW. Body-mass index and mortality in a prospective cohort of US adults. N Engl J Med. 1999;341:1097-1105.

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 * -0.2 3 Δ A1C (%) -0.4 Δ HDL Cholesterol (mg/dL) 2 -0.6 1 * -0.8 Systolic Diastolic -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 ± SE Intensified 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 5

Exenatide Continued to Reduce Weight in 3-Year Completers (n=217) Exenatide produced progressive weight loss over a 3-year period.   Buse J, Macconell L, Stonehouse A, et al. Exenatide maintained glycemic control with associated weight reduction over three years in patients with type 2 diabetes. Presented at: ADA 67th Scientific Sessions; June 22-26, 2007; Chicago, IL. Abstract 0283-OR.

Effect of Exenatide on Body Weight Change in body weight in participants with T2DM treated with placebo and exenatide, 5 µg bid

Mechanism of Incretins Incretin Mimetic Glucose dependent  Insulin (GLP-1and GIP)  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 X DPP-4 enzyme Glucose- dependent DPP-4 inhibitor Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of JANUVIA™ (sitagliptin phosphate). The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.  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.

Change in Weight by Quartile at 82 Weeks Not all participants treated with exenatide lose weight. Approximately one-quarter lose no weight (quartile 4), while one-quarter experience marked weight loss (quartile 1) (11.4 kg). Other participants have intermediate weight loss (quartiles 2 and 3).

Change in A1C as a Function of Change in Weight at 82 Weeks The decrease in A1C in exenatide-treated participants with diabetes is related to the magnitude of the weight loss. In participants who experienced no weight loss, the decline in A1C is 0.7% (quartile IV). This reflects the effect of exenatide to augment insulin secretion, to inhibit glucagon secretion, and to delay gastric emptying. In participants who experienced a large weight loss (quartile I), an additional drop in A1C (0.8%) can be expected secondary to the beneficial effects of weight reduction on glucose homeostasis.

Change in Triglycerides and HDL-C as Function of Weight-Change Quartile at 82 Weeks Exenatide per se has no effect to reduce the plasma triglyceride concentration. However, with progressive weight loss, there was a progressive decline in the group with the greatest weight loss (quartile I). With respect to HDL cholesterol, it appears that exenatide per se may have a modest effect to increase the levels of this lipoprotein (quartile IV). With increasing weight loss, there is a progressive further rise in HDL.

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.

Change in Blood Pressure as Function of Weight-Change Quartile at 82 Weeks In patients with T2DM treated with exenatide, any amount of weight loss was associated with a decline in blood pressure. If participants failed to lose any weight whatsoever, there was no decrease in blood pressure.

Exenatide Treatment: 3.5-Year Follow-up Exenatide treatment for 3.5 years produces a durable reduction in A1C, FPG, and body weight.

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.

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 GLP-1 and its metabolites may have clinically important effects to enhance cardiac performance.

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

Summary of Pharmacologic Incretin Actions on Different Target Tissues Heart Brain Neuroprotection Stomach Appetite Gastric Emptying Cardioprotection Cardiac Output GLP-1 emphasize cardiac aspects. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):154-165. _ 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.

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.