New Perspectives and Emerging Treatment Paradigms for Individualizing Obesity Management

1. Please Take A Moment to Complete the Pre-Program Clinical Performance and Knowledge Gap Assessment Survey

2. Investigations  Stratification Front Line Clinical Applications New Perspectives and Emerging Treatment Paradigms for Individualizing Obesity Management Focus on Maximizing Behavioral, Cardiometabolic, and Weight Loss Outcomes with Pharmacologic Agents Targeting the Central Nervous System Program Co-Chairs Ken Fujioka, MD Director, Nutrition and Metabolic Research Center | Director, Center for Weight Management | Scripps Clinic San Diego, CA Lee M. Kaplan, MD, PhD Director, Obesity, Metabolism & Nutrition Institute | Massachusetts General Hospital| Associate Professor of Medicine | Harvard Medical School| Boston, Massachusetts

3. Welcome and Program Overview CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCCommercial Support: This CME activity is supported by an educational grant from Eisai, Inc.

4. Distinguished Faculty Program Co-Chairman Lee M. Kaplan, MD, PhD Associate Professor of Medicine Harvard Medical SchoolDirector, Obesity, Metabolism & Nutrition Institute Massachusetts General Hospital Boston, Massachusetts Louis J. Aronne, MD Sanford I. Weill Professor of Metabolic ResearchWeill-Cornell Medical CollegeAttending PhysicianThe New York-Presbyterian Hospital, Weill-Cornell Medical CollegeNew York, NY  Program Co-Chairman Ken Fujioka, MDDirector, Nutrition and Metabolic Research Center Director, Center for Weight Management Scripps Clinic San Diego, CA Robert F. Kushner, MD Professor of Medicine Northwestern University Feinberg School of Medicine Clinical Director, Northwestern Comprehensive Center on Obesity Chicago, Illinois

5. COI Disclosures

6. New Perspectives and Emerging Treatment Paradigms Current Challenges and Barriers to Obesity Treatment in the Primary Care Setting Ken Fujioka, MD – Program Co-Chair Director, Nutrition and Metabolic Research Center | Director, Center for Weight Management | Scripps Clinic in San Diego, CA

7. Are you Biased Against Overweight Patients? • Fat people are good and lazy; thin people are bad and motivated • Fat people are bad and motivated; thin people are good and lazy • Fat people are bad and lazy;thin people are good and motivated • Fat people are good and motivated; thin people are bad and lazy

8. Are you Biased ? • Anywhere from 30% to 40% of health care providers who specialized in obesity treatment answered: Fat people are bad and lazy; thin people are good and motivated • Indicating bias or negative attitudes towards the overweight and obese patient • Much of this bias is related to a lack of knowledge Teachman BA, Brownell KD. Int J ObesRelatMetabDisord. 2001;25(10):1525-1531.

9. Knowledge of Obesity • Lack of knowledge is cited by many studies as a reason why health care professionals do not even attempt obesity management • Not surprising • Understanding the mechanism of why it is so hard to lose weight and keep it off is recent Fujioka K, Bakhru N. Office based management of Obesity;.Mt Sinai J Med. 2010 Sep-Oct;77(5):466-71. Review.

10. Pathophysiology of ObesityWhy is it So Hard to Lose Weight? • Need to know how humans regulate weight to understand the treatment options • Patient A • 48-year-old with a sedentary job • Weight - 150 pounds • Develops lower back pain and is placed on prednisone (steroids) to decrease inflammation in compressed nerve causing severe pain • Patient on “the steroids” for 2 months and unable exercise for 6 months and gains 50 pounds

11. The Patient has Gained 50 pounds • The patient has gone from 150 pounds to 200 pounds • With this weight gain his fasting blood sugar is now 105 • The patient is now a “pre-diabetic” • If the patient is Asian or Hispanic, he will see pre-diabetes emerge with less weight gain (20 to 30 pounds) • The patient is now technically obese

12. Motivated Patient Trying to Lose Weight • The patient recovers from the back injury and decides to lose weight • The patient begins a diet and exercise program • He loses about 20 pounds (over 3 months) • 200 down to 180 • Despite staying on the diet and exercising 2 to 3 days a week, the patient stops losing weight • A few months later the patient notes that weight is starting to slowly go up

13. Weight Regulation in Humans • The human body is hardwired to know how many fat cells are on board and to keep the body weight stable • At about 5% to 10% of weight loss the human body will respond by: • Lowering metabolic rate (more than 5%-10%) • Lower the hormones that signal satiety or fullness after eating • Increase thoughts and hormones to make humans seek out and eat more food • All part of defense of body weight • This does not get better with time (always trying to get back to that highest weight) • Sumithran P et al. N Engl J Med. 2011;365:1597-1604

14. The Good News on 5% to 10% Weight Loss • Sustained weight loss of 3%-5% is likely to result in clinically meaningful reductions in triglycerides, blood glucose, HbA1C, and the risk of developing type 2 diabetes • Greater amounts of weight loss will reduce blood pressure, improve LDL–C and HDL–C, and reduce the need for medications to control blood pressure, blood glucose and lipids as well as further reduce triglycerides and blood glucose • Jensen MD, et al.2013 AHA/ACC/TOS Obesity Guideline

15. Treatment Options2012 Diet • Meal replacements, VLCDs, standard low calorie diets Exercise • Just figured out that a combination of cardio and resistance training is better Phentermine • Short term medication Orlistat • Fat blocker with limited efficacy and well known side effects Bariatric surgery • Lap band • Gastric bypass

16. Treatment Options2014 • Medications approved in 2013 • Lorcaserin • Phentermine/Topiramate ER • Medications going to the FDA for possible approval • Liraglutide • Bupropion SR/ Naltrexone SR

17. Proper Use of Obesity Medications • Recognizing non-responders • An obese patient is started on a weight loss medication and is not losing adequate amounts of weight • STOP the medication • Lorcaserinpatient should lose 5% or more of their weight by 3 months, otherwise stop • Phentermine/topiramate patient should lose 3% by 3 months or 5% by 6 months

18. REMs Risk Evaluation Mitigation Strategy • Phentermine/Topiramate ER • Possible cleft lip or palate in fetus exposed to topiramate • REMS • Physicians and pharmacies trained on use of the medication • Only certified pharmacies can dispense • Help to ensure the patient is educated to not get pregnant while on the medication

19. Bariatric Surgery • Bariatric surgery • Sleeve gastrectomy comes of age • Procedure between an adjustable band and gastric bypass • Excellent weight loss • Fewer nutritional problems after (compared to bypass)

20. Financial • AMA – Obesity defined as a “disease” • CMS – Primary care practitioners (includes NPs and PAs) can get reimbursed for “obesity treatment” • They have specific guidelines on how to treat • Weight loss medications • More insurance companies are now starting to reimburse for weight loss medications • The overall number is still low (less than 50%) • Bariatric surgery • Vast majority of insurances cover

21. New Perspectives and Emerging Treatment Paradigms for Individualizing Obesity Management Treating Patients with Obesity: Who, Why, How and to What Ends Lee M. Kaplan, MD, PhD Obesity, Metabolism & Nutrition Institute Massachusetts General Hospital Harvard Medical School LMKaplan@partners.org April 11, 2014

22. Disclosures • I receive funding for basic research from the U.S. National Institutes of Health and Ethicon Surgical Care. • I am a member of scientific advisory boards for the following companies: • Astra-Zeneca Eisai Ethicon Fractyl • Gelesis GI Dynamics MedImmune Metavision • Novo Nordisk Rhythm Second Genome Takeda • USGI Medical Vivus Zafgen • I have equity in the following companies: • Fractyl Gelesis • GI Dynamics Rhythm • I may discuss the off-label / unapproved use of several drugs or devices, including: bupropion, canagliflozin, EndoBarrier, exenatide, liraglutide, metformin, naltrexone, phentermine, pramlintide, topiramate, zonisamide

23. Why is weight regain after dieting so common? Exercise, not diet, is the most effective means of losing weight The body reacts to weight loss by decreasing daily energy expenditure Diet foods are boring and patients stop eating them Dieting increases the body’s set point for fat mass Weight loss often leads to unwanted effects that cause patients to sabotage their efforts Question 1 • Please Enter Your Response On Your Keypad

24. Question 2 Which of the following is NOT a demonstrated benefit of modest regular exercise? • Enhances weight loss effect of other lifestyle changes • Causes weight loss directly • Alters appetite to favor healthier foods • Stimulates fat to burn more calories • Decreases cardiovascular risk • Please Enter Your Response On Your Keypad

25. Question 3 Which of the following comorbidities of obesity has NOT been shown to improve with modest (5-10%) weight loss? • Type 2 diabetes • Hypertension • Dyslipidemia • Cardiovascular risk • Fatty liver disease • Please Enter Your Response On Your Keypad

26. Question 4 If a patient with prediabetes and obesity maintains a 4% weight loss over 4 years, how much do they lower their risk of developing diabetes? • <10% • ~25% • ~50% • ~75% • >90% • Please Enter Your Response On Your Keypad

27. Question 5 Which of the following medications is NOT currently approved by the FDA for the treatment of obesity? • Orlistat • Liraglutide • Phentermine • Lorcaserin • Phentermine / Topiramate ER combination • Please Enter Your Response On Your Keypad

28. Question 6 Which of the following weight loss medications do NOT work through central nervous system mechanisms? • Bupropion • Lorcaserin • Liraglutide • Topiramate ER • Phentermine • Please Enter Your Response On Your Keypad

29. Question 7 Which of the following is NOTa primary mechanism of weight loss from centrally-acting weight loss medications? • Change in food preferences • Decrease in appetite • Increase in resting and post-meal energy expenditure • Demonstrating the value of a healthier weight to the patient • Lower physiologically defended body weight • Please Enter Your Response On Your Keypad

30. Medical Complications of Obesity Stroke Intracranial hypertension Cognitive dysfunction Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Cataracts Coronary heart disease Pancreatitis Diabetes Dyslipidemia Fatty liver disease steatosis steatohepatitis cirrhosis Hypertension Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Gallstones Cancer breast, uterus, cervix, ovary, prostate, kidney, colon, esophagus pancreas, gallbladder, liver Osteoarthritis Phlebitis venous stasis Skin disorders Gout

31. Complications of Obesity Metabolic Structural Inflammatory Degenerative Neoplastic Psychological 65

32. Metabolic Structural Inflammatory Degenerative Neoplastic Psychological Complications of Obesity Several of these complications exacerbate the underlying obesity, creating a vicious cycle: Diabetes Many diabetes drugs cause weight gain PCOS Insulin resistance promotes lipogenesis Sleep apnea Disrupted sleep can cause weight gain Arthritis Limit exercise capacity Back pain Inflammatory Steroids often cause disorders weight gain DepressionEating disorders and Psychological many psychotropic agents cause weight gain

33. Benefits of Modest Intentional Weight Loss • Improvement in comorbid diseases • Type 2 diabetes • Hypertension • Dyslipidemia • Fatty liver disease • Obstructive sleep apnea • Asthma • Osteoarthritis • Cancer risk • Improved quality of life • Decreased health care costs • Decreased surgical complication rates • Orthopedic surgery • Heart surgery • General and thoracic surgery • The effect on cardiovascular risk is less clear

34. <22 <23 23-24 24-25 25-27 27-29 29-31 31-33 33-35 >35 Relationship Between BMI and Risk of Type 2 Diabetes 93.2 Men Women 54.0 Age-Adjusted Relative Risk 42.1 40.3 27.6 21.3 15.8 8.1 5.0 11.6 4.3 2.9 2.2 6.7 4.4 1.5 1.0 1.0 1.0 Body Mass index (kg/m2) Chan J et al. Diabetes Care 1994;17:961. Colditz G et al. Ann Intern Med 1995;122:481.

35. Benefits of Intensive Medical Intervention Diabetes Prevention Program DPP Research Group, N Engl J Med, 2002

36. 40 30 20 10 0 Diabetes Prevention Placebo Metformin Cumulative Incidence of Diabetes (%) Lifestyle 0 1 2 3 4 Year Diabetes Prevention Program Research Group N Engl J Med, 2002

37. Obesity results from a failure of normal weight and energy regulatory mechanisms

38. Obesity: A Failure of Weight Regulation Cortex Genetics HT Development GI Tract Food intake Energy expenditure Nutrient handling Leptin Environment Adipose tissue The current obesity epidemic results primarily from changes in the environment

39. Macroenvironmental Influences* • 24-hour lifestyle • Economic structure • Time pressures • Workload • Loss of downtime • Speed of life • Global stressors *Amenable only to societal intervention

40. Microenvironmental Influences* • Types of nutrients • Eating schedules • Physical activity • Sleep health • Drugs and medications • Local stressors *Amenable to individual action

41. The goal of lifestyle-based therapies is to normalize the patient’s microenvironment

42. Overall Treatment Strategy Typical Algorithm (progress through algorithm as clinically required) Self-directed Lifestyle Change Professionally-directed Lifestyle Change Add Medications Weight Loss Surgery Post-surgical Combination Therapies

43. Lifestyle Treatment of the Patient with Obesity • Healthy diet – to change the nutrient environment by changing the diet chemistry • Improves nutrient signaling to the brain • Emphasize unprocessed foods • Encourage complexity • Number of calories is MUCH less important • Regular exercise • To improve muscle health, not to burn calories acutely • Long-term exercise more important than type or intensity • Stress reduction • Reduce both perceived and “invisible” stresses • Restore sleep • Regularize circadian rhythms

44. Pharmacological Therapies

45. Medication-induced Weight Gain Medications account for 5-10% of obesity in the U.S. In each relevant category, remove or substitute weight gain-promoting medications with weight neutral or weight loss-promoting alternatives

46. Weight Loss from Other Medications Strategy: Aim for Double Benefits when Possible

47. Medications Approved for Obesity * Beyond placebo

48. Practical Use of Weight Loss Medications • Understand risks, cautions and monitoring essentials • Start when weight is stable (within 3% over 3 months) • Aim for weight stability with lifestyle management • Assess effects at 1 and 3 months • Continue medication beyond 3 months if ≥ 5% total weight loss • Some use “4x3” rule - ≥ 4 lbs. weight loss/month x 3 months • Weight plateau with increased hunger is expected • Medication still working if substantial weight regain absent

49. Foundational Role of the Central Nervous System in Appetite Regulation Robert Kushner, MD, FACP Professor of Medicine Northwestern University Feinberg School of Medicine rkushner@northwestern.edu

50. Disclosures I am a consultant, speaker, advisor, or receive research support from: Aspire Bariatrics Novo Nordisk Retrofit Takeda Pharmaceuticals VIVUS Inc. Weight Watchers Zafgen Inc.