1. The Obesity/Diabetes Epidemic: Perspectives, Consequences, Prevention, Treatment 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 8

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-CDC’s diabetes prevention program and other Evidence-Based Interventions- –Basics, –Next Lecture in Series

3. Diet and Exercise Treatment Considerations- Next Lecture in Series

5. Drugs to Influence Gut-Brain Interactions on Hunger/Satiety

6. Brain Central signals Stimulate NPY AGRP galanin Orexin-A dynorphin Inhibit  -MSH CRH/UCN GLP-I CART NE 5-HT External factors Emotions Food characteristics Lifestyle behaviors Environmental cues Peripheral signalsPeripheral organs Food intake Glucose CCK, GLP-1, Apo A-IV Vagal afferents Insulin Leptin Cortisol – – + Gastrointestinal tract Adipose tissue Adrenal glands Ghrelin + Regulation of Food Intake: Potential Targets for ObesityTherapy

7. Considering the Epidemic of Metabolic Syndrome, Prediabetes,Prevention Data, Undiagnosed Diabetes- SCREENING IS CRITICAL! Risk factors and screening for diabetes: Family history: whether parents or siblings have had diabetesFamily history: whether parents or siblings have had diabetes Obesity: especially with an increase in abdominal girthObesity: especially with an increase in abdominal girth High-risk ethnic group: African Americans, Hispanics, Native Americans, Asians, and Pacific IslandersHigh-risk ethnic group: African Americans, Hispanics, Native Americans, Asians, and Pacific Islanders Age: we’re looking at all ages, if patient seems at riskAge: we’re looking at all ages, if patient seems at risk Impaired fasting glucose or impaired glucose toleranceImpaired fasting glucose or impaired glucose tolerance Hypertension: blood pressure ≥ 140/90 mm Hg in adultsHypertension: blood pressure ≥ 140/90 mm Hg in adults High density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dLHigh density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dL Gestational diabetes or given birth to an infant weighing > 9 poundsGestational diabetes or given birth to an infant weighing > 9 pounds

8. 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

9. Potential Causes of Weight Gain With Treatment of Type 2 Diabetes Improved glycemic control –reduce glycosuria, store food that shouldn’t be eating Fear of, or treatment for, hypoglycemia-eats extra Increased appetite –insulin/ SU Weight gain with insulin treatment –Correlates with insulin dose –Mean weight gain 3.2 - 4.4 kg per 1% reduction in A1C –About ⅔ adipose tissue and ⅓ lean body mass Westphal SA, et al. Insulin. 2007;2:31-36.

10. 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

12. 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

13. GLP-1 RAs effect on A1c and weight Exenatide liraglutide

14. 5.1 lbs mean weight loss in 26 weeks Exenatide Extended Release (once a week) effect on A1c and weight

15. 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- 3. GLP-1 RA’s and SGLT-2s may 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 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 pioglitazone, metformin, if possible add SGLT-2 inhibitor add incretin, GLP-1 preferred May be able to stop insulin, lose weight

17. Monotherapy Metformin Pioglitazone GLP-1 agonist Bromocriptine DPP-4 Inhibitor SGLT-2 Colsevelam AGI Dual Combination Metformin Pioglitazone GLP-1 agonist Bromocriptine DPP-4 Inhibitor SGLT-2 Colesevelam AGI Triple Combination M etformin Pioglitazone GLP-1 agonist Bromocriptine DPP-4 Inhibitor SGLT-2 Colesevelam AGI Insulin* +/- Other agents *Insulin analogs  Not NPH/regular  If over 9.0% or above and symptomatic  If triple combo fails 5.7 HbA1c Continuum 6.5%– if not at goal, advance Rx7.5% 9.0 12% Asymptomati c Symptomati c Principles of the AACE Guidelines / A1C Goal less than or equal to 6.5% 1. Minimize risk/severity of Hypoglycemia5. Lifestyle Modification Essential and NO SMOKING 2. Minimize risk/severity of Weight gain 6. Combination frequently required; Complimentary mechanisms of action 3. Fast therapeutic changes (2-3 months, earlier even better) 7. When using insulin, add an insulin-sensitizing agent if possible 4. Address fasting and postprandial glucose 8. Cost is important but, safety and efficacy trump cost Future Guidelines- Modest Proposal Therapeutic Choice Should Match The Drug Characteristics With Patient Characteristics- NO SU/GLINIDES Diet and Exercise Prevention Pioglitazone [Incretin] [Bromocriptine] Metformin Colsevelam

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