1. Therapy of Type 2 Diabetes Mellitus: UPDATE Glycemic Goals in the Care of Patients with Type 2 Diabetes- 2013 ADA and AACE Guidelines: Room For Improvement (Be HAPPY/ Avoid Burnout, While Caring for Patients with DM) Stan Schwartz MD, FACP, FACE Affiliate, Main Line Health System Clinical Associate Professor of Medicine, Emeritus, U of Pa. Part 5

2. 8-10x 2-4x

3. 3 82WEEK WEIGHT Dec.- Not correlated to nausea exenatide Effect on hypothalamus, Slower gastric emptying, Not related to nausea

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

5. DPP-4 Inhibitors and CV Events: A Meta-analysis 52% reduction in risk for CV events compared to other oral agents or placebo. Patil HR, et al. Am J Cardiol. 2012;110(6):826-833. First Author DPP4iComparator Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI EventsTotalEventsTotalWeight Aschner152835223.7%0.33 (0.03, 3.16) Bosi E130022943.3%0.49 (0.04, 5.37) Chan1065122637.7%0.33 (0.16, 0.67) Defronzo22640642.1%1.23 (0.06, 25.54) Foley05460 Not estimable Foley Je029030Not estimable NCT0031608242913748.6%0.34 (0.08, 1.48) NCT003749070201161.9%0.27 (0.01, 6.21) NCT0069893242840 2.2%9.00 (0.49, 166.39) NCT0091887901070106Not estimable NCT0126349653910832.3%2.36 (0.13, 42.22) Pfuntzer233573287.7%0.28 (0.06, 1.34) Pi-Sunyer0262092Not estimable Rosenstock1130639511.9%1.14 (0.32, 4.00) Rosenstock J03960202Not estimable Schweitzer216921664.9%0.98 (0.14, 6.89) Schweitzer A052622542.0%0.10 (0.00, 2.01) Williams-Herman31791136411.7%0.55 (0.16, 1.96) Total (95% CI)49983546100.0%0.48 (0.31,0.75) Total events4546 Heterogeneity: Tau 2 = 0.00; Chi 2 = 11.22, df = 12 (P = 0.51); I 2 = 0% Test for overall effect: Z = 3.28 (P = 0.001) 0.001 DPP4i better 0.11101000 DPP4i worse

6. SavorN Engl J Med. 2013 Oct 3;369(14):1317-1326. Epub 2013 Sep 2. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; the SAVOR-TIMI 53 Steering Committee and Investigators.N Engl J Med. Scirica BMBhatt DLBraunwald ESteg PGDavidson JHirshberg BOhman PFrederich RWiviott SDHoffman EBCavender MA Udell JADesai NRMosenzon OMcGuire DKRay KK Leiter LARaz I the SAVOR-TIMI 53 Steering Committee and Investigators SavorN Engl J Med. 2013 Oct 3;369(14):1317-1326. Epub 2013 Sep 2. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; the SAVOR-TIMI 53 Steering Committee and Investigators.N Engl J Med. Scirica BMBhatt DLBraunwald ESteg PGDavidson JHirshberg BOhman PFrederich RWiviott SDHoffman EBCavender MA Udell JADesai NRMosenzon OMcGuire DKRay KK Leiter LARaz I the SAVOR-TIMI 53 Steering Committee and Investigators

7. 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 Exenatide and CV outcomes- 430,000 patients-near 40,000 on exenatide

8. Nausea Story Observations –The most common AEs associated with exenatide (vs placebo) in three 30-week, placebo- controlled clinical trials were nausea (44% vs 18%), vomiting (13% vs 4%), diarrhea (13% vs 6%), –5 years later, monotherapy study was only 19%; e.g.: learned how to use it- stop eating when full –Both exenatide/liraglutide, nausea decreases over time –Exenatide-QW 1/3 risk of nausea as liraglutide 1.8 mg/d –Etiology-  Oversensitive hypothalamic sensitivity  Slower gastric emptying; patients keep eating after first sense of fullness  High fiber, high fat meals –In Hospital- –TEACH PATIENTS TO STOP EATING AT FIRST SENSE OF FULLNESS!! –Patients eat slowly, decreased speed of eating, decreased quantity of eating, less fatty meals The ~1 % hypothalamic nausea can be treated with metochlopromide/ ondansetron - Diabet Med. 2010 Oct;27(10):1168-73. doi: 10.1111/j.1464-5491.2010.03085.x. Diabet Med.

9. Pancreatic Cancer- NOT 1.15 yr. Age difference, control to incretin 2.Compared type 1 to type 2 pancreases 3.Polyclonal nonspecific antibody vs monoclonal antibody (proves no GLP1 receptors on epithelium) 4.Alpha cell hyperplasia Butler saw is not cell type leading to pancreatic cancer Pancreatic Cancer- NOT 1.15 yr. Age difference, control to incretin 2.Compared type 1 to type 2 pancreases 3.Polyclonal nonspecific antibody vs monoclonal antibody (proves no GLP1 receptors on epithelium) 4.Alpha cell hyperplasia Butler saw is not cell type leading to pancreatic cancer

10. Exenatide-QW carries same warning GLP-1 Receptors on rodent C- cells, but not on Human C-Cells Endo, 2010 ADA, 2013, EASD 2013

11. Patient Types/ Situations 0.Treat Late Post-Prandial Hypoglycemia 1. Prevention / Delay of DM 2. Cardiovascular- as above, likely reduced CV outcomes with weight neutrality, no undue hypoglycemia 3. Guideline based 4. Approach to Weight reduction in Diabetes 5. Type 1/ Type 2 on insulin (on/off label) 6. Discontinue Insulin 7. Hospital/ stress/ steroid dm

12. 12 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 ie: ALWAYS USE GLP-! BEFORE GO TO INSULIN

13. Weight Loss in Obese Non- Diabetics over 2 years with Lira- glutide

14. Incretins in Type-2 Patients My Experience: Fewer patients need bolus insulin: DPP-4 inh=~50% GLP-1 RA=~ 20%

15. GLP-1 RAs in Type 1 Diabetes Liraglutide Exenatide with a meal Data Suggests: less dawn effect, less variability, decrease insulin doses, less hypoglycemia Recent epiphany: I prescribe less pump therapy