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Investigations  Stratification Front Line Clinical Applications New Frontiers and Emerging Treatment Paradigms for Optimizing Management of Obesity Focus.

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Presentation on theme: "Investigations  Stratification Front Line Clinical Applications New Frontiers and Emerging Treatment Paradigms for Optimizing Management of Obesity Focus."— Presentation transcript:

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2 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 Chai rman Associate Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Anschutz Health and Wellness Center University of Colorado School of Medicine Denver, CO

3 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

4 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

5 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

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

7 Complications of Obesity Psychological Neoplastic Inflammatory Structural Metabolic Degenerative

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

9 Obesity is Counterintuitive  Hides in plain sight Most obesity NOT recognized by physicians or the publicMost 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 subtypesPossibly 100 or more clinically meaningful subtypes This recognition is essential to solving the problemThis recognition is essential to solving the problem

10 Cause of Obesity Historical view Historical view  Lifestyle choice  Characterological flaw (willpower, psychology) Current perspective 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

11 Weight and Energy Balance FoodIntake EnergyExpenditure By the laws of physics…

12  Average adults consume kcal/day Average adults therefore consume 2-3 times as much food as requiredAverage adults therefore consume 2-3 times as much food as required Excess intake is available for physiological emergenciesExcess 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/dayCorresponds to accuracy of 4-5 kcal/day Less than one-half potato chipLess than one-half potato chip  Maintenance of normal fat stores (and body weight) requires precise disposal of 60-70% of ingested calories daily The Normal Physiology of Energy Balance Thus, daily energy balance is likely an evolved physiological trait largely independent of cultural or behavioral differences.

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

14 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?

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

16 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  is normal, is overweight, is class I, is class II, >40 is class III

17 Relationship Between Mortality and BMI Data from Lew EA: Mortality and weight: insured lives and the American Cancer Society studies. Ann Intern Med 103: , VeryLow Low Moderate High VeryHigh MenWomen Mortality Ratio Body Mass Index, kg/m 2

18 Mortality: Diastolic Blood Pressure

19 Mortality: Body Mass Index

20 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

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

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

23 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. 2009;33:289-95

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

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

26 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

27 NHANES – Prevalence of Obesity

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

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

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

31 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.

32 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. 2005;29(3):281-6

33 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.

34 The Prevalence of Diabetes in the US CDC website

35 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

36 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 ► 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

37 Obesity Increases Risk of Diabetes

38 Obesity Increases Disability

39 Mortality Risk with Staging System Kuk JL et al. Appl Physiol Nutr Metab. 2011;36: HR for All Cause HR for All CVD Ref * * * *

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

41 Obesity Related Disease Improves with Weight Loss Sjostrom L et al. N Engl J Med. 2007;357(8):741-52

42 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

43 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 Investigations  Stratification Front Line Clinical Applications 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

44 Weight Regulating Mechanisms and Effect of Anti-obesity Drugs – Its Complicated! Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi: /clpt Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways Slide:Dr. Caroline Apovian

45 High Energy ENERGY ENERGY Sedentary Lifestyle Dense Foods (sugar or fat) INTAKE EXPENDITURE Genetic & Biological Susceptibilities (Underlying basis)

46 Controlled System Controller Feedback Model Afferent Signals Efferent Controls Fat

47 Controlled System Controller Afferent Signals Efferent Controls Fat Anatomy Monoamines Peptides Cytokines Feedback Model

48 Picture of Frohlich’s Case of Hypothlamic Obesity

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

50 Controlled System Controller Afferent Signals Efferent Controls Fat Anatomy Monoamines Peptides Cytokines Feedback Model

51 Monoamines, Peptides, Amino Acids & Drugs Affecting Food Intake ► 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 IncreaseDecrease

52 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

53 ► Activation of 5-HT 1A auto-receptor increases feeding ► Activation of 5-HT 1B and 5-HT 2C by any 5-HT agonist will reduce food intake ► 5-HT receptors in PVN specifically decrease fat intake ► Knock-out of 5-HT 2C receptor produces obesity and convulsions. ► Serotonin reuptake inhibitors and releasers can precipitate weight loss or weight gain Serotonin Biology - II

54 CarbohydrateFatProtein 2-Hr Food Intake (kcal) Saline Serotonin Smith B et al AJP 1999 Macronutrient Choice Serotonin (and Other Agonists) in PVN Reduce Food Intake

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

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

57 ► 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. Serotonin Interacts with Melanocortin Pathways Regulating Energy Homeostasis Heisler LK, Dowley MA Kishi T. Ann N Y Acad Sci Jun;994:

58 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:

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

60 Time in Weeks Continuous Phentermine Alternate Phentermine & Placebo Placebo 5 10 Weight loss (kg) Weight loss (lbs) 0 Phentermine: A Noradrenergic Drug Reduces Body Weight Munro JF et al BMJ 1968;1:352-4

61 Controlled System Controller Afferent Signals Efferent Controls Fat Anatomy Monoamines Peptides Cytokines Feedback Model

62 ► 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) IncreaseDecrease Peptides That Affect Food Intake

63 IncreaseDecrease ► 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)

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

65 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

66 Controlled System Controller Afferent Signals Efferent Controls Fat Anatomy Monoamines Peptides Cytokines Feedback Model

67 “….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): Obesity Is Associated with Inflammatory Hypothalamic Injury

68 Hypothalamic Inflammatory Markers Increase on High Fat Diet Il1-b Il-6 Tnf-α Socs3 Nfkb IkBkb IkBkθ Inflammatory Markers mRNA (fold increase) Thaler JP et al J Clin Invest 2012;122: Data are after 3 days of eating a high fat diet

69 “….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): Obesity Is Associated with Inflammatory Hypothalamic Injury

70 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

71 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? Fattening Foods Cause Dropout of POMC Neurons and Glial Ensheathment of ARC Neurons. Does That Explain Why It’s So Hard To Lose Weight?

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

73 Food Intake Gut and Liver Pancreas Autonomic Nervous System Energy Expenditure Adipose Tissue © 2007 LJ Aronne MD. Adapted from Campfield LA et al. Science. 1998;280: ; Porte D et al. Diabetologia. 1998;41: Adrenal Cortex Energy Balance and Adipose Stores Meal Size Adrenal Steroids Leptin Amylin Insulin External Factors Food Availability, Palatability Adiponectin GhrelinGLP-1CCKVagus Afferent Signals Efferent NPY AGRP galanin Orexin-A Dynorphin Cannabinoids Stimulate α-MSH CRH/UCN GLP-I CART NE 5-HT Inhibit Central Signals What is Causing the Epidemic of Obesity and Why Is It So Hard to Lose Weight?

74 Weight Regulating Mechanisms and Effect of Anti-obesity Drugs – It’s Complicated! Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi: /clpt Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways Slide:Dr. Caroline Apovian

75 Treatment Gap in the Management of Obesity Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities 0% 5%10%15%20%25%30%35% Current Pharmacotherapy Lap BandGastric Bypass Treatment Gap What will fill the gap ? New meds, combos, less invasive surgery Too risky for many people

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

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

78 Guide to Selecting Obesity Treatment

79 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

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

81 Chronic Disease Drug 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 ► 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) Hypertension Obesity

82 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

83 Weight Loss Drugs Approved by FDA Phentermine/TopiramateQsymia LorcaserinBelviq Orlistat Xenical, Alli PhentermineAdipex, Fastin, Ionamin Diethylpropion Tenuate, Tenuate, Dospan Phendimetrazine Bontril, Plegine, Prelu-2, X-Trozine Methamphetamine Desoxyn Benzphetamine Didrex Mazindol Sanorex, Mazanor Generic Name Trade Name Generic Name Trade Name

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

85 Phentermine ► Mechanism: ● 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%)

86 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

87 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

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

89 5.81 ± 0.16% 2.16 ± 0.14% 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

90 47.5% 20.3% 22.6% 7.7% 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

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

92 Summary of Echocardiographic Safety Monitoring ► 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)

93 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

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

95 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

96 Gadde KM et al. Lancet. 2011;377(9774): Phentermine/Topiramate Phase III Trial

97 Gadde KM et al. Lancet. 2011;377(9774):

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

99 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.

100 Obesity Drugs and CVD Risk Factors Bays HE. Specialty Corner: Investigational Anti-obesity Agents to Treat Adiposopathy and "Sick Fat.” pages Anti-Obesity Agent BPLDL-CTGHDL-C Phentermine/ Topirmate ER  Lorcaserin  No significant change

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

102 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

103 Bupropion 360 & Naltrexone 32 mg Placebo (N=511) NB32 (N=471) NB16 (N=471) ITT-LOCF Observed 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 Placebo Completers (N=290) NB32 Completers (N=296) NB16 Completers (N=284) Completers Greenway FL et al. Lancet. 376(9741): , 2010

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

105 Zonisamide 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

106 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?

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

108 Belornib – Weight Loss in Humans ► Impact of 2-18 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.

109 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

110 Real World Challenges in Obesity Management Case Study-Based Learning Workshops and Clinical Simulations in Obesity Management Investigations  Stratification Front Line Clinical Applications 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

111  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

112  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

113 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: 1.Recommend diet and lifestyle changes 2.Initiate orlistat 3.Initiate lorcaserin 4.Initiate phentermine 5.Initiate phentermine HCl/topiramate CR Please Enter Your Response On Your Keypad

114 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: 1.Modify diet and lifestyle recommendations and reassess in 90 days 2.Initiate orlistat 3.Initiate lorcaserin 4.Initiate phentermine 5.Initiate phentermine HCl/topiramate CR Please Enter Your Response On Your Keypad

115 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: 1.Cease pharmacotherapy and recommend diet and lifestyle changes 2.Cease pharmacotherapy, recommend diet and lifestyle changes, and revisit in 90 days 3.Maintain current pharmacotherapy 4.Switch to alternative pharmacotherapy Please Enter Your Response On Your Keypad

116 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: 1.Cease pharmacotherapy and recommend diet and lifestyle changes 2.Cease pharmacotherapy, recommend diet and lifestyle changes, and revisit in 90 days 3.Maintain current pharmacotherapy 4.Switch to alternative pharmacotherapy

117 42-year-old man with BMI 37 Weight 242 lbs., up 5 lbs. from 6 months earlierWeight 242 lbs., up 5 lbs. from 6 months earlier Gout well-controlled on allopurinolGout well-controlled on allopurinol Hyperlipidemia (on low-dose simvastatin); bilateral knee arthritisHyperlipidemia (on low-dose simvastatin); bilateral knee arthritisExamination Central obesity with waist circumference 44 in.Central obesity with waist circumference 44 in. BP 132/82BP 132/82 Laboratory studies Fasting glucose 90Fasting glucose 90 Fasting triglycerides 260Fasting triglycerides 260 Cholesterol 220; LDL cholesterol 146; HDL cholesterol 38Cholesterol 220; LDL cholesterol 146; HDL cholesterol 38 Other tests normalOther tests normal Case Study 2

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

119 Case Study 2 - Question 1 You increase the dose of simvastatin. What would you do to treat the obesity? 1.Recommend a healthier and more regular diet 2.Encourage a more vigorous exercise program 3.Refer him to a psychologist for behavior modification 4.Initiate orlistat therapy 5.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

120 Clinical progress He listens to your dietary advice and stops snackingHe 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 travelingHis 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 regularlyContinues to exercise regularly Lost 4 lbs. (to 238 lbs.) in the first month but none since, despite maintaining his new lifestyleLost 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 rangeAt 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

121 What would you do now? 1.Continue to encourage a healthy diet 2.Refer to dietitian for nutritional management 3.Refer to a stress management program 4.Initiate phentermine therapy 5.Initiate lorcaserin therapy Case Study 2 – Question 2 Please Enter Your Response On Your Keypad

122 Clinical progress He sees a dietitian who recommends a specific dietary regimen, which he follows reasonably wellHe sees a dietitian who recommends a specific dietary regimen, which he follows reasonably well Over the ensuing 3 months, he loses 12 lbs.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)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 normalHis cholesterol levels and BP remain normal His fasting glucose is 114, and his triglyceride level is 222, and his HbA1c is 6.6%His fasting glucose is 114, and his triglyceride level is 222, and his HbA1c is 6.6% Case Study 2

123 What would you do now? 1.Continue to encourage a healthy diet 2.Refer back to the dietitian for additional counseling 3.Refer to a stress management program 4.Initiate phentermine therapy 5.Initiate lorcaserin therapy Case Study 2 – Question 3 Please Enter Your Response On Your Keypad

124 Clinical progress You begin phentermine at 15 mg/day, monitoring BP and pulse carefullyYou 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 effectsHe 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 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 phentermineAt 3 months, he weighs 223 lbs. (BMI 34.1), having lost 14 lbs. (5.9%) on phentermine He continues the recommended dietary changesHe 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)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%)Total weight loss 20 lbs. since first visit; total weight loss on phentermine 15 lbs. (6.3%) Case Study 2

125 Case Study 2 - Question 4 What would you do now? 1.Continue the phentermine at 15 mg/day and re- emphasize the recommended diet and lifestyle changes 2.Stop the phentermine and follow his clinical progress 3.Stop the phentermine and start orlistat at 120 mg tid 4.Increase the phentermine to 30 mg/day 5.Recommend consultation for bariatric surgery Please Enter Your Response On Your Keypad

126 Clinical progress He tolerates the increased dose of phentermine well with only transient dry mouthHe 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 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 overallAt 3 months, he weighs 221 lbs. (BMI 33.8), having lost 16 lbs. (5.9%) on phentermine overall Case Study 2

127 Case Study 2 - Question 5 What would you do now? 1.Continue the phentermine at 30 mg/day and refer back to the dietitian 2.Stop the phentermine and follow his clinical progress 3.Stop the phentermine and start orlistat at 120 mg tid 4.Add topiramate by substituting the low-dose combination of phentermine (3.75 mg/day) and topiramate (23 mg/day) for the phentermine alone 5.Recommend consultation for bariatric surgery Please Enter Your Response On Your Keypad

128 Clinical progress He tolerates the low-dose phentermine-topiramate combination (“phen-top”) well, without adverse effectsHe 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 dailyAfter 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)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)Over the next 3 months, he loses an additional 8 lbs. to a weight of 210 lbs. (BMI 32.1) Case Study 2

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

130 Case Study 2 - Question 6 What would you do now? 1.Continue the phen-top at current dosing 2.Stop the phen-top, re-enforce lifestyle adjustments and follow his clinical progress 3.Increase the phen-top dosing to 15 mg phentermine + 92 mg topiramate daily (“high dose”) 4.Add lorcaserin at 10 mg bid 5.Recommend consultation for bariatric surgery Please Enter Your Response On Your Keypad

131 51-year-old woman with BMI year-old woman with BMI 43.3 Weight 252 lbs., height 5’4”Weight 252 lbs., height 5’4” Well-controlled hypertension, hypothyroidism, Barrett’s esophagus, osteoarthritis (s/p knee replacement), colonic polyps, and depressionWell-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)Type 2 diabetes on pioglitazone, glimepiride and insulin (long- and short-acting to total of 65 units/day) no eye, neurological or vascular complicationsno eye, neurological or vascular complications Sleep apnea well-controlled on CPAPSleep apnea well-controlled on CPAP Other medications include losartan, hydrochlorthiazide, omeprazole, levothyroxine, omeprazole, aspirin and sertralineOther medications include losartan, hydrochlorthiazide, omeprazole, levothyroxine, omeprazole, aspirin and sertraline Case Study 3

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

133 Weight and lifestyle history Normal weight as a child; overweight in college and graduate school (weight ; BMI 26-30)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 portionsProgressive 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 maintainedNumerous 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 weightAverage weight stable over the past few years; currently at highest lifetime weight Married with grown children; works as financial plannerMarried with grown children; works as financial planner Cooks regularly and well, and entertains oftenCooks regularly and well, and entertains often Exercises three times a week with a physical trainerExercises three times a week with a physical trainer Case Study 3

134 Case Study 3 - Question 1 You increase the dose of L-thyroxine. How would you initiate obesity treatment? 1.Recommend a meal-replacement program 2.Substitute citalopram for sertraline 3.Refer her to a psychologist for cognitive- behavior therapy for the depression 4.Substitute metformin for glimepiride 5.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

135 Clinical progress You discontinue the sulfonylurea and start metformin at 500 mg bid, monitoring her glucose carefully and adjusting short- acting insulin as requiredYou 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)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 bidYou increase the metformin to 750 mg bid At 3 months, she has lost a total of 14 lbs. (5.6%) to 238 lbs.At 3 months, she has lost a total of 14 lbs. (5.6%) to 238 lbs. She reports a noticeably diminished appetite and cravingsShe reports a noticeably diminished appetite and cravings Insulin requirement falls from 65 to 52 units/dayInsulin 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%)3 months later, her weight is stable at 235 lbs. (BMI 40.3), down 17 lbs. (6.7%) Case Study 3

136 Case Study 3 - Question 2 What would you do now to treat the obesity? 1.Refer to a commercial weight loss program 2.Substitute bupropion for sertraline 3.Initiate therapy with a combination of phentermine and topiramate 4.Initiate therapy with lorcaserin 5.Refer for bariatric surgery Please Enter Your Response On Your Keypad

137 Clinical progress Low-dose phen-top (phentermine 3.75 mg + topiramate 23 mg daily) initiated and well-toleratedLow-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 dailyAfter 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)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.At 3 months, she has lost a total of 6 lbs. (2.6%) to 229 lbs. Case Study 3

138 Case Study 3 - Question 3 What would you do now? 1.Continue the phen-top at current dosing and add orlistat at 120 mg tid 2.Stop the phen-top and start phentermine at 15 mg daily 3.Stop the phen-top and start lorcaserin at 10 mg bid 4.Stop the phen-top and start orlistat at 120 mg tid 5.Stop the phen-top and substitute liraglutide s.c. for the pioglitazone Please Enter Your Response On Your Keypad

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

140 Case Study 3 - Question 4 What would you do now? 1.Stop all weight loss medications and refer to a dietitian to reinforce healthy eating habits 2.Stop all weight loss medications and refer to a psychologist for behavioral therapy 3.Continue the current regimen and restart a combination of phentermine and topiramate 4.Stop all weight loss medications and institute an 8-week physician-supervised very low calorie diet (VLCD) 5.Stop all weight loss medications and refer for bariatric surgery Please Enter Your Response On Your Keypad

141 Clinical progress She undergoes uneventful laparoscopic Roux-en-Y gastric bypass with post-operative weight loss ~50 lbs.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)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 symptomsOther 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 monthsOne 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)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

142 Case Study 3 - Question 5 What would you do now? 1. Indicate that there is no further therapy beyond surgery and r einforce the need to follow a healthy lifestyle 2.Refer her to a psychologist to help address her expectations 3.Encourage her to extend post-operative weight loss with a low-calorie (calorie restricted) diet 4.Institute pharmacological therapy with lorcaserin 5.Refer her back to the surgeon for consideration of revising the surgical procedure Please Enter Your Response On Your Keypad

143 Clinical progress Lorcaserin at 10 mg/day is started and well-toleratedLorcaserin 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)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%)Her comorbidities remain improved, and her diabetes is in remission off all medications (HbA1c 6.3%) Case Study 3

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

145 46-year-old woman with BMI 30.7 Weight 190 lbs., up 5 lbs. from 6 months earlierWeight 190 lbs., up 5 lbs. from 6 months earlier Hypertension, heartburn, weight-bearing joint painHypertension, heartburn, weight-bearing joint painExamination Central obesity with waist circumference 36 in.Central obesity with waist circumference 36 in. BP 134/90BP 134/90 Laboratory studies Glucose 118; HbA1c 6.4%Glucose 118; HbA1c 6.4% Triglycerides 255 mg/dL, LDL cholesterol 140Triglycerides 255 mg/dL, LDL cholesterol 140 HDL cholesterol 42 mg/dLHDL cholesterol 42 mg/dL Other tests normalOther tests normal Case Study 4

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

147 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

148 Clinical progress Modest, regular, aerobic exercise program initiated and maintainedModest, 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)At follow-up 2 months later, her weight was down 6 lbs. to 184 lbs. (BMI 29.7) Case Study 4

149 You recommend that she continue the exercise program. What else would you recommend now? 1.Laud her success and encourage continuing a healthy lifestyle 2.Refer to exercise trainer to help with exercise 3.Encourage a more regular eating pattern 4.Suggest that she change to day shift 5.Initiate pharmacotherapy for obesity Case Study 4 – Question 2 Please Enter Your Response On Your Keypad

150 Clinical progress Continued regular exercise programContinued regular exercise program Stopped grazing and began eating on regular scheduleStopped grazing and began eating on regular schedule Change in eating schedule resulted in stabilization of sleep patterns as wellChange 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)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-esteemShe describes increased energy and improved self-esteem Case Study 4

151 What would you recommend now? 1.Encourage a healthy diet and reassess HbA1c 2.Refer to dietitian for nutritional management 3.Initiate pharmacotherapy for obesity 4.Recommend bariatric surgical evaluation for type 2 diabetes 5.Refer to plastic surgeon for liposuction Case Study 4 – Question 3 Please Enter Your Response On Your Keypad

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

153 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

154 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?

155 Questions and Answers Investigations  Stratification Front Line Clinical Applications

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