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Presentation on theme: "Please Take A Moment to Complete the Pre-Program Clinical Performance and Knowledge Gap Assessment Survey."— Presentation transcript:

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

2 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 Lee M. Kaplan, MD, PhD Director, Obesity, Metabolism & Nutrition InstituteMassachusetts General HospitalAssociate Professor of Medicine Harvard Medical SchoolBoston, Massachusetts Lee M. Kaplan, MD, PhD Director, Obesity, Metabolism & Nutrition Institute | Massachusetts General Hospital | Associate Professor of Medicine | Harvard Medical School | Boston, Massachusetts Investigations  Stratification Front Line Clinical Applications Ken Fujioka, MD Director, Nutrition and Metabolic Research Center | Director, Center for Weight Management | Scripps Clinic San Diego, CA Program Co-Chairs

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

4 Distinguished Faculty Program Co-Chairman Lee M. Kaplan, MD, PhD Associate Professor of Medicine Harvard Medical School Director, Obesity, Metabolism & Nutrition Institute Nutrition Institute Massachusetts General Hospital Boston, Massachusetts Louis J. Aronne, MD Sanford I. Weill Professor of Metabolic Research Weill-Cornell Medical College Attending Physician The New York-Presbyterian Hospital, Weill-Cornell Medical College New York, NY Research Weill-Cornell Medical College Attending Physician The New York-Presbyterian Hospital, Weill-Cornell Medical College New York, NY Program Co-Chairman Ken Fujioka, MD Director, Nutrition and Metabolic Research Center Director, Center for Weight Management Scripps Clinic 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 Comprehensive Center on Obesity Chicago, Illinois

5 COI Disclosures Faculty MemberRelationshipCorporation/Manufacturer Kenneth Fujioka, MDConsultant: Speaker’s Bureau: Grant/Research Orexigen, Novo Nordisk, Zafgen, NPS, Eisai, Nazura, Pathway Genomics, Isis Abbott, NPS, Eisai, Vivus Orexigen, Novo Nordisk, Enteromedics, NPS, Eisai, Weight Watchers Lee Kaplan, MD, PhDScientific Advisor: Grant/Research: Ethicon, Astra Zeneca, Eisai, GI Dynamics, MedImmune, Novo Nordisk, Rhythm, Takeda, Vivus, Zafgen Ethicon Robert F. Kushner, MDConsultant: Grant/Research Novo Nordisk, Vivus, Retrofit Weight Watchers, Aspire Bariatrics Louis J. Aronne, MDConsultant: Grant/Research: Ownership Interest: Board of Directors: Eisai, Ethicon Endo-Surgery, Novo Nordisk, Vivus, Zafgen Medical University of South Carolina, Novo Nordisk, GI Dynamics, Aspire Bariatrics Cardiometabolic Support Network, LLC, Myos Corporation, Zafgen Myos Corporation

6 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 Director, Nutrition and Metabolic Research Center | Director, Center for Weight Management | Scripps Clinic in San Diego, CA New Perspectives and Emerging Treatment Paradigms

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 Obes Relat Metab Disord. 2001;25(10):

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 Sep-Oct;77(5): Review..

10 Pathophysiology of Obesity Why 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 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 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) 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) 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:

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 AHA/ACC/TOS Obesity Guideline

15 Treatment Options 2012 Diet Meal replacements, VLCDs, standard low calorie diets Meal replacements, VLCDs, standard low calorie dietsExercise Just figured out that a combination of cardio and resistance training is better Just figured out that a combination of cardio and resistance training is betterPhentermine Short term medication Short term medicationOrlistat Fat blocker with limited efficacy and well known side effects Fat blocker with limited efficacy and well known side effects Bariatric surgery Lap band Lap band Gastric bypass Gastric bypass

16 ► Medications approved in 2013 ● Lorcaserin ● Phentermine/Topiramate ER ► Medications going to the FDA for possible approval ● Liraglutide ● Bupropion SR/ Naltrexone SR Treatment Options 2014

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 Lorcaserin patient should lose 5% or more of their weight by 3 months, otherwise stop Lorcaserin patient 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 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 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 Procedure between an adjustable band and gastric bypass Excellent weight loss Excellent weight loss Fewer nutritional problems after (compared to bypass) 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%) The overall number is still low (less than 50%) ► Bariatric surgery ● Vast majority of insurances cover

21 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 April 11, 2014 New Perspectives and Emerging Treatment Paradigms for Individualizing Obesity Management

22 Disclosures 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 I am a member of scientific advisory boards for the following companies: Astra-ZenecaEisaiEthiconFractyl GelesisGI DynamicsMedImmuneMetavision Novo NordiskRhythmSecond GenomeTakeda USGI MedicalVivusZafgen I receive funding for basic research from the U.S. National Institutes of Health and Ethicon Surgical Care. I have equity in the following companies: FractylGelesis GI DynamicsRhythm

23 Why is weight regain after dieting so common? 1.Exercise, not diet, is the most effective means of losing weight 2.The body reacts to weight loss by decreasing daily energy expenditure 3.Diet foods are boring and patients stop eating them 4.Dieting increases the body’s set point for fat mass 5.Weight loss often leads to unwanted effects that cause patients to sabotage their efforts Question 1 Please Enter Your Response On Your Keypad

24 Which of the following is NOT a demonstrated benefit of modest regular exercise? 1.Enhances weight loss effect of other lifestyle changes 2.Causes weight loss directly 3. Alters appetite to favor healthier foods 4. Stimulates fat to burn more calories 5. Decreases cardiovascular risk Please Enter Your Response On Your Keypad Question 2

25 Which of the following comorbidities of obesity has NOT been shown to improve with modest (5-10%) weight loss? 1.Type 2 diabetes 2.Hypertension 3.Dyslipidemia 4. Cardiovascular risk 5. Fatty liver disease Please Enter Your Response On Your Keypad Question 3

26 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? 1.<10% 2.~25% 3. ~50% 4. ~75% 5. >90% Please Enter Your Response On Your Keypad Question 4

27 Which of the following medications is NOT currently approved by the FDA for the treatment of obesity? 1. Orlistat 2. Liraglutide 3. Phentermine 4. Lorcaserin 5. Phentermine / Topiramate ER combination Please Enter Your Response On Your Keypad Question 5

28 Which of the following weight loss medications do NOT work through central nervous system mechanisms? 1. Bupropion 2. Lorcaserin 3. Liraglutide 4. Topiramate ER 5. Phentermine Please Enter Your Response On Your Keypad Question 6

29 Which of the following is NOT a primary mechanism of weight loss from centrally- acting weight loss medications? 1.Change in food preferences 2.Decrease in appetite 3.Increase in resting and post-meal energy expenditure 4.Demonstrating the value of a healthier weight to the patient 5.Lower physiologically defended body weight Please Enter Your Response On Your Keypad Question 7

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

31 Complications of Obesity Psychological Neoplastic Inflammatory Structural Metabolic Degenerative

32 Several of these complications exacerbate the underlying obesity, creating a vicious cycle: Diabetes Many diabetes drugs cause weight gain PCOSInsulin resistance promotes lipogenesis Sleep apneaDisrupted sleep can cause weight gain ArthritisLimit exercise capacity Back pain InflammatorySteroids often cause disordersweight gain DepressionEating disorders and Psychologicalmany psychotropic agents cause weight gain Psychological Neoplastic Inflammatory Structural Metabolic Degenerative

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

34 Relationship Between BMI and Risk of Type 2 Diabetes Chan J et al. Diabetes Care 1994;17:961. Colditz G et al. Ann Intern Med 1995;122:481. Age-Adjusted Relative Risk Body Mass index (kg/m 2 ) Men Women <22< >

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

36 Diabetes Prevention Diabetes Prevention Program Research Group N Engl J Med, 2002 Cumulative Incidence of Diabetes (%) Placebo Metformin Lifestyle Year

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

38 Obesity: A Failure of Weight Regulation Genetics Development Environment Adipose tissue Leptin HT Food intake Energy expenditure Nutrient handling Cortex GI Tract 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) Post-surgical Combination Therapies Weight Loss Surgery Add Medications Professionally-directed Lifestyle Change Self-directed Lifestyle Change

43 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 Lifestyle Treatment of the Patient with Obesity

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 Medication Indicated Uses Comments BupropionDepression Avoid in bipolar disease TopiramateSeizuresMigraines Mood disorders May produce neurological side effects ZonisamideSeizures Mood disorders Few studies Metformin Type 2 diabetes PCOS Rare liver toxicity Liraglutide. Exenatide Type 2 diabetes Injectable Pramlintide Injectable Pramlintide Injectable Strategy: Aim for Double Benefits when Possible

47 Medications Approved for Obesity Medication Average Weight Loss* Mechanism of Action Potential Side Effects Phentermine (short- term treatment) ~ 5% Adrenergic Tachycardia, hypertension Phentermine / Topiramate 10% Adrenergic, CNS Tachycardia, hypertension, cognitive dysfunction, neuropathy, teratogenicity Lorcaserin3.5% Serotonergic (5HT 2C ) Headache Orlistat3% Lipase inhibitor Steatorrhea, incontinence * Beyond placebo

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

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.

51 Clinical Application “Doctor, I know I need to reduce my calories and exercise more in order to lose weight. I have done it more times that I would like to admit. But I get hungry and its hard to stay on a calorie reduced diet. What is it about my metabolism that causes me to be so hungry?”

52 Woods, S. C. et al. J Clin Endocrinol Metab 2008;93:s37-s50 Model summarizing the 3 levels of control over energy homeostasis

53 Gut Peptides that Regulate Appetite Murphy KG, Bloom SR. Nature 2006;444:

54 Ghrelin Signals Hunger BR LUDI (24 hour clock) Ghrelin Level Adapted from Williams DL, Cummings DE. J Nutr 2005;135:

55 Gut peptides and regulation of appetite PeptideWhere synthesized Effect on feeding GhrelinStomachOrexigenic CCKDuodenumAnorexigenic PYYDistal small intestine Anorexigenic GLP-1Small intestineAnorexigenic AmylinPancreasAnorexigenic CCK = cholecystokinin; PYY = polypeptide YY; GLP-1 = glucagon-like peptide 1; [exenatide, liraglutide]; Amylin [pramlintide]

56 Woods, S. C. et al. J Clin Endocrinol Metab 2008;93:s37-s50 Model summarizing the 3 levels of control over energy homeostasis

57 Leptin is reduced in response to reduction in calories and weight loss; increasing appetite Wadden TA et al. J Clin Endocrinol Metab 1998;83: BDD = balanced deficit diet (1200 kcal/d week 2 – 20, then 1200 – 1800 kcal/d week 21 – 40) LCD = low calorie diet (1000 kcal/d week 2 – 13, 1200 kcal/d week 14-20, then 1200 – 1800 kcal/d weeks 21-40)

58 Woods, S. C. et al. J Clin Endocrinol Metab 2008;93:s37-s50 Model summarizing the 3 levels of control over energy homeostasis

59 Fat Cells ob gene ob gene Hypothalamus ob gene Anorexigenic CART POMC  MSH Orexigenic Neuropeptide Y Agouti-related protein Leptin Effector Signaling Molecules Adapted from: L. A. Campfield, F. J. Smith, P. Burn, Horm. Metab. Res. 28, 619 (1996); Endocrinol. Metab. 4, 81 (1997).

60 Neuron Populations in the ARC Suppress food intake POMC (proopiomelanocortin) CART (cocaine- and amphetamine- regulated transcript) Two neuron populations with opposing effects on food intake in the hypothalamic arcuate nucleus (ARC): Stimulate food intake NPY (neuropeptide Y) AgRP (agouti-related peptide) Suzuki K, Jayasena CN, Bloom SR. J Obes. 2011; 2011: doi: /2011/

61 The Pivotal Role of Leptin Leptin activation of neurons in the arcuate nucleus Leptin inhibits appetite through its actions on the appetite-stimulating neuropeptide Y (NPY) neurons and the appetite-inhibiting POMC neurons, located in the hypothalamic arcuate nucleus. Leptin inhibits the NPY/AgRP neurons by acting on its receptors and causing a decrease in the release of the inhibitory neurotransmitter GABA. This causes the POMC neurons to become free of inhibition and so they can increase their firing rate leading to the production of alpha MSH - an inhibitor of appetite. Leptin also acts directly on the POMC neurons. University of Edinburgh Increase hunger Reduce hunger

62 Hypothalamic Appetite Regulation Farooqi S. Cell Metab 2006;4: Increased hunger Reduced hunger

63 Clinical Application Are some cases of severe obesity due to defects in signaling and neuroregulation?

64 Farooqi et al. NEJM 341, 1999 A Case of Congenital Leptin Deficiency

65 Hypothalamic Appetite Regulation Farooqi S. Cell Metab 2006;4: % of subjects with severe early onset obesity had a LEPR mutation 6% children with severe obesity had a mutation in the MC4 receptor

66 Clinical Application Can we target some of these signals for pharmacological intervention?

67 Hypothalamic Appetite Regulation Farooqi S. Cell Metab 2006;4: Increased hunger Reduced hunger Adrenergic R Topiramate 5-HT 2c R

68 Clinical Application “But doctor, sometimes I get cravings that I can’t control. I’m not even hungry and I eat. I feel like I am addicted to food!”

69 Berthoud HR. Curr Opin Neurobiology 2011;21:

70 Regulation of Eating: Homeostatic versus Hedonic Signaling Pathways AN = arcuate nucleus. PVN = paraventricular nucleus, LHA = lateral hypothalamic area VTA = ventral tegmental areas, SN = substantia nigra, DS = dorsal striatum, NAc = nucleus accumbens Wang GJ et al. J Addict Med 2009;3:8-18

71 Activation of Regional Brain Areas by Visual Images of Foods Mehta S et al. Am J Clin Nutr 2012;96:

72 Key Learning Take Away’s from the Presentation The ‘ying-yang’ hypothalamic system is balanced between 2 primary neurons: NYP/AGRP (hunger) and POMC/CART (satiety) There are 2 peripheral signals that inform the brain about energy balance Satiation signals arise from gut hormones and indicate meal-to-meal hunger (ghrelin) and fullness (GLP-1, PYY) Adiposity signals arise from fat cells (leptin) and monitor longer-term energy balance Two new pharmacological agents (phentermine-topiramate and lorcaserin) act on the primary neurons to alter neurotransmission The hedonic signaling pathway is responsible to ‘liking or craving’ food

73 Results and Implications of Multicenter Trials Evaluating the Safety and Efficacy of Centrally Acting Agents as part of Multimodal Management for Obesity A Review of Metabolic Benefits, Side Effects, and Rationale for Achieving Moderate Weight Loss Through Drug Based Therapy March 2014 Louis J. Aronne, MD, FACP Sanford I. Weill Professor of Metabolic Research Weill Medical College of Cornell University Medical Director, Center for Weight Management and Metabolic Clinical Research New York Presbyterian Hospital New York, NY March 2014

74 Disclosures Ownership Interest: BMIQ Cardiometabolic Support Network Myos Corporation Zafgen, Inc. Board of Directors: Myos Corporation Jamieson Laboratories I am a consultant, speaker, advisor, or receive research support from: Aspire Bariatrics Amylin Pharmaceuticals Inc Arena Pharmaceuticals Eisai Inc. Ethicon Endo-Surgery Inc. GlaxoSmithKline Consumer Healthcare LP GI Dynamics High Point Pharmaceuticals LLC Medical University of South Carolina Novo Nordisk Pfizer Takeda Pharmaceuticals USGI VIVUS Inc. Zafgen Inc. As faculty of Weill Cornell Medical College, we are committed to providing transparency for any and all external relationships prior to giving an academic presentation.

75 Obesity Pharmacotherapy

76 An adjunct to lifestyle modification – not a substitute Can increase chances of meaningful weight loss 76

77 Anti-obesity Medications Rationale and Criteria Non-drug interventions should be attempted for at least 6 months before considering pharmacotherapy 1 For patients with BMI > 30 For patients with BMI > 27 or above with concomitant risk factors or diseases (hypertension, dyslipidemia, CHD, type 2 diabetes, sleep apnea) 1 1. NIH Clinical Guidelines Evidence Report, Sept

78 Lets think about for a minute: >120 drugs in 10 categories Up to triple drug combinations available Hypertension Treatment 78 Diuretics Beta-blockers ACE inhibitors Angiotensin II receptor blockers Calcium channel blockers Alpha blockers Alpha-2 Receptor Agonist Combined alpha and beta-blockers Central agonists Peripheral adrenergic inhibitors Source: L. Aronne

79 Potential Anti-obesity Drugs and Their Pathways Complex System with Redundancy-That’s Why It’s Hard to Lose Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi: /clpt Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways 79

80 Anti-obesity Drugs Presently on the Market and Pending Approval 80 Modified from Zhi-yun Zhang Z-y and Wang M-w. Acta Pharmacologica Sinica 2012;33:145–147. New! 90%!

81 Expected Weight Loss with Newly Approved and Investigational Anti-obesity Medications Modified from Powell AG, Apovian CM, Aronne LJ. Clin Pharmacol Ther Jul;90(1): Pending Pending for obesity

82 Recently Approved Pharmacotherapy *2 year extension data available Gadde KM, et al. Lancet. 2011;377: Garvey WT, et al. Am J Clin Nutr. 2012;95: Smith SR, et al. N Engl J Med. 2010;363: O’Neil PM, et al. Obesity. 2012;20:

83 Emerging Pharmacotherapy 83 Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors (The Light Study) ; Clinicaltrials.gov. Effect of Liraglutide on Body Weight in Non-diabetic Obese Subjects or Overweight Subjects With Co-morbidities: SCALE - Obesity and Pre-diabetes

84 Phentermine/Topiramate 2012

85 Indications Indications and Dose and Dose Approved by FDA, July 2012, schedule IV Indication Weight loss in pts with BMI ≥30 kg/m 2 or BMI ≥27 kg/m 2 with weight-related co-morbid condition(s) Treatment Dose Daily phentermine 7.5 mg topiramate ER 46 mg Max Dose Daily phentermine 15 mg topiramate ER 92 mg Phentermine/Topiramate ER Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; Mechanism of Action Phentermine Sympathomimetic amine, NE release Blunts appetite Topiramate Increases GABA activity, antagonize AMPA/ kainate glutamate receptor, carbonic anhydrase inhibitor Prolongs satiety Contraindications and Warnings Contraindications Pregnancy, glaucoma, hyperthyroidism, MAOIs Warnings Fetal toxicity Increased heart rate Suicide and mood and sleep disorders Acute myopia and glaucoma Cognitive impairment Metabolic acidosis Creatinine elevations Hypoglycemia with diabetes meds

86 Once-a-day, oral, extended release topiramate Low doses of previously approved medications to minimize side effects mg Topiramate ER 0 30mg (free base) Phentermine Maximum Approved Doses LowMidFull DOSING Begin with low dose for 2 wks phentermine 3.75/ topiramate ER Advance to treatment dose phentermine 7.5/ topiramate ER 46 If <3% weight loss after 12 wks, either discontinue or advance to full dose phentermine 15/ topiramate ER 92 (transition dose phentermine 11.25/ topiramate ER 69 for 2 wks) If <5% weight loss after 12 wks on full dose, discontinue (take every other day for one wk) DOSING Begin with low dose for 2 wks phentermine 3.75/ topiramate ER Advance to treatment dose phentermine 7.5/ topiramate ER 46 If <3% weight loss after 12 wks, either discontinue or advance to full dose phentermine 15/ topiramate ER 92 (transition dose phentermine 11.25/ topiramate ER 69 for 2 wks) If <5% weight loss after 12 wks on full dose, discontinue (take every other day for one wk) Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; Phentermine/Topiramate ER 86

87 SEQUEL Double-blind, placebo-controlled, three-arm, prospective study Extension of CONQUER Trial Same treatment as CONQUER study in a blinded fashion: either once-a-day treatment with 15 mg QNEXA (n=295), 7.5 mg QNEXA (n=153), or placebo (n=227) 108-week treatment period, all patients were advised to follow a simple lifestyle modification program including reduction of food intake by 500 calories per day Phentermine/ Topiramate Trials 87 EQUIP CONQUER

88 Effect of Phentermine/Topiramate ER on Weight Loss in Obese Adults Over 2 Years Garvey WT, et al. Am J Clin Nutr. 2012;95: % -10.5% -1.8% Data are shown with least squares mean (95% CI). SEQUEL Study Placebo Phentermine/topiramate CR 7.5/46 Phentermine/topiramate CR 15/92 88

89 Phentermine/Topiramate ER Improves Risk Factors and Manifestations of Cardiometabolic Disease CONQUER Study Changes from baseline to week 56 in secondary endpoints Gadde KM, et al. Lancet. 2011;377(9774):

90 Metabolic Effects of Phentermine/Topiramate ER in Non-Diabetic Patients: SEQUEL Study GlucoseInsulin *P≤0.005 vs placebo. Phen/TPM CR, phentermine/topiramate controlled release. * * * * * PlaceboPhen/TPM ER 7.5/46 mgPhen/TPM ER 15/92 mg * 90 Garvey WT, et al. Am J Clin Nutr. 2012;95:

91 Phentermine/Topiramate ER: EQUIP and CONQUER Most Commonly Reported Treatment Emergent Adverse Events Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus;

92 Summary of Phentermine and Topiramate Neuropsychiatric Safety No serious AEs related to depression, anxiety or cognition No increase in the risk of suicidality (C-SSRS*, PHQ-9**, and AE reporting) in a population where 20% had a prior history of depression Can be prescribed in patients with stable depression and patients on SSRIs *Columbia Suicide Severity Rating Scale ** Patient Health Questionnaire 9-item depression scale 92 Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012.

93 Phentermine/Topiramate ER REMS Program FDA Pregnancy Category X: Contraindicated Topiramate monotherapy for epilepsy in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts Risk Evaluation and Mitigation Strategy (REMS) Inform patients about increased risk of orofacial clefts, in infants exposed to phentermine/ topiramate during the first trimester of pregnancy Importance of contraception in women of child- bearing potential and pregnancy checks Need to discontinue phentermine/topiramate immediately if pregnancy occur Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; Phentermine and topiramate extended-release capsules CIV Healthcare Provider Training Program. Vivus; 08/

94 Lorcaserin 2012

95 Lorcaserin Lorcaserin hydrochloride [package insert]. Woodcliff Lake, NJ: Eisai Inc.; Mechanism of Action Selective 5-HT2C receptor agonist Stimulates α-MSH production from POMC neurons resulting in activation of MC4R Increases satiety Indications and Dose Approved by FDA June 2012 Indication: Weight loss in patients with BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with weight-related co- morbid condition(s) 10 mg po bid Schedule IV Discontinue if 5% weight loss is not achieved in 12 wks Contraindications and Warnings Contraindications Pregnancy Warnings Co-administration with other serotonergic or anti-dopaminergic agents Valvular heart disease Cognitive impairment Psychiatric disorders (euphoria, suicidal thoughts, depression) Priapism Risk of hypoglycemia with diabetes meds

96 96 Increase in serotonin bioavailability (due to food intake or pharmacological compounds such as sibutramine and fenfluramine) or direct agonism of 5HT2CRs and 5HT1BRs modulates firing of POMC/CART and AgRP NPY neurones within the arcuate nucleus of the ARC Anorectic POMC neurones expressing 5HT2CR depolarize on receptor activation and release α- melanocyte-stimulating hormone (α-MSH), which in turn activates second-order melanocortin 4 receptor (MC4R) expressing neurones, principally within the paraventricular nucleus of the hypothalamus (PVH; Balthasar et al. 2005) Concomitant activation of 5HT1BRs expressed on orexigenic AgRP/NPY neurones within the ARC causes membrane hyperpolarization and subsequent inhibition of neuropeptide release Inhibitory 5HT1BR activation also attenuates inhibitory postsynaptic currents onto POMC/CART neurones further potentiating anorexigenesis Subsequent downstream neuroendocrine signalling promotes satiety and the cessation of food intake Garfield A S, and Heisler L K. J Physiol. 2009;587: Proposed Model of a Serotonergic Pathway Modulating Food Intake

97 Lorcaserin Phase 3 Trials n=3,182 2 years tx Dosage 10 mg QD 1 1.Smith SR, et al. N Engl J Med 2010;363: Fidler MC, et al. J Clin Endocrinol Metab, October 2011, 96(10):3067– O’Neil PM, et al. Obesity (16 March 2012) | doi: /oby Arena Pharmaceuticals n=4,008 1 year tx Dosage 10 mg QD 2 n=604 obese/ overweight with type 2 DM 1 year+ tx Dosage 10 mg BID or 10 mg QD 3 97

98 Lorcaserin: Those Who Lost ≥ 4.5% Total Body Weight by Week 12 Were Week 52 Responders Studies 009 and 011, MITT % STOP -2.46% Responder: Lorcaserin BID Non-responder: Lorcaserin BID Slide courtesy Dr. Steve Smith; May 10, 2012 FDA Advisory Committee Meeting 98

99 Lorcaserin ─ BLOOM Study: Key Secondary Endpoints Intention-to-Treat Analysis with LOCF Imputation 99 Smith SR, et al. NEJM. 2010;363:

100 Randomized Placebo ‐ Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 DM BLOOM ‐ DM Study - HbA 1c O’Neil PM, et al. Obesity (Silver Spring) Jul;20(7):

101 101 Randomized Placebo ‐ Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 DM BLOOM ‐ DM Study Weight Loss O’Neil PM, et al. Obesity (Silver Spring) Jul;20(7):

102 Lorcaserin: Adverse Events Reported by >5% in Any Group 102 Smith SR, et al. NEJM. 2010;363: Intention-to-Treat Analysis with LOCF Imputation

103 Naltrexone SR/Bupropion Target of

104 Naltrexone/Bupropion Mechanism of Action –Naltrexone ─ Opioid receptor antagonist –Bupropion ─ Dopamine/noradrenaline reuptake inhibitor Approved by FDA committee but FDA did not approve until a CVD outcome study is performed due to concerns about blood pressure and pulse in some patients The Light Study (CVD outcomes) is under way; estimated completion: July 2017 Apovian C, et al. Obesity Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors (The Light Study)

105 Mean Weight Loss Greenway FL, et al. Lancet 2010 Aug 21; 376:595. DOI: /S (10) Naltrexone/ Bupropion 56 Weeks – Completer Population COR-I Phase 3 105

106 A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II) Apovian CM, Aronne L, et al. Obesity (Silver Spring) May;21(5): Naltrexone SR / Bupropion SR Phase 3 Trial (COR-II) 106

107 Improvement in risk factors with use of Naltrexone SR / Bupropion SR 107 Apovian CM, Aronne L, et al. Obesity (Silver Spring) May;21(5):

108 Side Effects Most frequent events: –Nausea N=171 (29.8%) naltrexone 32 mg plus bupropion N=155 (27.2%) naltrexone 16 mg plus bupropion N=30 (5.3%) placebo –Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups vs. placebo –Transient increase of ~1·5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups –Combination treatment was not associated with increased depression or suicides vs. placebo Naltrexone/Bupropion Greenway FL, et al. Lancet Aug 21;376(9741): PMID:

109 Liraglutide 2010 for Type 2 DM for anti-obesity

110 Liraglutide Glucagon-Like Peptide 1 (GLP-1) receptor agonist approved in 2010 for treatment of type 2 diabetes (1.8 mg/day) Appetite effect mediated by both the activation of GLP-1 receptors expressed on vagal afferents and hypothalamus Affects visceral fat adiposity, appetite, food preference, and cardiovascular biomarkers in patients with type 2 diabetes Suppresses appetite, and delays gastric emptying Phase III trials assessing effects of doses as high as 3.0 mg/day submitted to FDA 110

111 Effects of Liraglutide and Orlistat on Body Weight in Nondiabetic Obese Adults Data are mean (95% CI) for the ITT population 111 Astrup A, et al. Lancet Nov 7;374(9701):

112 Liraglutide Weight Loss: One Year 112 Supplementary Information Table 3: Mean changes in body weight Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.

113 Liraglutide Weight Loss: Two Years 113 Liraglutide 3.0 mg for 1 year (and then maintained on 2.4/3.0 mg for the second year) maintained a mean weight loss of 10.3±7.1 kg from screening over 2 years 3.0 mg 10.3±7.1 kg weight loss Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.

114 Generally well tolerated and improved quality of life Adverse events mostly mild or moderate Gastrointestinal events (particularly nausea and vomiting), consistent with the known physiological effects of GLP-1, were more frequent than with placebo At year 1, nausea and/or vomiting was associated with greater weight loss with liraglutide 3.0 mg, but even those who did not experience these events lost more weight than those on placebo or orlistat Injection regimen did not impair adherence or cause significant withdrawal during treatment or run-in Liraglutide: Adverse Events 114 Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.

115 Obesity Drugs in the Pipeline Beloranib

116 N=19 obese women Mean BMI 38 kg/m 2 Dosage at 0.9 mg/m 2 associated with a 42% reduction in triglycerides 18% reduction in LDL-cholesterol –Improvement in C-reactive protein and reduced sense of hunger Most frequent AE’s: headache, infusion site injury, nausea, and diarrhea Nausea and infusion site injury occurred more with beloranib vs placebo Loss of venous access most common reason for discontinuation Beloranib: Phase 1 Trial Results – 4 weeks 116 Fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor Hughes TE, et al. Obesity (Silver Spring) Mar 20. doi: /oby [Epub ahead of print] No evidence of major tolerability or safety issues (Phase 1 trials)

117 Completers: n=19 Mean BMI 37.9 kg/m 2 Administered through subcutaneous injections 2x weekly over 12 weeks Patients ate normally; not counseled to change exercise habits Beloranib-patients showed improvements in cardiometabolic risk factors including reduced triglycerides, LDL cholesterol and C-reactive protein (an inflammatory marker) versus placebo Beloranib: Phase 2 Trial Interim Analysis - 12 Weeks 117 Fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor ADA Poster Session 19-B Abstract #188-LB June 22, 2013 No evidence of major tolerability or safety issues (Phase 1 trials)

118 Anti-obesity Medications in Development Kim GW, et al. Clin Pharmacol Ther Oct 8. doi: /clpt [Epub ahead of print] 118

119 Few choices of anti-obesity medications Two new medications approved in 2012 Two more are pending approval Medications can enhance weight loss for select candidates and improve cardiometabolic outcomes Medications are always only adjunct to diet and exercise When we have more medications, we will treat obesity more frequently. Summary 119

120 Case Based Learning, Front-Line Practice Strategies, and Real World Implementation of Obesity Management in the Primary Care Setting When, In Whom, Why, and How to Treat Obesity New Perspectives and Emerging Treatment Paradigms Ken Fujioka, MD – Program Co-Chair Director, Nutrition and Metabolic Research Center | Director, Center for Weight Management | Scripps Clinic in San Diego, CA Director, Nutrition and Metabolic Research Center | Director, Center for Weight Management | Scripps Clinic in San Diego, CA

121 Case Study 1 Metabolically Healthy Obese ► 43-year-old male accountant ● 6 feet tall, weight 225 pounds ● Gained about 35 pounds after college (played basketball in college) ● Still plays recreational basketball and lifts weights ● Wants to lose weight so he can dunk a basketball ● And his much younger wife sent him in for his snoring ● No known medical problems

122 Case Study 1 Physical Exam  BP: 124/72 Pulse 74 ► BMI = 30 ► Waist is 35 inches ► ENT: normal ● Upper airway looks OK maybe a little narrowed ► Skin normal ► The rest of the exam is completely normal ► What tests do you order?

123 Which test is not needed in the work up of the obese male ? 1)Comprehensive metabolic panel 2)Thyroid function 3)Overnight oximetry 4)Total testosterone 5)A1c 6)Lipids 7)Vitamin D level (25 OH) Case Study 1 - Question 1 Please Enter Your Response On Your Keypad

124 Case Study 1 The Basketball Player ► Comprehensive metabolic panel ● Completely normal ● Fasting glucose 84 ● TSH 2.8 normal ● Total testosterone 402 ● Lipids all with in normal parameters ► Overnight oximetry : Sleep apnea work up ● Normal

125 Which lipid parameter has very little improvement with weight loss? 1)Triglycerides 2)LDL 3)HDL 4)All lipid parameters are dramatically improved with weight loss and made worse by obesity Case Study 1 - Question 2 Please Enter Your Response On Your Keypad

126 Classify or stage the severity of this patient’s obesity: 1)Stage 0 2)Stage 1 3)Stage 2 4)Stage 3 5)Stage 4 Case Study 1 - Question 3 Please Enter Your Response On Your Keypad

127 What would be the best treatment option for this patient? 1)Do nothing and reassure him he is healthy 2)Diet and lifestyle modification 3)Medications plus diet and lifestyle 4)Bariatric surgery Case Study 1 - Question 4 Please Enter Your Response On Your Keypad

128 Case Study 2 Hispanic Male ► 46-year-old Hispanic male born and raised in Florida ► Presents for his annual physical ● Not good about getting an annual physical but got moved up to a vice president job and needs a physical for life insurance ► BMI is 27 ► No history of medical problems ► He has no complaints and feels great

129 ► BMI 27 ► Waist 38 inches ► Fasting blood sugar 104 ► A1c 5.9 ► Lipids ● TGs 289 ● HDL 27 ● LDL 109 ► The rest of his labs are all normal Case Study 2 Hispanic Male

130 Does this patient meet the definition of obesity ? 1.No (not obese just overweight) 2.Yes (obese) 3.It depends on what which definition of obesity you use (International vs. American) 4.It depends on what country you are in Case Study 2 - Question 1 Please Enter Your Response On Your Keypad

131 Classify or Stage the severity of this patient’s obesity: 1)Stage 0 2)Stage 1 3)Stage 2 4)Stage 3 5)Stage 4 Case Study 2 - Question 2 Please Enter Your Response On Your Keypad

132 What would be the best treatment option for this patient? 1)Do nothing and reassure him he is healthy 2)Diet and lifestyle modification 3)Medications plus diet and lifestyle 4)Bariatric surgery Case Study 2 - Question 3 Please Enter Your Response On Your Keypad

133 Which medications would you consider ? 1)Metformin 2)Orlistat 3)Lorcaserin 4)Phentermine/Topiramate ER 5)Phentermine Case Study 2 - Question 4 Please Enter Your Response On Your Keypad

134 Case Study 3 ► 37-year-old newly married Caucasian female ► Has known polycystic ovarian syndrome ► Told by her Ob-gyn to lose weight to improve her chances of getting pregnant ► The patient specifically asks for a “weight loss” medication to kick start her weight loss ► She also wants her thyroid tested and says a doctor in the past gave her thyroid meds

135 Case Study 3 PCO Patient ► BMI 34 ► Skin: acne scars with 6 inflammatory acne lesions on the face ► Hair: some lose on the scalp ► Waist 44 inches ► A1c 6.5 ► Fasting glucose 138 ► TSH is normal (1.8) and not on thyroid replacement

136 Classify or stage the severity of this patient’s obesity: 1)Stage 0 2)Stage 1 3)Stage 2 4)Stage 3 5)Stage 4 Case Study 3 - Question 1 Please Enter Your Response On Your Keypad

137 Should you start thyroid replacement therapy? 1)Give her low dose replacement since she was on it before 2)Her TSH is normal and she does not need replacement 3)Give her low dose replacement as she will need more thyroid hormone when she is pregnant Case Study 3 - Question 2 Please Enter Your Response On Your Keypad

138 What would be the best treatment option for this patient? 1)Do nothing and reassure the patient she is healthy 2)Diet and lifestyle modification 3)Medications plus diet and lifestyle 4)Bariatric surgery Case Study 3 - Question 3 Please Enter Your Response On Your Keypad

139 Which diabetic medications would you consider ? 1) 1)Metformin 2)Sulfonylurea 3) 3)DPP-4 inhibitor 4) 4)GLP-1 5) inhibitor 5)SGLT-2 inhibitor 6)Pioglitazone 7)Insulin Case Study 3 - Question 4 Please Enter Your Response On Your Keypad

140 Which weight loss medication would you consider ? 1)1. Orlistat 2)2. Phentermine 3)3. Phentermine/topiramate ER 4)4. Lorcaserin Case Study 3 - Question 5 Please Enter Your Response On Your Keypad

141 Case Study 4 ► 55-year-old morbidly obese male ► Had a myocardial infarction 8 months ago and is finishing up cardiac rehab ► No CHF and had a CABG with excellent results ► Has bilateral degenerative joint disease and the orthopedic surgeon will not operate until he loses weight ► Due to his weight and knees he now has trouble just walking from room to room ● Can’t go up and down stairs

142 Case Study 4 Morbidly Obese Male ► BMI 51 ► BP: 124/82 ; pulse 80 ► Very narrowed upper airway (pharynx) ► + 2 pitting edema of the lower legs ► Mood is depressed ► Everything else normal ► Labs all normal (normal blood sugar) ► Lipids very well controlled

143 Patient is on the following medications: which medication will make weight loss more difficult 1)HCTZ 2)ARB 3)Beta-blocker 4)Metformin Case Study 4 - Question 1 Please Enter Your Response On Your Keypad

144 Classify or stage the severity of this patient’s obesity: 1)Stage 0 2)Stage 1 3)Stage 2 4)Stage 3 5)Stage 4 Case Study 4 - Question 2 Please Enter Your Response On Your Keypad

145 What would be the best treatment option for this patient? 1)Do nothing and reassure him he is healthy 2)Diet and lifestyle modification 3)Medications plus diet and lifestyle 4)Bariatric surgery Case Study 4 - Question 3 Please Enter Your Response On Your Keypad

146 Case Study 5 ► 48-year-old depressed female ► Peri-menopausal ► Wants to lose weight to feel better about herself ● “ I am depressed about being fat” ► I follow a gluten free diet and exercise 1 to 2 hours a day and can’t lose weight ► It has to be my thyroid or some hormonal problem

147 Case Study 5 Obese Peri-menopausal Female ► Medications: 30 mgs paroxetine ► No health problems ► BMI 32 ► Labs ● TSH 1.3 (WNLs) ● Lipids normal ● Glucose normal

148 Classify or stage the severity of this patient’s obesity Case Study 5 - Question 1 Please Enter Your Response On Your Keypad 1)Stage 0 2)Stage 1 3)Stage 2 4)Stage 3 5)Stage 4

149 What would be the best treatment option for this patient? 1)Do nothing and reassure her she is healthy 2)Diet and lifestyle modification 3)Medications plus diet and lifestyle 4)Bariatric surgery Case Study 5 - Question 2 Please Enter Your Response On Your Keypad

150 Which medication changes would you consider ? 1)Wean off paroxetine 2)Start bupropion 3)Orlistat 4)Lorcaserin 5)Phentermine/topiramate ER 6)Phentermine Case Study 5 - Question 3 Please Enter Your Response On Your Keypad

151 Case Study 6 ► A 49-year-old female with severe obesity presents for assistance with weight loss ● T2DM x 4 years Metformin 500 mg BID, liraglutide 1.8 mg sc q d Metformin 500 mg BID, liraglutide 1.8 mg sc q d ● Hypertension Losartan 100 mg q d, diltiazem 360, chlorthalidone 50 mg q d Losartan 100 mg q d, diltiazem 360, chlorthalidone 50 mg q d ● Hyperlipidemia Simvastatin 20 mg q d Simvastatin 20 mg q d ● GERD Lansoprazole 30 mg q d Lansoprazole 30 mg q d ● OSA – nightly CPAP ● Arthralgias of knees

152 Case Study 6 ► Weight history ● Overweight since high school followed by progressive, ratcheting weight gain since entering the work force to highest weight of 340 lbs. ● Attributes obesity to work and family stress, and providing care to family members ● Previously participated in commercial programs (Jenny Craig and Weight Watchers) and saw RD when she was diagnosed with T2DM ► Social history ● Single, living with brother and Labrador retriever ‘Bear’, works as quality assurance analyst for BCBS

153 ► Diet history ● Skips breakfast, first meal at 11:00 AM is left-overs or fast food. Second meal is 6:30 PM, either fast food or easy prep foods [although appetite reduced since starting on liraglutide, selection of foods and portions have not changed]. ► Physical activity history Limited to ADLs. Has stationary bike and treadmill in home but seldom used Limited to ADLs. Has stationary bike and treadmill in home but seldom used Case Study 6

154 ► Examination ● Weight 352 lbs, height in, BMI 52.1 kg/m 2 ● BP 128/62, HR 92 ● Heart – Grade 2/6 SEM ● Extremities – dystrophic skin changes, 1+ edema ► Labs ● Glucose 95 mg/dl, HbA1c 6.5% ● BUN 19 mg/dl, eGFR 73 ml/min/1.73 ● TC 152 mg/dl, LDLc 70 mg/dl, HDLc 46, TG 181 mg/dl Case Study 6

155 What would you recommend regarding weight management? 1)Refer to commercial program 2)Refer to registered dietitian 3)Initiate lifestyle counseling yourself 4)One of the above + pharmacotherapy 5)Refer for bariatric surgery Case Study 6 - Question 1 Please Enter Your Response On Your Keypad

156 Case Study 6 RD Visit ► Further assessment ● Brother does the grocery shopping – will not buy healthier foods since he believes it is too expensive ● Eats out often, choosing fast foods ● Eats out of boredom and anxiety ► Counseling ● Make small changes, do not skip breakfast ● Track diet [patient response “is not going to happen”] ● Healthy ‘budget conscious’ items ● Snack and meal ideas

157 Case Study 6 Follow Up at 7 Weeks ► Implemented some changes from RD visit: not skipping meals, less ‘junk food’ ► 6 lbs. weight loss initially, no change in past 3 weeks. ► Went to bariatric surgery seminar at my request but considers surgery a ‘mutilation’ and is not interested ► Perceives lifestyle changes to be very hard. Difficult of focus on self-care and is feeling pessimistic

158 Weight Graph from EHR

159 What would your approach be at this time? 1)Stay the course and reinforce importance of adherence 2)Refer to mental health professional 3)Prescribe a very-low-calorie diet (VLCD) to reduce caloric intake further 4)Emphasize need to start an exercise program 5)Initiate pharmacotherapy 6)Revisit her negative view of bariatric surgery Case Study 6 - Question 2 Please Enter Your Response On Your Keypad

160 Rationale for Prescribing Anti-Obesity Medications ► Weight loss, and maintenance of lost weight, is difficult for many patients ► The primary function of anti-obesity medication is to assist with weight loss and maintenance of lost weight by reducing hunger and/or increasing satiety, thus allowing patients to follow a calorie- reduced diet with more resolve *an anti-obesity medication may have independent effects, e.g., orlistat on LDLc, liraglutide on glucose

161 Case Study 6 Follow Up ► The addition of pharmacotherapy was discussed and patient’s attitudes assessed. ► Use and side effects of phentermine/topiramate ER were discussed and asked her to review the company website [lorcaserin was not available at the time] ► Patient elected to try medication and a prescription was provided

162 Weight Graph from EHR 46 lbs = 14%

163 Case Study 6 Biomarkers ValueBaseline 3 months 7 months 10 months 14months Weight, lbs, (% wt loss) (6.6%) 290 (10.7%) 282 (13.2%) 280 (13.8%) (13.8%) Glucose, mg/dl HbA1c, % TC, mg/dl LDL-c, mg/dl HDL-c. mg/dl TG, mg/dl

164 New Perspectives and Emerging Treatment Paradigms for Individualizing Obesity Management Optimizing Weight Loss in the Primary Care Setting: Where Are We Now, and Where Are We Going? Lee M. Kaplan, MD, PhD Obesity, Metabolism & Nutrition Institute Massachusetts General Hospital Harvard Medical School April 11, 2014

165 What is Obesity? The presence and severity of obesity can be estimated by a variety of biomarkers The presence and severity of obesity can be estimated by a variety of biomarkers Body mass index (BMI) Body mass index (BMI) Body composition Body composition Body fat distribution Body fat distribution Risk scores Risk scores Comorbidities Comorbidities But these markers should not define obesity But these markers should not define obesity Excessive fat accumulation that presents a risk to health

166 Calling it a disease would define one-third of Americans as being ill and could lead to more reliance on costly drugs and surgery rather than lifestyle changes Calling it a disease would define one-third of Americans as being ill and could lead to more reliance on costly drugs and surgery rather than lifestyle changes Some people might be overtreated because their BMI was above a line designating them as having a disease, even though they were healthy Some people might be overtreated because their BMI was above a line designating them as having a disease, even though they were healthy Why Obesity is NOT a Disease It is a lifestyle choice It is a lifestyle choice No specific symptoms associated with it No specific symptoms associated with it It is a risk factor for disease, not a disease itself* It is a risk factor for disease, not a disease itself* * What about high cholesterol or hypertension?

167 Why Obesity IS a Disease It is associated with impaired body function It is associated with impaired body function Like other diseases, it results from physiological dysfunction (precipitated by numerous forces in modern society) Like other diseases, it results from physiological dysfunction (precipitated by numerous forces in modern society) It causes, exacerbates or accelerates more than 65 significant comorbid diseases It causes, exacerbates or accelerates more than 65 significant comorbid diseases It is associated with a substantial burden of morbidity and premature death It is associated with a substantial burden of morbidity and premature death

168 Obesity Complications – Targets of Therapy Diabetes Diabetes Hypertension Hypertension Hyperlipidemia Hyperlipidemia Fatty liver disease Fatty liver disease Sleep apnea Sleep apnea GERD GERD Arthritis Arthritis Inflammatory and autoimmune diseases Inflammatory and autoimmune diseases Cancer (12 types) Cancer (12 types) Cognitive dysfunction Cognitive dysfunction

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

170 There is broad variability in the weight loss response to ALL therapies for obesity The Heterogeneity of Obesity Core Principle of Obesity Treatment Lifestyle interventions Medications Surgery

171 Weight Loss Variability after Gastric Bypass Bessler et al., 2008

172 Weight Loss Variability after Gastric Banding

173 Adapted from Hansen DL et al., IJO 2001; 25:496 Responder Tail Sibutramine-induced Weight Loss Weight Loss Variability with Sibutramine

174 Lorcaserin-induced Weight Loss % Weight Loss % of Patients Weight Loss Variability with Lorcaserin

175 Weight Loss Variability on Different Diets Atkins Diet Zone Diet LEARN Program Ornish Diet Weight Change No. of Subjects Adapted from Gardner et al, JAMA 2007

176 Wide variability in therapeutic response is best explained by clinically important subtypes

177 Prader- Willi syndrome Bardet-Biedl syndrome Alström syndrome Hypothalamic Hyperphagic Thermogenesis deficient Circadian-disrupted Stress-induced Central Peripheral Diffuse Neonatal Early childhood Peripubertal Gestational Menopausal “Healthy” Metabolic Inflammatory The Obesities – A Plethora of Discrete Disorders Multiple Subtypes = Variation in Treatment Response Leptin deficiency LepR deficiency MC4R deficiency MSH deficiency Sim-1 deficiency PC-1 deficiency KSR2 deficiency MRAP2 deficiency SH2B1 deficiency BDNF deficiency trkB deficiency Carpenter syndrome Cohen syndrome Ayazi syndrome MOMO syndrome Rubenstein-Taybi syndrome Fragile X syndrome BFL syndrome Albright osteodystrophy Diet-dependent Exercise-sensitive Sleep-sensitive Insulin-induced Steroid-induced Progesterone-induced Psychotropic-induced Antibiotic-induced Endocrine disruptor Phentermine-responsive Lorcaserin-responsive Topiramate-responsive Metformin-responsive Bupropion-responsive GLP-1 responsive Bypass-responsive Bypass-resistant Gastric band-responsive

178 What Differs Among Different Obesity Subtypes Timing of obesity onset Fat location and distribution Metabolic consequences Phenotypic differences Hunger Satiety Reward-based eating Energy expenditure Response to environmental causes Eating Exercise Stress Sleep deprivation Circadian disruption Response to therapies

179 Weight Loss 0 Number of Subjects Heterogeneity of Response Highly responsive subgroup

180 Conclusions Obesity IS a disease, regardless of its designation Obesity IS a disease, regardless of its designation There are implications (to all of us) of thinking about it this way There are implications (to all of us) of thinking about it this way Physiologically based therapies Physiologically based therapies Heterogeneity of cause Heterogeneity of cause Variable treatment response Variable treatment response Opportunity to benefit selected subpopulations – value of predictive markers Opportunity to benefit selected subpopulations – value of predictive markers Attitudes about obesity underlie the major barriers to its treatment Attitudes about obesity underlie the major barriers to its treatment Education and (evidence-based) participation by all stakeholders is the key to ultimate success Education and (evidence-based) participation by all stakeholders is the key to ultimate success

181 Take-home Messages Obesity Treatment Lifestyle adjustment is the mainstay of therapy Lifestyle adjustment is the mainstay of therapy Medications can be effective Medications can be effective In selected patients In selected patients Medications work differently in different patients – requires ‘trial and error’ approach Medications work differently in different patients – requires ‘trial and error’ approach Combination therapies look particularly promising Combination therapies look particularly promising

182 Go Slow and Try Different Approaches Test therapies sequentially Test therapies sequentially Pursue combination therapies – including combinations of specific lifestyle changes with more classical medical approaches Pursue combination therapies – including combinations of specific lifestyle changes with more classical medical approaches Be supportive Be supportive Be persistent Be persistent Be there for the patient Be there for the patient Practical Guidance Aim for “cure,” but always provide care.

183 Why is all this so important? The current standard of care for obesity is: The current standard of care for obesity is:0 For ultimate success, this needs to change For ultimate success, this needs to change Ignoring obesity needs to become no more acceptable than ignoring other disorders Ignoring obesity needs to become no more acceptable than ignoring other disorders There needs to be incentive to embrace obesity treatment There needs to be incentive to embrace obesity treatment

184 A Call to Action Determine BMI at each visit Determine BMI at each visit Counsel patients with obesity on the risks of excess weight and the benefits of weight loss Counsel patients with obesity on the risks of excess weight and the benefits of weight loss Identify the medical comorbidities of obesity in each patient Identify the medical comorbidities of obesity in each patient Pursue a step-wise strategy for weight loss – lifestyle, medications and surgery as needed Pursue a step-wise strategy for weight loss – lifestyle, medications and surgery as needed Help patients maintain weight loss by optimizing the patients lifestyle – healthy diet, regular exercise, adequate sleep, stress reduction Help patients maintain weight loss by optimizing the patients lifestyle – healthy diet, regular exercise, adequate sleep, stress reduction 184

185 Why is weight regain after dieting so common? 1.Exercise, not diet, is the most effective means of losing weight 2.The body reacts to weight loss by decreasing daily energy expenditure 3.Diet foods are boring and patients stop eating them 4.Dieting increases the body’s set point for fat mass 5.Weight loss often leads to unwanted effects that cause patients to sabotage their efforts Please Enter Your Response On Your Keypad Question 1

186 Which of the following is NOT a demonstrated benefit of modest regular exercise? 1.Enhances weight loss effect of other lifestyle changes 2.Causes weight loss directly 3. Alters appetite to favor healthier foods 4. Stimulates fat to burn more calories 5. Decreases cardiovascular risk Please Enter Your Response On Your Keypad Question 2

187 Which of the following comorbidities of obesity has NOT been shown to improve with modest (5-10%) weight loss? 1.Type 2 diabetes 2.Hypertension 3.Dyslipidemia 4. Cardiovascular risk 5. Fatty liver disease Please Enter Your Response On Your Keypad Question 3

188 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? 1.<10% 2.~25% 3. ~50% 4. ~75% 5. >90% Please Enter Your Response On Your Keypad Question 4

189 Which of the following medications is NOT currently approved by the FDA for the treatment of obesity? 1. Orlistat 2. Liraglutide 3. Phentermine 4. Lorcaserin 5. Phentermine / Topiramate ER combination Please Enter Your Response On Your Keypad Question 5

190 Which of the following weight loss medications do NOT work through central nervous system mechanisms? 1. Bupropion 2. Lorcaserin 3. Liraglutide 4. Topiramate ER 5. Phentermine Please Enter Your Response On Your Keypad Question 6

191 Which of the following is NOT a primary mechanism of weight loss from centrally- acting weight loss medications? 1.Change in food preferences 2.Decrease in appetite 3.Increase in resting and post-meal energy expenditure 4.Demonstrating the value of a healthier weight to the patient 5.Lower physiologically defended body weight Please Enter Your Response On Your Keypad Question 7

192


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