1. The Obesity/Diabetes Epidemic: Adiposopathy & Obesity- The New Disease! Dx & (Rx) of Insulin Resistance & early DM Stan Schwartz MD, FACP, FACE Private Practice, Ardmore Obesity Program Cardiometabolic Diabetes Center and Affiliate, Main Line Health System Emeritus, Clinical Associate Professor University of Pennsylvania Part 7 Final

2. Outline Epidemiology and Economics of obesity/diabetes Perspectives on Obesity Consequences of Obesity, Prediabetes, Obesity Obesity/ Diabetes Risk Factors, Obesity/ Diabetes Onset can be Prevented or Delayed – Early Risk Identification and Intervention. Medical Benefits to Weight Loss Treatment-- –Basics,

3. Impact of Intensive Therapy in Type 2 Diabetes Summary of Major Clinical Trials : BUT Subset Evaluations Show Reduced CV Outcomes if shorter duration of DM, without significant pre-existing complications StudyMicrovascularMacrovascularMortality UGDP ↔↔↔ UKPDS ↓↓↔↓↔↓ DCCT/EDIC* ↓↓↔↓↔ ↔ ACCORD ↓↔ ↑ (unadj.), ↔ (adj.) ADVANCE ↓↔↔ VADT ↔↔↔ Initial Trial Long Term Follow-up Meinert CL. Diabetes. 1970;19(suppl):789-830. Goldner MG. JAMA. 1971;218(9):1400-1410. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008;359(15):1577-1589. DCCT Research Group. N Engl J Med. 1993;329;977-986. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. Patel A, et al. N Engl J Med. 2008;358:2560-2572. Duckworth W, et al. N Engl J Med. 2009;360. *T1DM study. ↑- likely due to hypoglycemia hypoglycemia and weight gain

6. Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes, Treating Defronzo’s Octet: WITHOUT HYPOGLYCEMIA or WEIGHT GAIN Match Patient Characteristics to Drug Characteristics 5. Gut CHO Absorption: Incretin, Pramlintide, Glucosidase inh. Peripheral glucose uptake -- - 1.Pancreatic insulin Secretion: Incretin, ranolazine 2.Pancreatic glucagon Secretion- Incretin HYPERGLYCEMIA 6.Fat- TZD, metformin 7.Brain- TZD,INCRETIN, bromocryptine 8.Kidney- SGLT2 3. Muscle- TZD, Incretin 4.Liver Hepatic glucose production: Metformin, incretin De

7. Especially with hypoglycemic agents

8. All Insulin Regimens Improve Glycemic Control, but Often With Weight Gain A1C (%) 1. Riddle MC, et al. Diabetes Care. 2003;26:3080-3086. 2. Yki-Jarvinen H, et al. Ann Intern Med. 1999;130:389-396. 3. Holman RR. N Engl J Med. 2007;357:1716-1730. 4. Henry RR, et al. Diabetes Care. 1993;16:21-31. BASAL Insulin ∆ Weight (lb) 0 20 12 16 8 4 BID Insulin Intensive Insulin Prandial Insulin Biphasic Insulin Riddle et al 1 Yki-Jarvinen et al 2 Yki-Jarvinen et al 2 Henry et al 4 Riddle et al 1 Holman et al 3 Holman et al 3 +6.6 lb +8.6 lb +10.1 lb +19.2 lb +6.2 lb +4.2 lb +10.4 lb +12.6 lb Holman et al 3 -2.6% -2.1% -1.3% -1.4%-0.8% -2.1% -2.2% Landmark Insulin Studies in Which Exenatide Was Not a Comparator ADA GOAL 6 7 8 9 10 11 5

9. GLP-1 RAs effect on A1c and weight Exenatide Liraglutid e

10. Changes in Glycemia and Weight in 3 Head-to-Head Studies Exenatide vs. Insulin Heine R, et al. Ann Int Med. 2005;143:559-569. Barnett A, et al. Clin Thera. 2007;29(11):2333-2348. Nauck M, et al. Diabetologia. 2007;50(2):259-267. EXENATIDE AND NO undue HYPOglycemia Added by Dr S

11. SGLT-2 Inhibitor with Incretins

12. Pick Right Drug for Right Patient and Vice Versa: next slide

13. 147 newly diagnosed T2DM initial combination therapy with metformin + pioglitazone + exenatide (Triple Therapy, n=71) or escalating dose of metformin followed by sequential addition of glipizide (5→20 mg/d) and then basal insulin to maintain A1c < 6.5% (Conventional Therapy, n= 76). Results: Triple Therapy, A1c 8.6 to 6.1% at 6 mo and remained stable at 6.1% at 24 Conventional Therapy, 6.1% at 6 mo and then increased to 6.6% at 24 mo (p < 0.01). More subjects in Conventional Arm failed to achieve the treatment A1c goal <6.5% (46 vs 22%, p<0.0001)., Triple Therapy subjects had a 13.6-fold lower rate of hypoglycemia compared to subjects receiving Conventional Therapy. Triple Therapy subjects had mean weight loss of 1.2 kg versus 3.6 kg weight gain (p=0.02) in subjects on Conventional Therapy. Conclusion: Antidiabetic therapy targeting the core metabolic defects (insulin resistance and beta cell dysfunction) responsible for hyperglycemia is more effective and safer than therapy simply aimed at lowering the plasma glucose conc without correcting the underlying pathophysiologic disturbances present in T2DM. Initial Triple Combination Therapy is Superior to Stepwise Add-On ConventionalTherapy in Newly Diagnosed T2DM; RALPH A. DEFRONZO,

15. Can avoid bolus insulin in most by use of GLP-1 Agonists and SGLT-2 Inhibitor

16. Screen Patients for Diabetes Address Potential Causes of Weight Gain in Diabetes treatment Though drugs aimed at reducing insulin resistance and increasing beta cell function are logical pathophysiologically, ‘standard’ current pharmacologic therapy for Type 2 Diabetes increase weight (sulonylureas, glinides, insulin) BUT anything that reduces obesity (specifically visceral fat) will have the most significant benefit in preventing, treating and even reversing overt Diabetes. (even pioglitazone, GLP-1 RA’s, pramlintide, SGLT-2 inhibitors) Bariatric surgery, in many patients with Type 2 Diabetes has become a logical approach to prevent, treat, and even reverse, overt Diabetes AND reduce MORTALITY Diabetic Management of the Obese Patient

17. Weight Reduction Issues Schwartz, Fabricatore, Diamond, Weight Reduction in Diabetes, Book Chapter “Diabetes: An Old Disease, a New Insight,” edited by Dr. Ahmad., Landes Bioscience, 2011 1. In Metabolic Syndrome-consider Incretins/ SGLT-2 inh. 2. Incretins Before Pioglitazone- then don’t gain weight from pio- 3. GLP-1 RA’s and SGLT-2s have added wt. loss benefit 4. GLP-1 RA’s preferred over DPP-4 in ‘right patient’ 5. GLP-1 RA’s always before start Insulin, even a short trial- 6. Unless ‘sick’, avoid insulin if not following NCS diet 7. Keep on Incretin/SGLT-2 inhibitor (others) when add insulin- need for bolus insulin decreased 8. If on insulin- as start NCS diet, decrease 25% if was having hypoglycemia decrease 25% add incretin, GLP-1 preferred – dec. insulin as do so add SGLT-2 inhibitor- decrease insulins 25% add pioglitazone, metformin, if possible May be able to stop insulin, lose weight

18. Summary Epidemiology and Economics of obesity/diabetes-costly Perspectives on Obesity- culture Consequences of Obesity, Prediabetes, Obesity Obesity/ Diabetes Risk Factors, Obesity/ Diabetes Onset can be Prevented or Delayed – Early Risk Identification and Intervention. Medical Benefits to Weight Loss Treatment-CDC’s diabetes prevention program and other Evidence- Based Interventions- –Basics, Next Lecture in Series We can do Better, We must do better I’ll show you how next time