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

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

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

Welcome and Program Overview
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.

Distinguished Faculty
Program Co-Chairman Lee M. Kaplan, MD, PhD Associate Professor of Medicine Harvard Medical School Director, Obesity, Metabolism & 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 Program Co-Chairman Ken Fujioka, MD Director, 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 4

COI Disclosures 5 Faculty Member Relationship Corporation/Manufacturer
Kenneth Fujioka, MD Consultant: 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, PhD Scientific Advisor: Grant/Research: Ethicon, Astra Zeneca, Eisai, GI Dynamics, MedImmune, Novo Nordisk, Rhythm, Takeda, Vivus, Zafgen Ethicon Robert F. Kushner, MD Novo Nordisk, Vivus, Retrofit Weight Watchers, Aspire Bariatrics Louis J. Aronne, MD 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 5

Ken Fujioka, MD – Program Co-Chair
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

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

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):

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.

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

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

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

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:

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

Treatment Options 2012 Diet Exercise Phentermine Orlistat
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

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

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 Phentermine/topiramate patient should lose 3% by 3 months or 5% by 6 months

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

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)

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

Treating Patients with Obesity: Who, Why, How and to What Ends
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 April 11, 2014

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

Why is weight regain after dieting so common?
Question 1 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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

Please Enter Your Response On Your Keypad
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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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% Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

Question 6 Which of the following weight loss medications do NOT work through central nervous system mechanisms? Bupropion Lorcaserin Liraglutide Topiramate ER Phentermine Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

Question 7 Which of the following is NOT a 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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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

Complications of Obesity
Psychological Neoplastic Inflammatory Structural Metabolic Degenerative 65

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 Depression Eating disorders and Psychological many psychotropic agents cause weight gain Psychological Neoplastic Inflammatory Structural Metabolic Degenerative

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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case The effect on cardiovascular risk is less clear

Relationship Between BMI and Risk of Type 2 Diabetes
9108 Module 1.ppt Relationship Between BMI and Risk of Type 2 Diabetes 4/8/2017 5:15 AM 93.2 Men Women 54.0 Age-Adjusted Relative Risk 42.1 40.3 27.6 21.3 15.8 8.1 4.3 5.0 11.6 2.9 2.2 6.7 4.4 Relationship between BMI and risk of type 2 diabetes The risk of diabetes increases with increasing BMI values in men and women [1,2]. Moreover, the age-adjusted relative risk for diabetes begins to increase at BMI values that are considered normal for men (24 kg/m2) and women (22 kg/m2) based on mortality risk. The marked increase in the prevalence of obesity is an important contributor to the 25% increase in the prevalence of diabetes in the United States over the last 20 years [3]. Increases in abdominal fat mass, weight gain since young adulthood, and a sedentary lifestyle are additional obesity-related risk factors for diabetes [1,4,5]. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995;122: Chan JM, Rimm EB, Colditz GA, et al. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17: Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, Diabetes Care 1998;21: Ohlson LO, Larsson B, Svardsudd K, et al. The influence of body fat distribution on the incidence of diabetes mellitus. Diabetes 1985;34: Helmrich SP, Ragland DR, Leung RW, Paffenbarger Jr RS. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325: 1.0 1.0 1.5 1.0 <22 <23 23-24 24-25 25-27 27-29 29-31 31-33 33-35 >35 Body Mass index (kg/m2) Chan J et al. Diabetes Care 1994;17:961. Colditz G et al. Ann Intern Med 1995;122:481. MSB

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

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

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

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

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

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

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

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

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

Pharmacological Therapies

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

Weight Loss from Other Medications
Strategy: Aim for Double Benefits when Possible Medication Indicated Uses Comments Bupropion Depression Avoid in bipolar disease Topiramate Seizures Migraines Mood disorders May produce neurological side effects Zonisamide Few studies Metformin Type 2 diabetes PCOS Rare liver toxicity Liraglutide. Exenatide Injectable Pramlintide

Medications Approved for Obesity
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 Lorcaserin 3.5% Serotonergic (5HT2C) Headache Orlistat 3% Lipase inhibitor Steatorrhea, incontinence * Beyond placebo

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

Foundational Role of the Central Nervous System in Appetite Regulation
Robert Kushner, MD, FACP Professor of Medicine Northwestern University Feinberg School of Medicine

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.

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?”

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

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

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

Gut peptides and regulation of appetite
Where synthesized Effect on feeding Ghrelin Stomach Orexigenic CCK Duodenum Anorexigenic PYY Distal small intestine GLP-1 Small intestine Amylin Pancreas CCK = cholecystokinin; PYY = polypeptide YY; GLP-1 = glucagon-like peptide 1; [exenatide, liraglutide]; Amylin [pramlintide]

Leptin is reduced in response to reduction in calories and weight loss; increasing appetite
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) Wadden TA et al. J Clin Endocrinol Metab 1998;83:

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

Neuron Populations in the ARC
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) Suppress food intake POMC (proopiomelanocortin) CART (cocaine- and amphetamine-regulated transcript) Suzuki K, Jayasena CN, Bloom SR. J Obes. 2011; 2011: doi: /2011/

The Pivotal Role of Leptin
Reduce hunger Increase hunger 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

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

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

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

3% of subjects with severe early onset obesity had a LEPR mutation 6% children with severe obesity had a mutation in the MC4 receptor Farooqi S. Cell Metab 2006;4:

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

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

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!”

Berthoud HR. Curr Opin Neurobiology 2011;21:888-896

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

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

Key Learning Take Away’s from the Presentation
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 The ‘ying-yang’ hypothalamic system is balanced between 2 primary neurons: NYP/AGRP (hunger) and POMC/CART (satiety) 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

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 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 March 2014

Disclosures I am a consultant, speaker, advisor, or receive research support from: Ownership Interest: BMIQ Cardiometabolic Support Network Myos Corporation Zafgen, Inc. 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. Board of Directors: Myos Corporation Jamieson Laboratories 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.

Obesity Pharmacotherapy

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

Anti-obesity Medications Rationale and Criteria
Non-drug interventions should be attempted for at least 6 months before considering pharmacotherapy1 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 Combined therapy is one that combines all of the lifestyle approaches—dietary therapy, physical activity, and behavioral therapy. Strong evidence supports the recommendation that a combined intervention is most effective for weight loss and maintenance. It is important to note that nondrug or lifestyle interventions should be attempted for at least 6 months before considering any type of drug treatment. 1. NIH Clinical Guidelines Evidence Report, Sept 1998. 77

Hypertension Treatment
Lets think about for a minute: >120 drugs in 10 categories Up to triple drug combinations available 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

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

Anti-obesity Drugs Presently on the Market and Pending Approval
FDA-Approved Drug Company Mechanism of Action Comments Benzphetamine (Didrex) Pharmacia Norepinephrine/dopamine releasing stimulator Schedule III drug, approved 1960 for short-term use Phendimetrazine (Bontril) Valeant Schedule III drug, approved 1961 Phentermine (Adipex, Suprenza) Gates, Alpex Noradrenaline/dopamine Schedule IV drug, approved 1973 Diethylpropion (Tenuate) Watson Labs/ Corepharma Orlistat (Xenical) (Alli –OTC) Roche, GSK Pancreatic lipase inhibitor Approved for long-term use in 1999 Phentermine/Topiramate (Qysmia) (formerly Qnexa) Vivus Noradrenaline releasing + modulator of ɣ aminobutyric acid (GABA)/ carbonic anhydrase inhibition Approved July 2012 Lorcaserin (Belviq) Arena Pharma Selective 5-HT2Creceptor agonist Approved June 2012 Anti-obesity Drugs that Await Decisions Bupropion/Naltrexone (Contrave) Orexigen Inhibitor of dopamine and noradrenaline reuptake + µ opiate antagonist FDA requested data on long-term cardiovascular risk assessment in 2011 Liraglutide Novo Nordisk GLP-1 agonist Approved January 2010 for treatment of Type 2 DM; phase III for anti-obesity at higher doses 90%! New! New! ; doi: /aps Modified from Zhi-yun Zhang Z-y and Wang M-w. Acta Pharmacologica Sinica 2012;33:145–147.

Expected Weight Loss with Newly Approved and Investigational Anti-obesity Medications
Mechanism of Action Agent Brand Name Drug (kg) Placebo Net Weight Loss (kg) Duration FDA Approval Selective serotonin 2C receptor agonist Lorcaserin Belviq 8.2 3.4 4.8 52 weeks June 2012 Combination- Sympathomimetic/gaba-ergic migraine med Topiramate/ phentermine Qsymia 10.2 1.4 8.8 56 weeks July 2012 Combination Antidepressant/ Opiate antagonist Bupropion/ naltrexone Contrave 1.9 6.2 48 weeks Application Pending Glucagon-like peptide 1 (GLP-1) Liraglutide 3.0 mg Victoza 10.3±7.1 104 weeks Pending Pending Pending for obesity EXENATIDE DATA: Moreno JL, Willett KC, Desilets AR. Ann Pharmacother. 2012 Dec;46(12): LIRA DATA: Astrup A, et al. International Journal of Obesity (2012) 36, 843–854 Belllloranib Obesity (Silver Spring) Mar 20. doi: /oby [Epub ahead of print] Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women. Hughes TE, Kim DD, Marjason J, Proietto J, Whitehead JP, Vath JE. Source Zafgen, Inc., Cambridge, MA, USA. Abstract Objective: Evaluate the safety and tolerability of beloranib, a fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor, in obese women over 4 weeks. Design and Methods: Thirty-one obese (mean BMI 38 kg/m2 ) women were randomized to intravenous 0.1, 0.3, or 0.9 mg/m2 beloranib or placebo twice weekly for 4 weeks (N = 7, 6, 9, and 9). Results: The most frequent AEs were headache, infusion site injury, nausea, and diarrhea. Nausea and infusion site injury occurred more with beloranib than placebo. The most common reason for discontinuation was loss of venous access. There were no clinically significant abnormal laboratory findings. In subjects completing 4 weeks, median weight loss with 0.9 mg/m2 beloranib was -3.8 kg (95% CI -5.1, -0.9; N = 8) versus -0.6 kg with placebo (-4.5, -0.1; N = 6). Weight change for 0.1 and 0.3 mg/m2 beloranib was similar to placebo. Beloranib (0.9 mg/m2 ) was associated with a significant 42 and 18% reduction in triglycerides and LDL-cholesterol, as well as improvement in C-reactive protein and reduced sense of hunger. Changes in β-hydroxybutyrate, adiponectin, leptin, and fibroblast growth factor-21 were consistent with the putative mechanism of MetAP2 inhibition. Glucose and blood pressure were unchanged. Conclusions: Beloranib treatment was well tolerated and associated with rapid weight loss and improvements in lipids, C-reactive protein, and adiponectin. Copyright © 2013 The Obesity Society. Ann Pharmacother. 2012 Dec;46(12): doi: /aph.1R372. Epub 2012 Nov 27. Exenatide as a novel weight loss modality in patients without diabetes. Moreno JL, Willett KC, Desilets AR. SourceMassachusetts College of Pharmacy and Health Sciences, Worcester/Manchester, NH, USA. AbstractOBJECTIVE:To evaluate the potential role of exenatide for weight loss in overweight or obese adults without diabetes. DATA SOURCES:PubMed (1946-August 2012) and EMBASE (1974-August 2012) were used to conduct a literature search utilizing the terms exenatide, weight loss, obesity, and overweight. Additional references were identified by bibliographic review of relevant articles.STUDY SELECTION AND DATA EXTRACTION:Studies assessing the use of exenatide in adult subjects without type 2diabetes or polycystic ovary syndrome and reporting effects on body weight were included. DATA SYNTHESIS:Five studies were identified that reported use of exenatide in nondiabetic adults and included weight change as an outcomes measure. In all 5 of these studies, subjects taking exenatide experienced statistically significant weight loss, which ranged from 2.0 ± 2.8 to 5.1 ± 0.5 kg. Two of the trials were randomized, placebo-controlled studies; 1 trial was a randomized, open-label investigation; 1 study had a prospective, open-label cohort design; and the remaining study was a chart review. Adverse events experienced with exenatide were primarily gastrointestinal in nature, although each trial reported the drug to be well tolerated.CONCLUSIONS:Obesity continues to be a national epidemic, while choices for effective pharmacologic treatments are extremely limited. Exenatide appears to have promising effects on weight in overweight or obese adults without type 2 diabetes. Further investigations with large, placebo-controlled trials assessing long-term weight loss as a primary outcome are warranted.PMID: Modified from Powell AG, Apovian CM, Aronne LJ. Clin Pharmacol Ther Jul;90(1):40-51.

Recently Approved Pharmacotherapy
Agent Phentermine/topiramate ER1,2 Qsymia™ Lorcaserin3,4 Belviq® Approval Status Approved July 2012 Approved June 2012 Mechanism PHEN noradrenaline and dopamine releasing agent; TPM is an anticonvulsant and GABA modulator plus carbonic anhydrase inhibitor Selectively targets the 5-HT2C receptor Follow-up Duration 56 (108*) weeks 52 (104*) weeks Common Adverse Effects Dry mouth Tingling Constipation Altered taste sensation Upper respiratory infection Headache Dizziness Nausea *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:

Emerging Pharmacotherapy
Agent Naltrexone/BupSR1 Contrave ® Liraglutide2,3 ? Trade name Approval Status FDA requested additional Phase 3 data In Phase 3 clinical trials Mechanism Naltrexone: opioid receptor antagonist Bupropion: norepinephrine-dopamine reuptake inhibitor Glucagon-like peptide-1 analogue Follow-up Duration 56 weeks Common AEs Nausea Headache Constipation Dizziness Vomiting Dry mouth Gastro-intestinal effects 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

Phentermine/Topiramate
2012 Phentermine/Topiramate

Phentermine/Topiramate ER
Mechanism of Action Phentermine Sympathomimetic amine, NE release Blunts appetite Topiramate Increases GABA activity, antagonize AMPA/ kainate glutamate receptor, carbonic anhydrase inhibitor Prolongs satiety Indications and Dose Approved by FDA, July 2012, schedule IV Indication Weight loss in pts with BMI ≥30 kg/m or BMI ≥27 kg/m 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 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 Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012.

Phentermine/Topiramate ER
Once-a-day, oral, extended release topiramate Low doses of previously approved medications to minimize side effects 400 mg 200 100 300 50 150 250 350 Topiramate ER 30mg (free base) 15 5 10 25 3.75 7.5 Phentermine Maximum Approved Doses 20 23 46 92 Low Mid Full Topiramate at ¼-1/16 max approved dose Phentermine at ½-1/8 maximum approved dose Safety margin based on use of very low doses – might want to add “familiar compounds” since this is a point Dr. Look makes all the time (and different from a NCE or naltrexone or zonisamide) Three doses are: 3.75/23, 7.5/46, and 15/92 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 / 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; 2012.

Phentermine/ Topiramate Trials
EQUIP CONQUER 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

Effect of Phentermine/Topiramate ER on Weight Loss in Obese Adults Over 2 Years
SEQUEL Study Placebo -1.8% Phentermine/topiramate CR 7.5/46 -9.3% -10.5% Phentermine/topiramate CR 15/92 SM: CA slide from Pri-med Nov 2013 Of 866 eligible subjects, 676 (78%) elected to continue in the extension. Overall, 84.0% of subjects completed the study, with similar completion rates among treatment groups. At week 108, PHEN/TPM ER was associated with significant, sustained weight loss (intent-to-treat with last observation carried forward; P < compared with placebo) and that weight loss had been sustained for over two years at between 10-12% reduction in baseline body weight. Significantly more PHEN/TPM ER–treated subjects at each dose achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss compared with placebo (P < 0.001). 9.3% weight loss from baseline in the PHEN/TPM7.5/46 group and 10.5% sustained reduction in baseline body weight at 2 years with PHEN/TPM 15/92 – in the completers analysis. (Figure 2; P < compared with placebo at all time points assessed). At week 108, the LS mean percentage changes from baseline in body weight in the ITT-LOCF analysis were significantly greater in the PHEN/TPM CR groups compared with placebo: –1.8%, –9.3%, and –10.5% for placebo, 7.5/46, and 15/92, respectively (P < compared with placebo for all comparisons). For subjects who completed the study while still taking the study drug at week 108, the LS mean percentage changes from baseline in body weight were also significantly greater in the PHEN/TPM CR groups compared with placebo: –2.2%, –9.3%, and –10.7% for placebo, 7.5/46, and 15/92, respectively (P < compared with placebo for all comparisons). Absolute LS mean weight loss using ITT-LOCF data were –2.1, –9.6, and –10.9 kg for the placebo, 7.5/46, and 15/92 groups, respectively (P < compared with placebo for all comparisons). Greater proportions of subjects treated with each dose of PHEN/TPM CR experienced weight losses of ≥5%, ≥10%, ≥15%, and ≥20% when compared with placebo-treated subjects Data are shown with least squares mean (95% CI). Garvey WT, et al. Am J Clin Nutr. 2012;95:

Phentermine 7.5mg/ Topiramate 46 mg ER
Phentermine/Topiramate ER Improves Risk Factors and Manifestations of Cardiometabolic Disease CONQUER Study Changes from baseline to week 56 in secondary endpoints Variable Phentermine 7.5mg/ Topiramate 46 mg ER Placebo P value Waist circumference (cm)  -7.6 -2.4 <0.0001 Systolic BP (mm Hg) -4.7 0.0008 Diastolic BP (mm Hg) -3.4 -2.7 0.1281 Triglycerides (%) -8.6 4.7 LDL–C (%) -3.7 -4.1 0.7391 HDL–C (%)  5.2 1.2 CRP (mg/L) -2.49 -0.79 Adiponectin (µg/mL) 1.40 0.33 Gadde KM, et al. Lancet. 2011;377(9774):

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

Phentermine/Topiramate ER: EQUIP and CONQUER Most Commonly Reported Treatment Emergent Adverse Events Adverse Event (%) (N=3749) Placebo PHEN/TPM ER 3.75/23 PHEN/TPM ER 7.5/46 PHEN/TPM ER 15/92 Paresthesia 1.9 4.2 13.7 19.9 Dry mouth 2.8 6.7 13.5 19.1 Constipation 6.1 7.9 15.1 16.1 Upper respiratory tract infection 12.8 15.8 12.2 Headache 9.3 10.4 7.0 10.6 Dysgeusia 1.1 1.3 7.4 9.4 Nasopharyngitis 8.0 12.5 Insomnia 4.7 5.0 5.8 Dizziness 3.4 2.9 7.2 8.6 Sinusitis 6.3 7.5 6.8 7.8 Nausea 4.4 3.6 Back pain 5.1 5.4 5.6 6.6 Fatigue 4.3 5.9 Blurred vision 3.5 4.0 Diarrhea 4.9 6.4 Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.

Summary of Phentermine and Topiramate Neuropsychiatric Safety
QNEXA_Core_ _v03_NO_HIDDEN.ppt 4/8/2017 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 Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012. QNEXA

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; 2012. Phentermine and topiramate extended-release capsules CIV Healthcare Provider Training Program. Vivus; 08/2012.

2012 Lorcaserin

Lorcaserin Mechanism of Action Indications and Dose
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 comorbid 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 Lorcaserin hydrochloride [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012.

Proposed Model of a Serotonergic Pathway Modulating Food Intake
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 Figure 1. Proposed model of a serotonergic pathway modulating food intake An 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 pro-opiomelanocortin (POMC)/cocaine and amphetamine regulated transcript (CART) and agouti related protein (AgRP)/neuropeptide Y (NPY) neurones within the arcuate nucleus of the of the hypothalamus (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;587:49-60.

Lorcaserin Phase 3 Trials
2 years tx Dosage 10 mg QD1 n=4,008 1 year tx Dosage 10 mg QD2 n=604 obese/ overweight with type 2 DM 1 year+ tx Dosage 10 mg BID or 10 mg QD3 BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management) 3,182 patients over a two-year treatment period BLOSSOM (Behavioral modification and Lorcaserin Second Study for Obesity Management) 4,008 patients over a one-year treatment period BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus) 604 obese and overweight patients with type 2 diabetes over a one-year treatment period Smith SR, et al. N Engl J Med 2010;363: Fidler MC, et al. J Clin Endocrinol Metab, October 2011, 96(10):3067–3077. O’Neil PM, et al. Obesity (16 March 2012) | doi: /oby Arena Pharmaceuticals 97

Lorcaserin: Those Who Lost ≥ 4
Lorcaserin: Those Who Lost ≥ 4.5% Total Body Weight by Week 12 Were Week 52 Responders Studies 009 and 011, MITT Non-responder: Lorcaserin BID STOP -2.46% -10.22% Responder: Lorcaserin BID Source: We found that those who met 4.5% weight loss at Week 12, represented by the blue line achieved at least a 5% weight loss at week 52 and lost approximately 10 kilos or 22 lbs. Based on the phase III data this measure would capture approximately 80% of those who were week 52 responders. While no predictive measure can be perfect, this type of guidance can be used to help form a patient-physician decision to continue or not continue lorcaserin after a 3 month trial. MITT Lorcaserin BID Week 12 Completed Week 12 Completed Week 52 N = 3097 ≥4.5% wt loss 1369/3097 (44.2%) 1083/1369 (79.1%) <4.5% wt loss 1168/3097 (37.7%) 680/1168 (58.2%) Slide courtesy Dr. Steve Smith; May 10, 2012 FDA Advisory Committee Meeting

Lorcaserin ─ BLOOM Study: Key Secondary Endpoints
Placebo P value Waist circumference (cm)  −6.8 −3.9 <0.001 SBP/DBP (mm Hg) −1.4 / −1.1 −0.8 / −0.6 0.04/0.01 Cholesterol (% Δ) Total LDL HDL − 0.05 −0.21 0.72 Triglycerides (%) −6.15 −0.14 Safety HR (beats/min) Beck depression II −2.0 −1.1 −1.6 −0.9 0.049 0.26 Intention-to-Treat Analysis with LOCF Imputation Smith SR, et al. NEJM. 2010;363:

Randomized Placebo‐Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 DM BLOOM‐DM Study - HbA1c Figure 3. Change in glycemic parameters by study week. Values are mean ± SEM; modified intent to treat with last observation carried forward analysis. Lorcaserin 10 mg BID, closed circles with solid line; lorcaserin 10 mg QD, open diamonds with dotted line; placebo, open triangles with dashed line. Values are mean ± SEM. *P ≤ 0.001; **P < 0.05 compared with placebo. BID, twice daily; HbA1c, glycated hemoglobin; LS, least square; QD, once daily. O’Neil PM, et al. Obesity (Silver Spring) Jul;20(7):

Randomized Placebo‐Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 DM BLOOM‐DM Study Weight Loss Figure 2. Analyses of body weight change. (a) Proportion of patients who lost ≥5% or ≥10% of body weight from baseline to week 52 using the modified intent to treat (MITT) population (left panel) or the completers population (right panel). Lorcaserin 10 mg BID, solid bars; lorcaserin 10 mg QD, hatched bars; placebo, open bars. Values are proportion ± 95% confidence interval. *P < as compared to placebo. (b) Percent change in body weight from baseline to each study visit, using the MITT population (left panel) or the completers population (right panel). Lorcaserin 10 mg BID, closed circles with solid line; lorcaserin 10 mg QD, open diamonds with dotted line; placebo, open triangles with dashed line. Values are mean ± SEM. BID, twice daily; QD, once daily. O’Neil PM, et al. Obesity (Silver Spring) Jul;20(7):

Lorcaserin: Adverse Events Reported by >5% in Any Group
Placebo (N = 3185) Headache 537 (16.8) 321 (10.1) Dizziness 270 (8.5) 122 (3.8) Nausea 264 (8.3) 170 (5.3) Constipation 186 (5.8) 125 (3.9) Fatigue 229 (7.2) 114 (3.6) Dry mouth 169 (5.3) 74 (2.3) The adverse-event profile for the 2 groups is shown on this slide. Patients in the lorcaserin group experienced an increased incidence of headache, dizziness, nausea, constipation, fatigue, and dry mouth. There was no difference between groups in study withdrawal or discontinuation rates. Intention-to-Treat Analysis with LOCF Imputation Smith SR, et al. NEJM. 2010;363:

Naltrexone SR/Bupropion
2011 Naltrexone SR/Bupropion Target of 2014

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)

Mean Weight Loss Naltrexone/ Bupropion COR-I Phase 3 105
56 Weeks – Completer Population Background Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. Methods Men and women aged 18—65 years who had a body-mass index (BMI) of 30—45 kg/m2 and uncomplicated obesity or BMI 27—45 kg/m2 with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT Findings 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was −1·3% (SE 0·3) in the placebo group, −6·1% (0·3) in the naltrexone 32 mg plus bupropion group (p<0·0001 vs placebo) and −5·0% (0·3) in the naltrexone 16 mg plus bupropion group (p<0·0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p<0·0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p<0·0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29·8%]; naltrexone 16 mg plus bupropion, 155 [27·2%]; placebo, 30 [5·3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 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 suicidality events compared with placebo. Interpretation A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity. Greenway FL, et al. Lancet 2010 Aug 21; 376:595. DOI: /S (10) 105

Naltrexone SR / Bupropion SR
Phase 3 Trial (COR-II) FIGURE 3 Percent weight loss (observed; LS mean ± SE) by visit in the week 28 and 56 completers populations (NB32 data are weighted for weeks 32-56), and percent weight loss for the week 28 and 56 mITT-LOCF populations. ***P < for NB32 vs. Placebo. B) Categorical weight loss in week 28 and 56 mITT-LOCF and Completers populations. ***P < for NB32 vs. Placebo. In both panels, week 56 data for NB32 are weighted as described in the Statistical analyses section. Obesity (Silver Spring). 2013 May;21(5): doi: /oby A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, Kim D, Dunayevich E; COR-II Study Group. Collaborators (38) Source Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. Abstract OBJECTIVE: To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight-related risk factors in overweight and obese participants. DESIGN AND METHODS: CONTRAVE Obesity Research-II (COR-II) was a double-blind, placebo-controlled study of 1,496 obese (BMI kg/m(2) ) or overweight (27-45 kg/m(2) with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained-release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co-primary endpoints were percent weight change and proportion achieving ≥ 5% weight loss at week 28. RESULTS: Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (-6.5% vs. -1.9%) and week 56 (-6.4% vs. -1.2%). More NB32-treated participants (P < 0.001) experienced ≥ 5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant-reported weight-related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo. CONCLUSION: NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option. Copyright © 2013 The Obesity Society. PMID: 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):

Improvement in risk factors with use of Naltrexone SR / Bupropion SR
Week 28 Week 56 Measure Placebo N = 456 NB32 N = 825 P-value NB32 N = 702 Waist circumference, cm Baseline 108.9 ± 11.7 109.3 ± 11.9 108.6 ± 11.8 109.0 ± 11.8 Change −2.7 ± 0.4 −6.2 ± 0.3 <0.001 −2.1 ± 0.5 −6.7 ± 0.3 Triglycerides, mg/dL 113.4 ± 1.6 119.0 ± 1.6 112.8 ± 1.6 118.9 ± 1.6 Percent change (95% CI) −1.4% (−5.0%, +2.4%) −7.3% (−9.8%, −4.8%) 0.007 −0.5% (−4.5%, +3.7%) −9.8% (−12.4%, −7.1%) HDL-cholesterol, mg/dL 51.4 ± 13.1 51.4 ± 13.3 51.6 ± 12.9 51.8 ± 13.6 −1.4 ± 0.4 +1.2 ± 0.3 −0.9 ± 0.5 +3.6 ± 0.4 LDL-cholesterol, mg/dL 117.1 ± 32.6 119.8 ± 30.2 116.8 ± 32.9 120.5 ± 30.2 0.0 ± 1.3 −4.4 ± 0.9 0.004 −2.1 ± 1.3 −6.2 ± 0.9 0.008 Fasting blood glucose, mg/dL 94.2 ± 10.4 94.8 ± 11.2 95.0 ± 11.3 −1.7 ± 0.5 −2.1 ± 0.4 0.544 −1.3 ± 0.6 −2.8 ± 0.5 0.051 Fasting insulin, μIU/mL 10.7 ± 1.9 11.4 ± 1.9 −0.5% (−6.5%, +5.9%) −14.1% (−17.9%, −10.2%) +3.5% (−3.8%, +11.2%) −11.4% (−15.9%, −6.6%) Systolic blood pressure, mm Hg 118.2 ± 10.5 118.1 ± 10.0 117.9 ± 10.0 −1.2 ± 0.4 −0.9 ± 0.3 0.556 −0.5 ± 0.4 +0.6 ± 0.3 0.039 Diastolic blood pressure, mm Hg 76.8 ± 7.0 76.7 ± 7.0 −0.7 ± 0.3 +0.2 ± 0.2 0.017 +0.3 ± 0.3 +0.4 ± 0.2 0.847 NB32 resulted in improvements in various cardiometabolic parameters, including waist circumference, triglycerides, and HDL versus placebo at week 28 (Table 3). NB32 was also associated with reduced LDL, as well as reduced fasting insulin and HOMA-IR. In most cases, improvements in secondary endpoints were maintained at week 56. At week 28, NB32 was associated with improvement in total IWQOL-Lite score versus placebo (P < 0.001) and greater improvements for NB32 versus placebo were observed in the physical function, self-esteem, and sexual life subscales (P < 0.01; Supporting Information Section 2). Greater improvements in IWQOL-Lite total score and subscale scores were maintained through week 56. COEQ, Control of Eating Questionnaire; CI, confidence interval; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; hs-CRP, high-sensitivity C reactive protein; IDS-SR, Inventory of Depressive Symptomatology -Self Rated; IWQOL-Lite, Impact of Weight on Quality of Life–Lite version; LDL, low-density lipoprotein. SI Conversion Factors: To convert values for triglycerides to mmol/L, multiply by To convert values for HDL and LDL cholesterol to mmol/L, multiply by To convert values for glucose to mmol/L, multiply by To convert values for insulin to pmol/L, multiply by aData are for the mITT-LOCF population, where the last observation on study drug was carried forward. Unless otherwise specified, baseline values are mean ± SD and change values are LS mean ± SE. bWeek 56 data for NB32 are weighted as described in the Statistical analyses section. cSecondary endpoints that were significant according to the prespecified sequential closed testing procedure conducted to control for multiple comparisons. dBaseline values are geometric mean ± SD; percent change values are LS mean (95% CI); P-values are based on log transformed values. eIWQOL-Lite total score is based on a scale from 0 to 100 where a score of indicates moderate impairment. fCOEQ question #19: Generally, how difficult has it been to control your eating? (scoring: 0 = not at all difficult; 100 = extremely difficult) gIDS-SR total score is based on 30 items. The total score can range from 0-84, with 0 being no depressive symptoms and 84 being severe depressive symptoms. A total score ≤13 indicates no depression. Apovian CM, Aronne L, et al. Obesity (Silver Spring) May;21(5):

Side Effects Most frequent events: Nausea
Naltrexone/Bupropion 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 The Lancet, Volume 376, Issue 9741, Pages , 21 August PMID: Background Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. Methods Men and women aged 18—65 years who had a body-mass index (BMI) of 30—45 kg/m2 and uncomplicated obesity or BMI 27—45 kg/m2 with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT Findings 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was −1·3% (SE 0·3) in the placebo group, −6·1% (0·3) in the naltrexone 32 mg plus bupropion group (p<0·0001 vs placebo) and −5·0% (0·3) in the naltrexone 16 mg plus bupropion group (p<0·0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p<0·0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p<0·0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29·8%]; naltrexone 16 mg plus bupropion, 155 [27·2%]; placebo, 30 [5·3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 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 suicidality events compared with placebo. Interpretation A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity. Greenway FL, et al. Lancet Aug 21;376(9741): PMID:

for Type 2 DM 2010 Liraglutide for anti-obesity

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

Effects of Liraglutide and Orlistat on Body Weight in Nondiabetic Obese Adults
Lancet Nov 7;374(9701): doi: /S (09) Epub 2009 Oct 23. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, Madsen J, Rasmussen MF, Lean ME; NN Study Group. BACKGROUND: The frequency of obesity has risen dramatically in recent years but only few safe and effective drugs are currently available. We assessed the effect of liraglutide on bodyweight and tolerability in obese individuals without type 2 diabetes. METHODS: We did a double-blind, placebo-controlled 20-week trial, with open-label orlistat comparator in 19 sites in Europe. 564 individuals (18-65 years of age, body-mass index kg/m2) were randomly assigned, with a telephone or web-based system, to one of four liraglutide doses (1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg, n=90-95) or to placebo (n=98) administered once a day subcutaneously, or orlistat (120 mg, n=95) three times a day orally. All individuals had a 500 kcal per day energy-deficit diet and increased their physical activity throughout the trial, including the 2-week run-in. Weight change analysed by intention to treat was the primary endpoint. An 84-week open-label extension followed. This study is registered with ClinicalTrials.gov, number NCT FINDINGS: Participants on liraglutide lost significantly more weight than did those on placebo (p=0.003 for liraglutide 1.2 mg and p< for liraglutide mg) and orlistat (p=0.003 for liraglutide 2.4 mg and p< for liraglutide 3.0 mg). Mean weight loss with liraglutide mg was 4.8 kg, 5.5 kg, 6.3 kg, and 7.2 kg compared with 2.8 kg with placebo and 4.1 kg with orlistat, and was 2.1 kg (95% CI ) to 4.4 kg ( ) greater than that with placebo. More individuals (76%, n=70) lost more than 5% weight with liraglutide 3.0 mg that with placebo (30%, n=29) or orlistat (44%, n=42). Liraglutide reduced blood pressure at all doses, and reduced the prevalence of prediabetes (84-96% reduction) with mg per day. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment. INTERPRETATION: Liraglutide treatment over 20 weeks is well tolerated, induces weight loss, improves certain obesity-related risk factors, and reduces prediabetes. FUNDING: Novo Nordisk A/S, Bagsvaerd, Denmark. PMID: Data are mean (95% CI) for the ITT population Astrup A, et al. Lancet Nov 7;374(9701):

Liraglutide Weight Loss: One Year
Supplementary Information Table 3: Mean changes in body weight Supplementary Information Table 3: Mean changes in body weight, wait, and BP by ANCOVA and repeat from randomization to year 1 Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.

Liraglutide Weight Loss: Two Years
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 Int J Obes (Lond). Jun 2012; 36(6): 843–854. Published online Aug 16, 2011. doi: /ijo PMCID: PMC Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide A Astrup, Maintenance from screening: weight loss, BP reduction and pulse Mean weight reduction between screening and randomization was 1.3±1.4kg across groups. Figure 3a shows that participants randomized to liraglutide 3.0mg for 1 year (and then maintained on 2.4/3.0mg for the second year) maintained a mean weight loss of 10.3±7.1kg from screening over 2 years. Weight loss for the pooled group on liraglutide 2.4/3.0mg for 2 years was estimated to be 7.8kg by adjusted ANCOVA (Supplementary Figure 2a). Almost 70% of liraglutide 2.4/3.0mg recipients maintained weight loss >5% of screening weight at year 2, 43% maintained >10% loss and 25% maintained >15% loss (Supplementary Figure 2b). 3.0 mg 10.3±7.1 kg weight loss Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.

Liraglutide: Adverse Events
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 Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.

Obesity Drugs in the Pipeline
Beloranib

Beloranib: Phase 1 Trial Results – 4 weeks
Fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor Dosage Weight Loss (kg) Placebo -0.6 kg (-4.5, -0.1) 0.1 mg/m2 (n=7) 0.3 mg/m2 (n=6) 0.9 mg/m2 (n=8) -3.8 kg (95% CI -5.1, -0.9) N=19 obese women Mean BMI 38 kg/m2 Dosage at 0.9 mg/m2 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 No evidence of major tolerability or safety issues (Phase 1 trials) Obesity (Silver Spring) Mar 20. doi: /oby [Epub ahead of print] Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women. Hughes TE, Kim DD, Marjason J, Proietto J, Whitehead JP, Vath JE. Source Zafgen, Inc., Cambridge, MA, USA. Abstract Objective: Evaluate the safety and tolerability of beloranib, a fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor, in obese women over 4 weeks. Design and Methods: Thirty-one obese (mean BMI 38 kg/m2 ) women were randomized to intravenous 0.1, 0.3, or 0.9 mg/m2 beloranib or placebo twice weekly for 4 weeks (N = 7, 6, 9, and 9). Results: The most frequent AEs were headache, infusion site injury, nausea, and diarrhea. Nausea and infusion site injury occurred more with beloranib than placebo. The most common reason for discontinuation was loss of venous access. There were no clinically significant abnormal laboratory findings. In subjects completing 4 weeks, median weight loss with 0.9 mg/m2 beloranib was -3.8 kg (95% CI -5.1, -0.9; N = 8) versus -0.6 kg with placebo (-4.5, -0.1; N = 6). Weight change for 0.1 and 0.3 mg/m2 beloranib was similar to placebo. Beloranib (0.9 mg/m2 ) was associated with a significant 42 and 18% reduction in triglycerides and LDL-cholesterol, as well as improvement in C-reactive protein and reduced sense of hunger. Changes in β-hydroxybutyrate, adiponectin, leptin, and fibroblast growth factor-21 were consistent with the putative mechanism of MetAP2 inhibition. Glucose and blood pressure were unchanged. Conclusions: Beloranib treatment was well tolerated and associated with rapid weight loss and improvements in lipids, C-reactive protein, and adiponectin. Copyright © 2013 The Obesity Society. OTHER SOURCES Hughes TE, et al. Obesity (Silver Spring) Mar 20. doi: /oby [Epub ahead of print]

Beloranib: Phase 2 Trial Interim Analysis - 12 Weeks
Fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor Dosage Weight Loss (kg) Completers n=19 Placebo (n=5) +1.8 ±0.4 0.6 mg (n=5) -3.8 ± 0.8 1.2 mg (n=6) -6.1 ±1.5 2.4 mg (n=3) -9.9 ± 2.3 Completers: n=19 Mean BMI 37.9 kg/m2 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 No evidence of major tolerability or safety issues (Phase 1 trials) Patients had a mean age of 40.3 years, with body weight of kg, and a body mass index (BMI) of 37.9 kg/m2. Patients receiving 12 weeks of treatment in the full trial were randomized to 0.6 mg (n = 37), 1.2 mg (n = 36), or 2.4 mg (n = 34) of subcutaneous beloranib vs. placebo (n = 38). The interim analysis reflects results obtained in 19 patients completing 12 weeks of treatment with 0.6 mg (n = 5), 1.2 mg (n = 6) or 2.4 mg (n = 3) of subcutaneous beloranib vs. placebo (n = 5) as part of the dose-selection cohort. Beloranib appeared safe and showed dose responsive weight loss. After 12 weeks, subjects on 0.6 mg, 1.2 mg or 2.4 mg lost an average of (± SEM) -3.8 ± 0.8, -6.1 ±1.5, and ± 2.3 kg vs ±0.4 kg for placebo (all p<0.005 vs. placebo). Additionally, patients treated with beloranib showed improvements in cardiometabolic risk factors including reduced triglycerides, LDL cholesterol and C-reactive protein (an inflammatory marker) versus placebo. ADA Poster Session 19-B Abstract #188-LB June 22, 2013

Anti-obesity Medications in Development
Anti-Obesity Pharmacotherapy: New Drugs and Emerging Targets Gilbert W. Kim, Jieru E. Lin, Erik S. Blomain and Scott A. Waldman Clin Pharmacol Ther. 2013 Oct 8. doi: /clpt [Epub ahead of print] Anti-Obesity Pharmacotherapy: New Drugs and Emerging Targets. Kim GW, Lin JE, Blomain ES, Waldman SA. Abstract Obesity is a growing pandemic and related health and economic costs are staggering. Pharmacotherapy partnered with lifestyle modifications form the core of current strategies to reduce the burden of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing anti-obesity therapies, including targets, mechanisms, and developmental status are highlighted. Progress in this field is underscored by Belviq® (lorcaserin) and Qsymia® (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic management weight in obese patients. On the horizon, novel insights in metabolism and energy homeostasis reveal cGMP signaling circuits as emerging targets for anti-obesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off-the-shelf approaches leveraging existing approved drugs that modulate cGMP levels for the management of obesity.Clinical Pharmacology &Therapeutics (2013); Accepted article preview online 8 October 2013; doi: /clpt PMID: Kim GW, et al. Clin Pharmacol Ther Oct 8. doi: /clpt [Epub ahead of print]

Summary 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.

Ken Fujioka, MD – Program Co-Chair
New Perspectives and Emerging Treatment Paradigms 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 Ken Fujioka, MD – Program Co-Chair Director, Nutrition and Metabolic Research Center | Director, Center for Weight Management | Scripps Clinic in San Diego, CA

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

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?

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

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

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

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

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

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

Case Study 2 Hispanic Male
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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 Hypertension Losartan 100 mg q d, diltiazem 360, chlorthalidone 50 mg q d Hyperlipidemia Simvastatin 20 mg q d GERD Lansoprazole 30 mg q d OSA – nightly CPAP Arthralgias of knees

Case Study 6 Weight history Social 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

Case Study 6 Diet history Physical activity 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

Case Study 6 Examination Labs
Weight 352 lbs, height in, BMI 52.1 kg/m2 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 - Question 1 What would you recommend regarding weight management? Refer to commercial program Refer to registered dietitian Initiate lifestyle counseling yourself One of the above + pharmacotherapy Refer for bariatric surgery Please Enter Your Response On Your Keypad

Case Study 6 RD Visit Further assessment Counseling
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

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

Weight Graph from EHR

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

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

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

Weight Graph from EHR 46 lbs = 14%

Case Study 6 Biomarkers Value Baseline 3 months 7 months 10 months 14
Weight, lbs, (% wt loss) 325.2 303.5 (6.6%) 290 (10.7%) 282 (13.2%) 280 (13.8%) Glucose, mg/dl 95 93 89 85 88 HbA1c, % 6.5 6.3 6.0 5.9 TC, mg/dl 182 175 183 176 LDL-c, mg/dl 110 103 107 105 104 HDL-c. mg/dl 46 45 51 54 TG, mg/dl 181 135 127 83 98

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

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

Why Obesity is NOT a Disease
It is a lifestyle choice No specific symptoms associated with it It is a risk factor for disease, not a disease itself* 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 * What about high cholesterol or hypertension?

Why Obesity IS a Disease
It is associated with impaired body function 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 is associated with a substantial burden of morbidity and premature death

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

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

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

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

Weight Loss Variability after Gastric Banding
Bessler et al., 2008

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

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

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

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

The Obesities – A Plethora of Discrete Disorders
56 Leptin deficiency LepR deficiency MC4R deficiency aMSH 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 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 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 Multiple Subtypes = Variation in Treatment Response

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

Heterogeneity of Response
Number of Subjects Highly responsive subgroup Weight Loss

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

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

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

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

A Call to Action Determine BMI at each visit
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 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 184

Why is weight regain after dieting so common?
Question 1 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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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% Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

Question 6 Which of the following weight loss medications do NOT work through central nervous system mechanisms? Bupropion Lorcaserin Liraglutide Topiramate ER Phentermine Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

Question 7 Which of the following is NOT a 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 Audience Response System (ARS) Questions There are 4 types of questions: pre/post presentation questions, Action Plan post questions, Decision Points, and Key Questions. 3 pre/post presentation questions: These are used to gauge the audience’s level of knowledge prior to and after the presentation. Questions should be concise and specific to the learning objectives, and have one best answer. One of these should be case-based (Decision Point) and the other two should measure procedural knowledge (Key Question) Decision Points: These questions appear within case studies and allow the audience to work through the case by responding to different presented clinical scenarios. Decision points include case study photo, patient case information, and a case-based question Key Questions: These factual questions introduce a key learning point within the presentation Action Plan post question: After the action plan summary slide (see below), the audience will be asked which of these items they plan to incorporate into their practice ARS Question Format Do not use negative questions (“Which of the following is not…”; “All are true, except...”) Use a maximum of 4 answer choices Avoid “all of the above,” “none of the above,” “1 and 3” Format questions in sentence case Please Enter Your Response On Your Keypad

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

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

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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:

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