MARC-ANDRE CORNIER, MD - Program Chairman

MARC-ANDRE CORNIER, MD - Program Chairman
Investigations  Stratification Front Line Clinical Applications New Frontiers and Emerging Treatment Paradigms for Optimizing Management of Obesity Focus on Multimodal Interventions for Weight Loss and Novel Pharmacological Strategies Targeting the Central Nervous System MARC-ANDRE CORNIER, MD - Program Chairman Associate Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Anschutz Health and Wellness Center University of Colorado School of Medicine Denver, CO

Distinguished Faculty
MARC-ANDRE CORNIER, MD - Program Chairman Associate Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Anschutz Health and Wellness Center University of Colorado School of Medicine Denver, CO REKHA KUMAR, MD, MS Diabetes, Endocrinology and Metabolism Weill Cornell Medical College Assistant Professor of Medicine New York Presbyterian Hospital New York, NY ROBERT J. MALCOLM, MD Professor, Department of Psychiatry and Behavioral Sciences Associate Dean for Continuing Medical Education, College of Medicine Medical University of South Carolina Charleston, SC

Investigations  Stratification Front Line Clinical Applications Current Challenges and Barriers to Optimizing Management of Obesity A Year 2014 Status Report for the Primary Care Physician and Clinical Subspecialist MARC-ANDRE CORNIER, MD - Program Chairman Associate Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Anschutz Health and Wellness Center University of Colorado School of Medicine Denver, CO

Obesity by the Numbers Overweight U.S. adults: 67%
U.S. adults with obesity: 33% U.S. children with obesity: 17% Annual U.S. health care expenditures for obesity: > $ 200 billion U.S. consumer expenditures for weight loss products: > $ 50 billion Daily deaths from obesity complications > 1,000

Disproportionate Increase in Severe Obesity
Today, more than 1.7 million US adults with BMI>50 Sturm R, Pub Health, 2007

Complications of Obesity
Psychological Neoplastic Inflammatory Structural Metabolic Degenerative 65+

Long-term Control of Obesity – 2013
1% = 750,000 U.S. adults

Obesity is Counterintuitive
Hides in plain sight Most obesity NOT recognized by physicians or the public NOT mainly in America NOT simply a problem of eating too much NOT a single disorder – very heterogeneous Possibly 100 or more clinically meaningful subtypes This recognition is essential to solving the problem

Cause of Obesity Historical view Current perspective Lifestyle choice
Characterological flaw (willpower, psychology) Current perspective Complex physiology Epidemic from changes in modern environment Genetic Predisposition (physiology) in the wrong environment Widely recognized as a disease Huge burden of associated illness – a cause of more than 60 medical disorders (including 12 types of cancer) Devastating effect on efficacy and quality of life

Weight and Energy Balance
By the laws of physics… Food Intake Energy Expenditure

The Normal Physiology of Energy Balance
Average adults consume kcal/day Average adults therefore consume 2-3 times as much food as required Excess intake is available for physiological emergencies Maintaining weight within 20 lbs. between ages 21 and 65 requires matching of intake and expenditure within 0.2% Corresponds to accuracy of 4-5 kcal/day Less than one-half potato chip Maintenance of normal fat stores (and body weight) requires precise disposal of 60-70% of ingested calories daily Thus, daily energy balance is likely an evolved physiological trait largely independent of cultural or behavioral differences.

Obesity: A Failure of Weight Regulation
Adipose tissue Leptin HT Food intake Energy expenditure Nutrient handling Cortex GI Tract Genetics Environment Altered food supply Reduced physical activity Stress Drugs Others?

Barriers, Challenges and Opportunities to Obesity Management
Our biology Favors fat storage Can this be manipulated? Environment Macroenvironment – more difficult to change Microenvironment – can be changed by the individual? Health Care System Lack of “buy in” from providers, patients and insurers Others?

Investigations  Stratification
Front Line Clinical Applications Epidemiology and Clinical Approaches to Obesity Management What Do Trials, Algorithms, and Clinical Experience Teach Us About Sequencing Treatment Approaches for Obesity? REKHA KUMAR, MD, MS Diabetes, Endocrinology and Metabolism Weill Cornell Medical College Assistant Professor of Medicine New York Presbyterian Hospital New York, NY

Obesity Diagnosis Obesity is defined an excess of body fat
Body fat is difficult to measure cheaply For people with average lifestyles, Body Mass Index (BMI) has been the measure of obesity BMI = Wt in Kg divided by height in M squared BMI has been divided into categories 18-25 is normal, is overweight, is class I, is class II, >40 is class III

Relationship Between Mortality and BMI
2.5 2.0 1.5 1.0 Men Women Mortality Ratio Very Low Very High Low Moderate High Body Mass Index, kg/m2 Data from Lew EA: Mortality and weight: insured lives and the American Cancer Society studies. Ann Intern Med 103: , 1985.

Mortality: Diastolic Blood Pressure

Mortality: Body Mass Index

BMI Classes are Poor at Estimating Risk
The BMI classes assume that mortality and morbidity is proportional to BMI This is not necessarily true. There are very obese people who are otherwise healthy. In other chronic diseases like cancer there is a staging system to estimate risk An obesity staging system may be a better approach to estimating medical risk of obesity

EOSS Predicts Mortality in NHANES III
Padwal R, Sharma AM et al. CMAJ 2011

Edmonton Obesity Staging System (EOSS)
Stage 2 co-morbidity moderate end-organ damage severe pre-clinical risk factors mild Stage 1 Stage 3 end-stage Obesity Stage 0 Stage 4 absent absent absent Mental Medical Functional Sharma AM & Kushner RF, Int J Obes 2009

Edmonton Obesity Staging System
Stage 0: No obesity related risk factors Stage 1: Subclinical risk factors – borderline HTN or DM, minor aches or psychopathology Stage 2: Established obesity-related disease – HTN, DM, PCO, moderate limitations ADL Stage 3: Established organ damage – MI, CHF, DM comp, significant limitations of ADL Stage 4: Severe disabilities – end stage and limitations like wheelchair use Sharma AM and Kushner RF. Int J Obes ;33:289-95

EOSS Predicts Mortality at Every BMI Level NHANES III
Overweight Padwal R, Sharma AM et al. CMAJ 2011

EOSS Distribution Across BMI Categories NHANES III (1988-1994)
Overweight 23 million 10 million Class III 50 million 6 million Padwal R, Sharma AM et al. CMAJ 2011

Obesity is Leveling in Prevalence
The prevalence of obesity in 1961 was 10% in men and 15% in women defined as BMI >30 Obesity prevalence started to rise in 1980 The prevalence of obesity is now leveling off at 35.5% of the population. The prevalence of diabetes follows the prevalence of obesity by approximately 10 years Diabetes prevalence started to rise in 1990

NHANES – Prevalence of Obesity 1961-2012

Work Related Physical Activity is Falling
Church TS et al. Plos One.2011;6(5):e19657

Fall in Energy Expenditure at Work
Mean Occupation Related METs Year Energy Expenditure (calories) Occupation Related Daily Year Church TS et al. Plos One.2011;6(5):e19657

Weight Gain Predicted by Activity
et al. Plos One.2011;6(5):e19657

What is Causing the Epidemic
People are less active and are eating more There are many causes. We cannot just scapegoat fast food Obesity virus – Adenovirus D-36 is one cause Endocrine disruptors have been suggested Regardless of the cause, eating less and being more active will help – you will hear more in this seminar on ways to accomplish that.

Another Cause of Obesity
Adenovirus of D group 36 (AD-36) causes obesity in non-human primates but one cannot intentionally infect humans AD-36 antibodies: 30% of obese and 11% lean In identical twins discordant for antibodies, the positive twin had 2.1% more fat and had a BMI 1.4 units higher (p<0.03) This is insulin sensitive obesity with lower cholesterol and triglycerides Atkinson RL et al. Int J. Obes ;29(3):281-6

Is Obesity Prevalence Important?
Obesity is stigmatized especially in women and causes psychological distress. Obesity is associated with diabetes Obesity is associated with hypertension and heart disease Obesity is associated with cancer Obesity is associated with osteoarthritis and much disability.

The Prevalence of Diabetes in the US
CDC website

Diabetes The prevalence of diabetes has tripled since the 1980’s and is increasing It is estimated that 8.2% of the US population had Type 2 diabetes in 2010 and it is predicted that 10.8% will have Type 2 diabetes by 2020 0.2% of the population have type 1 diabetes and 3.1% have undiagnosed diabetes 28.4% of the US has pre-diabetes

Diabetes is Expensive It is estimated the diabetes costs the US health care system $194 billion in 2010 and will cost an estimated $500 billion in 2020. The US will spend approximately $3.4 trillion in the next decade on diabetes-related care The expense of diabetes and those associated obesity-related diseases like cancer, cardiovascular disease and others are and will stress our health care delivery system

Obesity Increases Risk of Diabetes

Obesity Increases Disability

Mortality Risk with Staging System
* * * * HR for All Cause HR for All CVD Ref Ref Kuk JL et al. Appl Physiol Nutr Metab ;36:

Association Between EOSS and Mortality Risk in Aerobics Center Longitudinal Study (n = 29 533)
Kuk JL, et al. Appl. Physiol. Nutr. Metab. 2011;36: 570

Obesity Related Disease Improves with Weight Loss
Sjostrom L et al. N Engl J Med ;357(8):741-52

Summary Obesity can be diagnosed by class and stage
People in the US are less active and eating more, but multiple causes for obesity exist Complications of obesity include diabetes, heart disease, cancer and increased mortality Obesity is expensive and straining our health care delivery system It is of utmost importance to screen for obesity and intervene in its management

Front Line Clinical Applications Regulating Energy Balance: The Pivotal Role of the Central Nervous System in Appetite Regulation Focus on 5HT2c Receptors and Other CNS Signaling Systems Controlling Neuroregulation of Energy Balance ROBERT J. MALCOLM, MD Professor, Department of Psychiatry and Behavioral Sciences Associate Dean for Continuing Medical Education, College of Medicine Medical University of South Carolina Charleston, SC

Weight Regulating Mechanisms and Effect of Anti-obesity Drugs – Its Complicated!
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

Biological Susceptibilities
Etiology of Obesity ENERGY EXPENDITURE Sedentary Lifestyle ENERGY Etiology of Obesity Obesity occurs when the body’s energy intake is out of balance with its expenditure over an extended period. The balance can be upset either by increased intake (eg, through a high-fat, high-calorie diet) or decreased expenditure (eg, through a sedentary lifestyle). A genetic predisposition to obesity accelerates the process. Treating obesity involves shifting the balance so that expenditure exceeds intake. INTAKE High Energy Genetic & Dense Foods Biological Susceptibilities (sugar or fat) (Underlying basis)

Feedback Model Controller Afferent Signals Controls Efferent Fat
Controlled System

Anatomy Monoamines Peptides Cytokines Afferent Signals Controls Efferent Fat Controlled System

Picture of Frohlich’s Case of Hypothlamic Obesity

Location of Hypothalamic Centers That Affect Feeding
Thalamus Mamillo-thalamic Track Dorsal Hyopthalmus Dorsomedial Hypo Lateral Hypo Surap-optic nucleus Ventromedial Hypo La Ventromedial Hypothalamic Lesions Lateral Hypothalamic Lesions

Monoamines, Peptides, Amino Acids & Drugs Affecting Food Intake
Increase Decrease Anandamide (cannabinoid agonist) Serotonin (5HT-1a auto) Serotonin Pump Inhibitors Anti-histamines Serotonin (5 HT-2c) Gamma-amino butyric acid (GABA) Histamine Noradrenergic Agents Cannabinoid Antagonists

Serotonin Biology - I Serotonin is most concentrated in the hypothalamus, basal ganglia and brainstem 7 groups of 14 serotonin receptors are known 5HT-1 - Intronless, G-protein coupled receptor that inhibits adenylyl cyclase 5HT-2 Contains introns, that are coupled to G-protein receptors that activate phospholipase C 5-HT2C is only in the brain 5HT-3 - Ligand-gated ion channel

Serotonin Biology - II Activation of 5-HT1A auto-receptor increases feeding Activation of 5-HT1B and 5-HT2C by any 5-HT agonist will reduce food intake 5-HT receptors in PVN specifically decrease fat intake Knock-out of 5-HT2C receptor produces obesity and convulsions. Serotonin reuptake inhibitors and releasers can precipitate weight loss or weight gain

Serotonin (and Other Agonists) in
PVN Reduce Food Intake 14 12 10 Saline 8 Serotonin 2-Hr Food Intake (kcal) 6 4 2 Carbohydrate Fat Protein Macronutrient Choice Smith B et al AJP 1999

Mice lacking 5-HT 2C receptors have hepatic insulin resistance
5-HT2CRs Expressed by Pro-opiomelanocortin Neurons Regulate Insulin Sensitivity in Liver Mice lacking 5-HT 2C receptors have hepatic insulin resistance Which is normalized by re-expression of 5-HT(2C) receptors only in pro-opiomelanocortin (POMC) neurons Evidence that 5-HT2C Rs expressed by POMC neurons are physiologically important in regulating hepatic glucose production and insulin sensitivity Moreover, this 5-HT2C R-melanocortin circuit is sufficient to mediate the anti-diabetic effects of 5- HT2CR agonists. Xu Y, et al Nat Neurosci Dec;13(12): Epub 2010 Oct 31

Serotonin 2c Receptor and Diabetes
POMC – Serotonin 5-HT2c Hypothalamus Insulin resistance Liver Intestines, Fat cells and the rest of the body sending up signals to stop eating

Serotonin Interacts with Melanocortin Pathways Regulating Energy Homeostasis
Anorectic serotonin (5-HT) drugs activate pro- opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. A serotonin 2C receptor is expressed on POMC neurons and contributes to this effect. Hypophagia induced by serotonin (5-HT) is attenuated by either pharmacological or genetic blockade of downstream melanocortin 3 and 4 receptors. Heisler LK, Dowley MA Kishi T. Ann N Y Acad Sci Jun;994:

Serotonin and Melancortin Receptors
We conclude that serotonin (5-HT) drugs require functional 5-HT2C receptors in the POMC that modulate melanocortin pathways to exert their effects on food intake. In animals without serotonin receptors, replacement specifically in the POMC neurons restores suppression of insulin by CNS serotonin Heisler LK, Dowley MA Kishi T. Ann N Y Acad Sci Jun;1994:169-74 .

Mean Weight Loss (% Initial Weight)
INDEX Study Completers dexfenfluramine n = 248 placebo n = 221 months 1 2 4 6 8 10 12 -3 -6 -8 -12 Treatment X Time Interaction To T12 p<0.001 / T6 T12 p<0.01 p<0.01 Mean Weight Loss (% Initial Weight) Guy-Grand et al INDEX study Lancet 1988

Phentermine: A Noradrenergic Drug Reduces Body Weight
Time in Weeks Continuous Phentermine Alternate Phentermine & Placebo Placebo 5 10 Weight loss (kg) Weight loss (lbs) Munro JF et al BMJ 1968;1:352-4

Peptides That Affect Food Intake
Increase Decrease Agouti-related peptide Dynorphin Ghrelin Melanin-concentrating hormone Neuropeptide Y Orexin A (Hypocretin) RF-2 peptides (arginine phenylalanine amide-2) Galanin-like-peptide α-MSH Corticotrophin-releasing hormone Cholecystokinin Cocaine-amphetamine regulated transcript Glucagon-like peptide-1 Leptin Amylin Bombesin/GRP Obestatin (part of ghrelin) Nesfatin-1 (NEFA-NUCB2)

Leptin the Ultimate Messenger of Fat Stores
POMC – Serotonin 5-HT2c Hypothalamus Weight Loss Leptin Fat Cells Intestines, Liver, Pancreas and the rest of the body sending up signals to stop eating

Model of the Arcuate Nucleus
Model showing the afferent signals from the periphery that modulate the activity of hypothalamic neurons in a reciprocal way to increase or decrease food intake Badman, Science 2005

Obesity Is Associated with
Inflammatory Hypothalamic Injury “….Consumption of a High Fat Diet rapidly induces neuronal injury in a brain area critical for energy homeostasis.“ Thaler, J et al, J Clin Invest Jan 3;122(1):

Hypothalamic Inflammatory Markers Increase on High Fat Diet
Data are after 3 days of eating a high fat diet 2.0 2.0 mRNA (fold increase) 1.5 1.0 0.5 Il1-b Il Tnf-α Socs3 Nfkb IkBkb IkBkθ Inflammatory Markers Thaler JP et al J Clin Invest 2012;122:

Obesity Is Associated with Inflammatory Hypothalamic Injury
“….Consumption of a HFD rapidly induces neuronal injury in a brain area critical for energy homeostasis.“ “In human beings there is MRI evidence for gliosis in the hypothalamus of obese humans.” “Collectively, this work identifies a potential link between obesity and hypothalamic injury in humans as well as animal models.” Thaler, J et al, J Clin Invest Jan 3;122(1):

Leptin Resistance and Cytokines
“Taking all of these phenomena into account, we think that it is possible that overconsumption of nutrients could be a reason for development of leptin resistance” “This line of thinking favors the fact that increased adiposity and consequent hyperleptinemia decreases the leptin action and creates the leptin resistance” Ergin A, Cell Metabolism 2008;12:2004

Does This Explain How Something Environmental Turns Into Something “Physical?”
High fat diets and inflammation Evidence of apoptosis and glial ensheathment of ARC neurons in animals rendered obese by chronic HFD feeding. Moreover, these responses were detected specifically in ARC POMC cells 25% reduction in the number of hypothalamic POMC neurons Mice chronically fed a HFD. POMC cells play an essential role to protect against obesity Loss of these cells is sufficient in and of itself to cause excess weight gain in mice Fattening Foods Cause Dropout of POMC Neurons and Glial Ensheathment of ARC Neurons. Does That Explain Why It’s So Hard To Lose Weight?

Hypothetical “Feed-forward,” Positive Feedback Mechanism Drives Weight Up
“Brain can’t tell how much fat is stored” Increases fat mass to restore equilibrium High Fat High Carb Food Hypothalamic injury POMC neuron dropout Leptin resistance Reduced sense of satiety and cravings Metabolic effects Increased Hypothalamic injury Increased leptin resistance Increased food intake Weight gain Wang J, Diabetes, 2001; DiMarzo V pers comm Ozcan L et al Cell Metabolism; 2009 © 2012 Louis J. Aronne, MD 72

What is Causing the Epidemic of Obesity and Why Is It So Hard to Lose Weight?
Afferent Signals Central Signals Efferent Stimulate Inhibit NPY AGRP galanin Orexin-A Dynorphin Cannabinoids α-MSH CRH/UCN GLP-I CART NE 5-HT Ghrelin GLP-1 CCK Vagus Autonomic Nervous System External Factors Food Availability, Palatability Food Intake Meal Size Gut and Liver Amylin Insulin Pancreas Energy Balance and Adipose Stores Energy Expenditure Leptin Adipose Tissue Adrenal Steroids Adrenal Cortex Adiponectin © LJ Aronne MD. Adapted from Campfield LA et al. Science. 1998;280: ; Porte D et al. Diabetologia. 1998;41:

Weight Regulating Mechanisms and Effect of Anti-obesity Drugs – It’s Complicated!
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

Treatment Gap in the Management of Obesity
QNEXA_Core_ _v03_NO_HIDDEN.ppt Treatment Gap in the Management of Obesity 4/13/2017 Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities Current Pharmacotherapy Too risky for many people Lap Band Gastric Bypass Treatment Gap Between diet and exercise and the current pharmacotherapy on one hand, and bariatric surgery on the other We need more treatments to fill the treatment gap, treat people in whom surgery is not indicated In hypertension we have 100 medications in 9 categories, 0% 5% 10% 15% 20% 25% 30% 35% What will fill the gap ? New meds, combos, less invasive surgery QNEXA

Investigations  Stratification Front Line Clinical Applications New Frontiers and Treatment Paradigms for Pharmacologic Management of Obesity Focus on Safety and Efficacy of Agents Affecting CNS Signaling Systems and Appetite Regulation MARC-ANDRE CORNIER, MD - Program Chairman Associate Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Anschutz Health and Wellness Center University of Colorado School of Medicine Denver, CO

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

Guide to Selecting Obesity Treatment

Where Have We Been? Where Are We Going?
Obesity: A physiologically controlled chronic disease. Medications work when taken. Safety and benefit issues with obesity The evolution of chronic disease medications Drugs recently approved Drugs in late development Obesity drugs in the future

Fenfluramine 1-Year Rx & 1-Year Follow-up

Chronic Disease Drug Development
Hypertension Obesity Orlistat – calories in stool CNS drugs – side effects eg. amphetamine and addiction Combinations to lower side effects and increase efficacy eg topiramate-phentermine Peripherally acting drugs (in development) Diuretics – salt in urine CNS drugs – side effects eg. reserpine and depression Combinations to lower side effects and increase efficacy Peripherally acting drugs eg. angiotensin receptor blockers

Obesity Pharmacotherapy A Bad Safety Record
1893: Thyroid hormone -> hyperthyroidism 1933: Dinitrophenol -> cataracts/neuropathy 1937: Amphetamine -> addiction 1967: Rainbow pills (digitalis & diuretics) -> CV sx 1997: Fenfluramine -> valvulopathy 2000: Phenylpropanolamine -> stroke 2004: Herbal caffeine & ephedra -> CV sx 2010: Sibutramine -> MI and stroke

Weight Loss Drugs Approved by FDA
Generic Name Trade Name Phentermine/Topiramate Qsymia Lorcaserin Belviq Orlistat Xenical, Alli Phentermine Adipex, Fastin, Ionamin Diethylpropion Tenuate, Tenuate, Dospan Phendimetrazine Bontril, Plegine, Prelu-2, X-Trozine Methamphetamine Desoxyn Benzphetamine Didrex Mazindol Sanorex, Mazanor This table lists the medications approved by the United States Food and Drug Administration (FDA) for the treatment of obesity; only sibutramine (Meridia) and orlistat (Xenical) have been approved for long-term use. All the approved medications act as anorexiants, with the exception of orlistat, which blocks the absorption of dietary fat. Anorexiants increase satiation (level of fullness, which regulates the amount of food consumed during a meal) or satiety (level of fullness after a meal, which determines frequency of eating), or both. Although approved by the FDA for short-term use, methamphetamine and benzphetamine are addictive and should be avoided. Three anorexiant medications have been removed from the marketplace because of increased risks of either valvular heart disease (fenfluramine and dexfenfluramine) [1] or hemorrhagic stroke (phenylpropanolamine) [2] associated with their use. References 1. Khan MA et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med. 1998;339: 2. Kernan WN et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000;343:

Efficacy of Currently Available Weight Loss Medications
Drug Phentermine Orlistat Lorcaserin Phentermine/Topiramate Average Weight Loss 3.6% > placebo 2.75% > placebo 3.3% > placebo 9% > placebo

Phentermine Mechanism: Dose: 15-37.5 mg daily (AM)
Appetite suppressant Inhibits NE and dopamine release Dose: mg daily (AM) FDA approved for short-term (3 months) use Side effects: Increased BP and HR, insomnia, agitation, dry mouth, headache, tremor Efficacy: More weight loss than placebo (~3-5%)

Orlistat Mechanism: Inhibits lipases and blocks fat absorption by ~30% (reduction in absorbed fat) Dose: mg TID (with meals) FDA approved for long-term use Side effects: mild to moderate GI “events”, potential for malabsorption of fat soluble vitamins, liver toxicity?, nephrolithiasis Efficacy: More weight loss than placebo (~4%) More lose at least 5% (35-69% vs 16-30% with placebo) More lose at least 10% (16-25% vs 4-12% with placebo) Prevention of diabetes incidence Improvements in glycemic control in T2D

Lorcaserin Brand name: Belviq
Approved in 2012 (10 mg BID) for long-term weight management Mechanism: Selective 5-HT2C receptor agonist increases satiety – appetite suppressant Bays HE. Expert Rev Cardiovasc Ther. 2009;7: ; Belviq [prescribing information]. Woodcliff Lake, NJ: Eisai; Inc

BLOOM Study Body Weight Over Years 1 and 2
2.16 ± 0.14% 5.81 ± 0.16% BLOOM = Behavioral Modification and Lorcaserin for Obesity. Smith SR, et al. N Engl J Med. 2010;363:

BLOOM Study Body Weight Over Years 1 and 2
47.5% 22.6% 20.3% 7.7% BLOOM = Behavioral Modification and Lorcaserin for Obesity. Smith SR, et al. N Engl J Med. 2010;363:

BLOOM-DM Change in Glycemic Parameters
HbA1C, -0.5% Fasting Plasma Glucose Change From Baseline (mg/dL) * Change From Baseline (%) † * * * * * Study Week Study Week Placebo Lorcaserin 10 mg twice a day *P <.001; †P <.05; least square mean change ± standard error of the mean. HbA1C = glycosylated hemoglobin. O’Neil PM, et al. Obesity. 2012;20:

Summary of Echocardiographic Safety Monitoring
Confidential Draft - For Discussion Purposes Only Summary of Echocardiographic Safety Monitoring 4/13/2017 More than 20,000 echocardiographs More than 7,500 patients Lorcaserin did not increase the risk of valvulopathy above the pre-specified margin relative to placebo Lorcaserin did not meaningfully affect regurgitant scores at any heart valve FDA defined valvulopathy relative risk: 1.16 (95% confidence interval (0.81, 1.67, NS) Taken together, data from more than 20,000 echoes in nearly 7500 patients show that lorcaserin did not increase the risk of valvulopathy above a pre-specified level, and did not meaningfully affect individual valve regurgitant scores. [PAUSE] Let’s move now to the evaluation of possible CNS effects…….

Lorcaserin Most common AEs: Headache, nausea, dizziness, fatigue, dry mouth, constipation Notes Discontinue if 5% weight loss is not achieved by week 12 Discontinue for evaluation if signs or symptoms of valvular heart disease DEA Schedule CIV Pregnancy category X Interesting effect on glycemia – greater benefit than expected for degree of weight loss Bays HE. Expert Rev Cardiovasc Ther. 2009;7: ; Belviq [prescribing information]. Woodcliff Lake, NJ: Eisai; Inc

Phentermine and Fenfluramine Phen - Fen
Weintraub M et al. Clin Pharmacol Ther. 51(5):586-94, 1992.

Phentermine/Topiramate ER
Brand name: Qsymia Approved in 2012 for long-term weight management Mechanism: Phentermine: inhibits NE and dopamine release Topiramate: mechanism on weight loss is not known Increases satiety – appetite suppressant Dosing: Start at 3.75/23mg daily x 2 weeks then↑to 7.5/46mg After 12 weeks can↑to 11.25/69mg and 15/92mg

Phentermine/Topiramate Phase III Trial
Gadde KM et al. Lancet ;377(9774):

Phentermine/Topiramate Phase III Trial
Garvey, et al. Am J Clin Nutr 2012;95:

Phentermine/Topiramate ER
Most common AEs: paresthesias, dizziness, dysgeusia, insomnia, constipation and dry mouth. Other AEs:  BP and HR, headache, suicidal thoughts, myopia/secondary angle closure glaucoma, cognitive impairment, metabolic acidosis,↑creatinine Notes Discontinue if 5% weight loss is not achieved by week 12 DEA Schedule Class IV Pregnancy category X Safety: fetal cleft palate - pregnancy test q mo.

Obesity Drugs and CVD Risk Factors
Anti-Obesity Agent BP LDL-C TG HDL-C Phentermine/ Topirmate ER   Lorcaserin No significant change Bays HE. Specialty Corner: Investigational Anti-obesity Agents to Treat Adiposopathy and "Sick Fat.” pages CP Hayes, S AU

New Frontiers and Treatment Paradigms for Pharmacologic Management of Obesity
What’s in the Pipeline?

Naltrexone/Bupropion
Not yet FDA approved CVD safety study in progress Dose: 3 week escalation to 16/180mg SR bid Mechanism: Naltrexone: opioid receptor antagonist Buproprion: NE/dopamine reuptake inhibitor Appetite suppressant, reduces cravings? Adverse events : Nausea, headache, constipation, dizziness, vomiting, insomnia, dry mouth & hot flushes

Bupropion 360 & Naltrexone 32 mg
Placebo (N=511) NB16 (N=471) NB32 (N=471) Placebo Completers (N=290) NB16 Completers (N=284) NB32 Completers (N=296) ITT-LOCF Observed Completers Placebo-subtracted weight loss Week 56 NB16: -3.7% NB32: -4.8% Placebo-subtracted weight loss Completers NB16: -4.9% NB32: -6.2% P<0.001 for NB16 and NB32 vs. Placebo at all time points Greenway FL et al. Lancet. 376(9741): , 2010

Liraglutide 3 mg/d in Obese Subjects
Astrup A et al. Lancet 374(9701): , 2009

Zonisamide 360 + Bupropion 360 mg Weight Loss at 1 Year of Treatment
Placebo (a) (N=72) Z120/B280 (N=27) Z120/B360 (N=36) Z240/B280 (N=36) Z240/B360 (N=26) Z360/B280 (N=32) Z360/B360 (N=39) (a) Placebo weight loss through 24 weeks as noted previously

Beloranib Methionine Aminopeptidase 2 (MetAP2) Inhibitor
METAP2 is an enzyme which plays a key role in the production and use of fatty acids Reduced food intake? Reduced lipogenesis? Increased lipolysis?

Belornib - Body Weight in Mice
Body weights during the course of 1 mg/kg/day fumagillin (ZGN-201) treatment

Belornib – Weight Loss in Humans
Impact of ug/kg/dose ZGN-433 treatment on body weight in obese women Values are medians ± SEM (n=6-8) for the per protocol population. *** p<0.001 by 2-way ANOVA and Bonferroni post-test.

Summary Obesity is a chronic physiologically controlled disease that requires chronic treatment We have two new CNS acting drugs for obesity lorcaserin and phentermine/topiramate There are 3 drugs in late stage development: naltrexone/bupropion, liraglutide, and zonisamide/bupropion Peripherally acting drugs are being developed but may be limited by side effects. There is significant variability in the weight loss response, so important to consider predictors of response as we move forward

Investigations  Stratification Front Line Clinical Applications Real World Challenges in Obesity Management Case Study-Based Learning Workshops and Clinical Simulations in Obesity Management MARC-ANDRE CORNIER, MD - Program Chairman Associate Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Anschutz Health and Wellness Center University of Colorado School of Medicine Denver, CO

Case Study 1 ER, a 46-year-old woman, initially presents with high blood pressure, which has been well controlled with a diuretic agent. Since her last visit 6 months ago, she has been experiencing some heartburn, self-treated with over-the-counter H2-blockers, and more aching in her weight-bearing joints. On exam, her height is 66 inches and body weight is 190 pounds, up 5 pounds from her last visit. Blood pressure is 134/90, up several points from her last visit as well. The rest of the exam is unchanged. Her previous lab tests were within normal limits. Current test results indicate a fasting glucose of 118 mg/dL, total triglycerides of 255 mg/dL, and high-density lipoprotein (HDL cholesterol) of 42 mg/dL. All other tests are normal.

Case Study 1 With a height of 66 inches and weight of 190 pounds, ER’s BMI is 31. This places her in Class I (mild) obesity. Her waist circumference is 36 inches. This, in addition to her triglycerides of 225 mg/dL, fasting glucose of 118 mg/dL, HDL cholesterol of 42 mg/dL, and blood pressure of 134/90, shows that she has the metabolic syndrome. This places her at increased risk of cardiovascular disease. In reviewing ER’s history, you identify five obesity-related conditions: Hypertension Gastroesophageal reflux disease (GERD) Impaired glucose tolerance (possible diabetes) Hypertriglyceridemia and low HDL-C levels Arthralgia

Please Enter Your Response On Your Keypad
Case Study 1 - Question 1 You decide to order additional tests to evaluate ER’s hypertension and diabetes. Based on the NHLBI algorithm, treatment for ER’s obesity is indicated. At this point you would: Recommend diet and lifestyle changes Initiate orlistat Initiate lorcaserin Initiate phentermine Initiate phentermine HCl/topiramate CR Please Enter Your Response On Your Keypad

Case Study 1 - Question 2 In this case, diet and lifestyle changes were recommended, with an assessment after 90 days. The patient returned with an additional 2 lb. weight gain and reported difficulty in maintaining diet. At this point you would: Modify diet and lifestyle recommendations and reassess in 90 days Initiate orlistat Initiate lorcaserin Initiate phentermine Initiate phentermine HCl/topiramate CR Please Enter Your Response On Your Keypad

Case Study 1 - Question 3 90 days later, she is tolerating the weight management drug well, has experienced a 5% weight loss, and improvement in metabolic parameters. She reports increased energy and improved self-esteem. At this point you would: Cease pharmacotherapy and recommend diet and lifestyle changes Cease pharmacotherapy, recommend diet and lifestyle changes, and revisit in 90 days Maintain current pharmacotherapy Switch to alternative pharmacotherapy Please Enter Your Response On Your Keypad

Case Study 1 - Question 4 90 days later, she is not tolerating the weight management drug well, has experienced a 5% weight loss, and improvement in metabolic parameters. She reports increased energy and improved self-esteem. At this point you would: Cease pharmacotherapy and recommend diet and lifestyle changes Cease pharmacotherapy, recommend diet and lifestyle changes, and revisit in 90 days Maintain current pharmacotherapy Switch to alternative pharmacotherapy

Case Study 2 42-year-old man with BMI 37
Weight 242 lbs., up 5 lbs. from 6 months earlier Gout well-controlled on allopurinol Hyperlipidemia (on low-dose simvastatin); bilateral knee arthritis Examination Central obesity with waist circumference 44 in. BP 132/82 Laboratory studies Fasting glucose 90 Fasting triglycerides 260 Cholesterol 220; LDL cholesterol 146; HDL cholesterol 38 Other tests normal

Case Study 2 Weight and lifestyle history Mildly heavy as a child
“Grew out of it” during adolescence; participated in competitive sports in high school and college Weight stable at ~185 lbs. (BMI 28.3) until 12 years ago Slowly progressive 55 lb. weight gain over last 10 years Works as salesman with hectic lifestyle; irregular meals; frequent fast foods and snacking No previous serious weight loss attempts; feels healthy Has exercised at gym 4x/week over the past year with only 4 lb. weight loss

Case Study 2 - Question 1 You increase the dose of simvastatin. What would you do to treat the obesity? Recommend a healthier and more regular diet Encourage a more vigorous exercise program Refer him to a psychologist for behavior modification Initiate orlistat therapy Initiate lorcaserin therapy 42 M BMI 37 Central distribution Pre-DM Dyslipidemia GERD Gout OA Childhood onset Steady adult gain Irregular eater Fast food diet Regular exerciser Hectic lifestyle Please Enter Your Response On Your Keypad

Case Study 2 Clinical progress
He listens to your dietary advice and stops snacking His hectic lifestyle continues, but he eats more meals at home and is able to change from fast food to family style restaurants when traveling Continues to exercise regularly Lost 4 lbs. (to 238 lbs.) in the first month but none since, despite maintaining his new lifestyle At follow-up 3 months later, his weight is 239 lbs., BP 128/84 and LDL and total cholesterol in the normal range

Case Study 2 – Question 2 What would you do now? Continue to encourage a healthy diet Refer to dietitian for nutritional management Refer to a stress management program Initiate phentermine therapy Initiate lorcaserin therapy Please Enter Your Response On Your Keypad

He sees a dietitian who recommends a specific dietary regimen, which he follows reasonably well Over the ensuing 3 months, he loses 12 lbs. At his annual visit 9 months after that, however, he has regained 10 of the 12 lbs. and weighs 237 lbs. (BMI 36.2) His cholesterol levels and BP remain normal His fasting glucose is 114, and his triglyceride level is 222, and his HbA1c is 6.6%

Case Study 2 – Question 3 What would you do now? Continue to encourage a healthy diet Refer back to the dietitian for additional counseling Refer to a stress management program Initiate phentermine therapy Initiate lorcaserin therapy Please Enter Your Response On Your Keypad

You begin phentermine at 15 mg/day, monitoring BP and pulse carefully He reports dry mouth that resolves after about 3 weeks; he otherwise tolerates the medication well, without tachycardia, hypertension or subjective adverse effects At 30 days, he has lost 5 lbs. (2.1% of pretreatment weight) At 3 months, he weighs 223 lbs. (BMI 34.1), having lost 14 lbs. (5.9%) on phentermine He continues the recommended dietary changes Two months later (on phentermine for 5 months), he has lost 1 additional lb. and weighs 222 lbs. (BMI 33.9) Total weight loss 20 lbs. since first visit; total weight loss on phentermine 15 lbs. (6.3%)

Case Study 2 - Question 4 What would you do now? Continue the phentermine at 15 mg/day and re- emphasize the recommended diet and lifestyle changes Stop the phentermine and follow his clinical progress Stop the phentermine and start orlistat at 120 mg tid Increase the phentermine to 30 mg/day Recommend consultation for bariatric surgery Please Enter Your Response On Your Keypad

He tolerates the increased dose of phentermine well with only transient dry mouth At 30 days, he has lost 2 additional lbs. (0.8% of pretreatment weight) At 3 months, he weighs 221 lbs. (BMI 33.8), having lost 16 lbs. (5.9%) on phentermine overall

Case Study 2 - Question 5 What would you do now? Continue the phentermine at 30 mg/day and refer back to the dietitian Stop the phentermine and follow his clinical progress Stop the phentermine and start orlistat at 120 mg tid Add topiramate by substituting the low-dose combination of phentermine (3.75 mg/day) and topiramate (23 mg/day) for the phentermine alone Recommend consultation for bariatric surgery Please Enter Your Response On Your Keypad

He tolerates the low-dose phentermine-topiramate combination (“phen-top”) well, without adverse effects After 14 days, you increase the phen-top dose to 7.5 mg phentermine + 46 mg topiramate daily In the first 30 days of phen-top therapy, he loses 3 lbs. to a weight of 218 lbs. (BMI 33.3) Over the next 3 months, he loses an additional 8 lbs. to a weight of 210 lbs. (BMI 32.1)

Case Study 2 Weight loss summary Initial weight 242 (BMI 37)
Diet modification – 5 lb. weight loss over 1 year (2.1%) Phentermine – 16 lb. weight loss over 8 months (6.8%) Phentermine-topiramate combination – 11 lb. additional weight loss over 4 months (4.9%) Total medication-induced weight loss – 27 lbs. (11.4%) Current weight 210 lbs. (BMI 32.1), down 32 lbs. (13.2%) overall since initial visit 2 years earlier

Case Study 2 - Question 6 What would you do now? Continue the phen-top at current dosing Stop the phen-top, re-enforce lifestyle adjustments and follow his clinical progress Increase the phen-top dosing to 15 mg phentermine + 92 mg topiramate daily (“high dose”) Add lorcaserin at 10 mg bid Recommend consultation for bariatric surgery Please Enter Your Response On Your Keypad

Case Study 3 51-year-old woman with BMI 43.3
Weight 252 lbs., height 5’4” Well-controlled hypertension, hypothyroidism, Barrett’s esophagus, osteoarthritis (s/p knee replacement), colonic polyps, and depression Type 2 diabetes on pioglitazone, glimepiride and insulin (long- and short-acting to total of 65 units/day) no eye, neurological or vascular complications Sleep apnea well-controlled on CPAP Other medications include losartan, hydrochlorthiazide, omeprazole, levothyroxine, omeprazole, aspirin and sertraline

Case Study 3 Examination
Central obesity with waist circumference 41 in. Benign, protuberant abdomen; no signs of chronic liver disease No signs of peripheral neuropathy Benign abdomen Laboratory studies Fasting glucose 111 HbA1c 7.1% AST 43, ALT 51, alkaline phosphatase 120 BUN 32; creatinine 1.2 TSH 5.64 Other tests normal

Case Study 3 Weight and lifestyle history
Normal weight as a child; overweight in college and graduate school (weight ; BMI 26-30) Progressive weight gain in adult life; “insatiable” appetite with frequent cravings and large portions Numerous unsupervised, supervised and structured diets with variable weight loss (up to 30 lbs.); none maintained Average weight stable over the past few years; currently at highest lifetime weight Married with grown children; works as financial planner Cooks regularly and well, and entertains often Exercises three times a week with a physical trainer

Case Study 3 - Question 1 You increase the dose of L-thyroxine. How would you initiate obesity treatment? Recommend a meal-replacement program Substitute citalopram for sertraline Refer her to a psychologist for cognitive- behavior therapy for the depression Substitute metformin for glimepiride Initiate treatment with a combination of phentermine and topiramate 51 F BMI 43.3 Central distribution T2DM (55 OSA Hypothyroidism GERD / Barrett’s OA Colonic polyps Depression Adult onset Healthy diet Often hungry Large portions Regular exerciser Please Enter Your Response On Your Keypad

You discontinue the sulfonylurea and start metformin at 500 mg bid, monitoring her glucose carefully and adjusting short-acting insulin as required In the next 30 days, she loses 5 lbs. to a weight of 247 lbs. (BMI 42.4) You increase the metformin to 750 mg bid At 3 months, she has lost a total of 14 lbs. (5.6%) to 238 lbs. She reports a noticeably diminished appetite and cravings Insulin requirement falls from 65 to 52 units/day 3 months later, her weight is stable at 235 lbs. (BMI 40.3), down 17 lbs. (6.7%)

Case Study 3 - Question 2 What would you do now to treat the obesity? Refer to a commercial weight loss program Substitute bupropion for sertraline Initiate therapy with a combination of phentermine and topiramate Initiate therapy with lorcaserin Refer for bariatric surgery Please Enter Your Response On Your Keypad

Low-dose phen-top (phentermine 3.75 mg + topiramate 23 mg daily) initiated and well-tolerated After 14 days, you increase the phen-top dose to phentermine 7.5 mg + topiramate 46 mg daily with no adverse consequences In the first 30 days of therapy, she loses 4 lbs. (1.7%) to 231 lbs. (BMI 39.6) At 3 months, she has lost a total of 6 lbs. (2.6%) to 229 lbs.

Case Study 3 - Question 3 What would you do now? Continue the phen-top at current dosing and add orlistat at 120 mg tid Stop the phen-top and start phentermine at 15 mg daily Stop the phen-top and start lorcaserin at 10 mg bid Stop the phen-top and start orlistat at 120 mg tid Stop the phen-top and substitute liraglutide s.c. for the pioglitazone Please Enter Your Response On Your Keypad

Case Study 3 Clinical progress She tolerates the new medication well
After 30 days, she reports feeling increased hunger and her weight has increased 3 lbs. to 232 lbs. After 60 days, her weight remains at 232 lbs. (BMI 39.8) Her diabetes remains well-controlled with a fasting glucose of 114 and HbA1c of 6.9%

Case Study 3 - Question 4 What would you do now? Stop all weight loss medications and refer to a dietitian to reinforce healthy eating habits Stop all weight loss medications and refer to a psychologist for behavioral therapy Continue the current regimen and restart a combination of phentermine and topiramate Stop all weight loss medications and institute an 8-week physician-supervised very low calorie diet (VLCD) Stop all weight loss medications and refer for bariatric surgery Please Enter Your Response On Your Keypad

She undergoes uneventful laparoscopic Roux-en-Y gastric bypass with post-operative weight loss ~50 lbs. Her diabetes remains well controlled (HbA1c 6.6%) without need for insulin, pioglitazone or liraglutide, and on a reduced dose of metformin (500 mg bid) Other comorbidities improved or resolved except for continued joint pain and reflux symptoms One year after surgery, her weight is down 51 lbs. to 181 lbs. (BMI 31.1), which has been stable for more than 3 months She feels much better overall but is a bit disappointed in the weight loss outcome (which is less than the average 65% excess weight loss from this operation)

Case Study 3 - Question 5 What would you do now? Indicate that there is no further therapy beyond surgery and reinforce the need to follow a healthy lifestyle Refer her to a psychologist to help address her expectations Encourage her to extend post-operative weight loss with a low-calorie (calorie restricted) diet Institute pharmacological therapy with lorcaserin Refer her back to the surgeon for consideration of revising the surgical procedure Please Enter Your Response On Your Keypad

Lorcaserin at 10 mg/day is started and well-tolerated Over the next 6 months, she loses an additional 15 lbs. to a weight of 164 lbs. (BMI 27.3) Her comorbidities remain improved, and her diabetes is in remission off all medications (HbA1c 6.3%)

Case Study 3 Weight loss summary Initial weight 252 (BMI 43.3)
Substitution for weight-promoting drugs – 23 lb. weight loss over 1 year (2.1%) Phentermine-topiramate combination – 16 lb. weight loss over 3 months (2.6%) Other pharmacological agents – 3 lb. weight gain over 2 months (1.3%) Total medical weight loss – 20 lbs. (7.9%) Gastric bypass – 51 lbs. (22.0%) weight loss over 1 year (58.8% excess weight loss) Lorcaserin after surgery – 15 lbs. over 6 months Current weight 159 lbs. (BMI 27.3), down 93 lbs. (36.9%) since initial visit 3 years earlier

Case Study 4 46-year-old woman with BMI 30.7
Weight 190 lbs., up 5 lbs. from 6 months earlier Hypertension, heartburn, weight-bearing joint pain Examination Central obesity with waist circumference 36 in. BP 134/90 Laboratory studies Glucose 118; HbA1c 6.4% Triglycerides 255 mg/dL, LDL cholesterol 140 HDL cholesterol 42 mg/dL Other tests normal

Case Study 4 Weight and lifestyle history Normal weight as child
Progressive weight gain after college exacerbated after having children in late 20s Previously on intermittent diets with up to 20 lb. weight loss, but invariable weight regain Eats mostly home-prepared food Little or no snacking, but eats meals irregularly Single mother of 2 teenagers, with steady boyfriend Works as nursing assistant on evening and night shift Walks extensively at work; no structured exercise

Case Study 4 - Question 1 What treatment would you initially recommend for this patient? 1. Broad-based diet and lifestyle counseling 2. Implementation of moderate structured exercise regimen 3. Cooking classes 4. Change jobs 5. Initiate pharmacotherapy for obesity 46 F BMI 30.7 Central distribution Pre-DM HTN Dyslipidemia GERD Joint pain Obesity onset 20s Failed diets Home-cooker Irregular eater Walks a lot Night shift worker Stressful life Please Enter Your Response On Your Keypad

Modest, regular, aerobic exercise program initiated and maintained At follow-up 2 months later, her weight was down 6 lbs. to 184 lbs. (BMI 29.7)

Case Study 4 – Question 2 You recommend that she continue the exercise program. What else would you recommend now? Laud her success and encourage continuing a healthy lifestyle Refer to exercise trainer to help with exercise Encourage a more regular eating pattern Suggest that she change to day shift Initiate pharmacotherapy for obesity Please Enter Your Response On Your Keypad

Case Study 4 Clinical progress Continued regular exercise program
Stopped grazing and began eating on regular schedule Change in eating schedule resulted in stabilization of sleep patterns as well At follow-up three months later, her weight was down 8 more lbs. (14 lbs. weight loss total ), to 176 lbs. (BMI 28.4) She describes increased energy and improved self-esteem

Case Study 4 – Question 3 What would you recommend now? Encourage a healthy diet and reassess HbA1c Refer to dietitian for nutritional management Initiate pharmacotherapy for obesity Recommend bariatric surgical evaluation for type 2 diabetes Refer to plastic surgeon for liposuction Please Enter Your Response On Your Keypad

Front Line Clinical Applications Summary and Vision Statement Near Term Challenges and Potential Strategies for Optimizing Obesity Management in the Primary Care Setting

Summary Obesity is a chronic physiologically controlled disease that requires chronic treatment Must be approached like other chronic diseases Yes, there are still many barriers and challenges to overcome with the management of obesity But there are also many opportunities Awareness and education are critical! Lifestyle modification is at the core of all our therapeutic options We have good pharmacotherapies and new agents on the horizon yet these are underused We must use all of the tools at our disposition

Summary Reasons Why You Should Treat Overweight-Obesity
Excess adiposity adversely impacts health Obesity is a medical condition with a physiologic and behavioral component like many other chronic medical conditions we routinely treat on an ongoing basis in primary care Our patients are asking for help If you don’t, then who will?

Questions and Answers Investigations  Stratification
Front Line Clinical Applications Questions and Answers

MARC-ANDRE CORNIER, MD - Program Chairman

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MARC-ANDRE CORNIER, MD - Program Chairman

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