2.  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.  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.www.cdc.gov/diabetes/statistics/survl99/chap5/figure1.htm

4. Overweight 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. Normal weightObese Relative Risk of Cardiovascular Disease Mortality 0.6 3.0 2.6 2.2 1.8 1.4 1.0 >18 25 30 >40 BMI, kg/m 2 Women Men

5. -0.8 -0.6 -0.4 -0.2 0 Δ A1C (%) * Δ HDL Cholesterol (mg/dL) * Intensified Lifestyle Intervention, 8.6% Weight Loss Diabetes Support and Education, 0.7% Weight Loss 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 -40 -30 -20 -10 0 Δ Triglycerides (mg/dL) * -7.5 -5.0 -2.5 0 Δ Blood Pressure (mm Hg) * * 0 1 2 3 4 SystolicDiastolic

8. Release of active incretins GLP-1 and GIP  Blood glucose in fasting and postprandial states Ingestion of food  Glucagon (GLP-1)  Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 X DPP-4 inhibitor  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  Insulin (GLP-1and GIP) Glucose- dependent Glucose dependent Pancreas Inactive GIP GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging the actions of these hormones. Beta cells Alpha cells  Glucose uptake by peripheral tissue Incretin Mimetic