1. Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Stan Schwartz MD,FACP Clinical Associate Professor of Medicine, U of Pa. Cardiometabolic Institute Penn-Presbyterian Hospital,, UPHS Part 5

2. Potential Mechanisms of reducing CV outcomes with DPP-4 inhibitors Fadini,G, Cardiovascular effects off DPP-4 Inhibition, Vascular Pharm., in press, 2011

3. 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 Exentide and CV outcomes- 430,000 patients-near 40,000 on exenatide

4. Mechanism of Incretins 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. S e c t i o n 12, 12.2 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

5. ? Pancreatitis, ? C-cell tumors? pancreatitis

6. Relative differences- sitagliptin vs exenatide

7. NO HYPO- can use NPO exenatide

8. 8 82WEEK WEIGHT Dec.- Not correlated to nausea exenatide

9. 9 Changes in Glycemia and Weight in 3 Studies of Exenatide vs Insulin Glargine, Once Daily Exenatide Insulin Aspart, 70/30 1. Heine R, et al. Ann Intern Med. 2005;143:559-569. 2. Barnett AH, et al. Clin Ther. 2007;29:2333-2348. 3. Nauck MA, et al. Diabetologia. 2007;50:259-267. 6 7 8 9 10 Change in A1C, % -1.4% -1.1% Barnett et al 2 Heine et al 1 -0.9% Nauck et al 3 -1.4% -1.1% -1.0% Barnett et al 2 Heine et al 1 Nauck et al 3 -2 Change in Weight, kg 1 2 0 -3 3 +1.8 kg +2.3 kg +2.9 kg -2.2 lb -2.5 kg -2.3 kg 4 ADA GOAL

10. Easy to Initiate: 31- g tips don’t hurt!! All MDs should poke themselves!!! After first use, BYETTA can be kept at a room temperature not to exceed 77ºF (25ºC) Initiate with 5-mcg BID fixed dose, prefilled pens increase dose to 10 mcg BID, based on glycemic / weight response and tolerability Take BYETTA with first bite, (and only 1 hour before a meal when tolerates 10 Pen) No dosage adjustments based on meal size or exercise No additional glucose monitoring required

11. Insulin Secretagogues: Sulfonylureas and “Glinides” Safety and Efficacy -Decreases HbA 1c approx 1–2%(sfu, repaglinide)(0.5- 1.0%,neteglanide) -Adverse events: Wt gain, sulfa allergy (sfu,rare),  -cell apoptosis (sfu) Main risk = hypoglycemia, inc ischemia risk(~50% less w/repaglinide,75% less with neteglanide) Increase Cancer vs Metformin Abnormal ischemia pre-conditioning SO WHY USE SOMETHING THAT DESTROYS BETA-CELLS THAT YOU’D LIKE TO SAVE Davies MJ. Curr Med Res Opin. 2002;18(Suppl 1):s22-30.

12. Meta-Analysis: Cardiovascular Risk With Sulfonylurea Plus Metformin Rao AD, et al. Diabetes Care. 2008;31:1672-1678. 0.25 1.0 4.0 Relative Risk (95% CI) 1.04 (0.62-1.75) 1.86 (1.33-2.61) 0.96 (0.82-1.12) 1.38 (1.13-1.69) 2.24 (1.26-3.99) 1.86 (1.03-3.35) 1.52 (0.84-2.76) 1.43 (1.10-1.85) Bruno (1999) Olsson (2000) Johnson (2005) Koro (2005) Evans (2006) (A) Evans (2006) (B) Evans (2006) (C) Overall Results With Combination Therapy Increased composite cardiovascular risk end point (RR 1.43; 95% CI, 1.10-1.85) All-cause mortality alone – not significant Cardiovascular disease mortality alone – not significant Composite end point: cardiovascular hospitalization or mortality Relative risk: combination therapy vs. diet, metformin alone, or sulfonylurea alone RR = relative risk

13. Higher Mortality Is Associated With Greater Exposure to Sulfonylurea Simpson SH, et al. CMAJ. 2006;174:169-174. A retrospective, inception cohort study conducted in 5795 new users of oral glucose-lowering medications - Insulin or combination therapy were excluded - Mean age: 66.3 years - Mean follow-up: 4.6 years - Main outcomes: all-cause mortality, death from acute ischemic event There was a greater risk of death associated with higher daily doses and better adherence for patients who used glyburide (HR = 1.3; 95% CI, 1.2-1.4), but not metformin (HR = 0.8; 95% CI, 0.7-1.1) 0 1 2 Glyburide (n = 4138) Metformin (n = 1537) 1.32 1.29 0.92 0.96 0.84 41.5 (37.6) 53.4 (70.2) Daily Dose Hazard ratio Monotherapy group Deaths/1000 person-years Lower (higher) 0 1 2 Glyburide (n = 4138) Metformin (n = 1537) 1.55 1.34 1.33 1.10 1.09 0.98 49.0 (75.8) 37.7 (41.3) Poor (good) Adherence Hazard ratio Monotherapy group Deaths/1000 person-years Unadjusted Adjusted for age, sex, chronic disease score (CDS), and nitrate use Adjusted for age, sex, CDS, nitrate use, physician visits, and hospital admissions

14.  Decrease HbA 1c 0.5–1%  Decrease PPG,TG  Delay DM Adverse events: flatulence,treat hypoglycemia with glucose Decrease b-cell demand- - dec CV outcomes, STOP- NIDDM

15. Other Meds with Glycemic Benefit Fast-acting Bromocryptine central dopaminergic effect on decreasing peripheral sympathetic tone decreasing insulin resistance Decreases CV outcomes 50% in 1 year Colsevelam lipid benefit (Ranolazine) Decrease angina ( or equivalent) Decreases arrhythmia Improves diastolic dysfunction, thus-decreases edema of Pio-, Decreases HgA1c, FBS in glucose dependent fashion, no hypoglycemia