Diabetes Mellitus 101 for Medical Professionals

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

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. 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

4. S e c t i o n 12, 12.2 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 inhibitor DPP-4 enzyme 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.

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

6. Relative differences-sitagliptinvsexenatide

7. Acutely Improving Beta-Cell ResponseBYETTA Reduced Hyperglycemia in Fasting Patients exenatide exenatide NO HYPO- can use NPO

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

9. Changes in Glycemia and Weight in3 Studies of Exenatide vs Insulin Heine et al1 Nauck et al3 Barnettet al2 Heine et al1 Barnettet al2 Nauck et al3 10 9 Change inA1C, % 8 ADA GOAL 7 -0.9% -1.0% -1.4% -1.1% -1.4% -1.1% 6 Glargine, Once Daily Insulin Aspart, 70/30 Exenatide 4 3 2 1 Change in Weight, kg 0 +2.9 kg +1.8 kg +2.3 kg -1 -2 -2.2 lb -2.3 kg -3 -2.5 kg 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.

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 HbA1c approx1–2%(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 Relative Risk (95% CI) Bruno (1999) Olsson (2000) Johnson (2005) Koro (2005) Evans (2006) (A) Evans (2006) (B) Evans (2006) (C) Overall 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) 0.25 1.0 4.0 • 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 Rao AD, et al. Diabetes Care. 2008;31:1672-1678. RR = relative risk

13. Higher Mortality Is Associated With Greater Exposure to Sulfonylurea Monotherapy group Monotherapy group Deaths/1000 person-years Deaths/1000 person-years Hazard ratio Hazard ratio Adherence Daily Dose Poor (good) 1.55 1.34 1.33 49.0 (75.8) Glyburide (n = 4138) 1.10 1.09 0.98 Lower (higher) 1.32 1.29 1.29 37.7 (41.3) Metformin (n = 1537) 53.4 (70.2) Glyburide (n = 4138) 0 1 2 0.92 0.96 0.84 41.5 (37.6) Metformin (n = 1537) Unadjusted Adjusted for age, sex, chronic disease score (CDS), and nitrate use Adjusted for age, sex, CDS, nitrate use, physician visits, and hospital admissions 0 1 2 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) • 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 Simpson SH, et al. CMAJ. 2006;174:169-174.

14. Decrease b-cell demand- - dec CV outcomes, STOP- NIDDM • Decrease HbA1c 0.5–1% • Decrease PPG,TG • Delay DM Adverse events: flatulence,treat hypoglycemia with glucose

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