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

Investigations Stratification Front Line Clinical ApplicationsNew 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 SystemMARC-ANDRE CORNIER, MD - Program ChairmanAssociate Professor of MedicineDivision of Endocrinology, Metabolism and DiabetesAnschutz Health and Wellness CenterUniversity of Colorado School of MedicineDenver, CO

Distinguished FacultyMARC-ANDRE CORNIER, MD - Program ChairmanAssociate Professor of MedicineDivision of Endocrinology, Metabolism and DiabetesAnschutz Health and Wellness CenterUniversity of Colorado School of MedicineDenver, CO

REKHA KUMAR, MD, MSDiabetes, Endocrinology and MetabolismWeill Cornell Medical CollegeAssistant Professor of MedicineNew York Presbyterian HospitalNew York, NY

ROBERT J. MALCOLM, MDProfessor, Department of Psychiatry and Behavioral SciencesAssociate Dean for Continuing Medical Education, College of MedicineMedical University of South CarolinaCharleston, SC

Investigations Stratification Front Line Clinical ApplicationsCurrent 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 ChairmanAssociate Professor of MedicineDivision of Endocrinology, Metabolism and DiabetesAnschutz Health and Wellness CenterUniversity of Colorado School of MedicineDenver, CO

Obesity by the NumbersOverweight 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 billionDaily deaths from obesity complications> 1,000

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

Complications of Obesity65+

Long-term Control of Obesity 20131% =750,000U.S. adults

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Obesity is CounterintuitiveHides in plain sightMost obesity NOT recognized by physicians or the publicNOT mainly in AmericaNOT simply a problem of eating too muchNOT a single disorder very heterogeneousPossibly 100 or more clinically meaningful subtypesThis recognition is essential to solving the problem

Cause of Obesity Historical viewLifestyle choiceCharacterological flaw (willpower, psychology) Current perspectiveComplex physiologyEpidemic from changes in modern environmentGenetic Predisposition (physiology) in the wrong environmentWidely 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 BalanceBy the laws of physics

Average adults consume 2000-2500 kcal/dayAverage adults therefore consume 2-3 times as much food as requiredExcess intake is available for physiological emergenciesMaintaining 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/dayLess than one-half potato chipMaintenance of normal fat stores (and body weight) requires precise disposal of 60-70% of ingested calories dailyThe Normal Physiology of Energy Balance

Obesity: A Failure of Weight RegulationGeneticsEnvironmentAltered food supplyReduced physical activityStressDrugsOthers?

Barriers, Challenges and Opportunitiesto Obesity Management Our biologyFavors fat storageCan this be manipulated?EnvironmentMacroenvironment more difficult to changeMicroenvironment can be changed by the individual?Health Care SystemLack of buy in from providers, patients and insurersOthers?

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 ApplicationsREKHA KUMAR, MD, MSDiabetes, Endocrinology and MetabolismWeill Cornell Medical CollegeAssistant Professor of MedicineNew York Presbyterian HospitalNew York, NY

Obesity DiagnosisObesity is defined an excess of body fatBody fat is difficult to measure cheaplyFor people with average lifestyles, Body Mass Index (BMI) has been the measure of obesityBMI = Wt in Kg divided by height in M squaredBMI has been divided into categories18-25 is normal, 25-30 is overweight, 30-35 is class I, 35-40 is class II, >40 is class III

Relationship Between Mortality and BMIData from Lew EA: Mortality and weight: insured lives and the American Cancer Society studies. Ann Intern Med 103:1024-1029, 1985.Very LowLowModerateHighVery High20 25 30 35 402.52.01.51.00MenWomenMortality RatioBody Mass Index, kg/m2

Mortality: Diastolic Blood Pressure

Mortality: Body Mass Index

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BMI Classes are Poor at Estimating RiskThe BMI classes assume that mortality and morbidity is proportional to BMIThis 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 riskAn obesity staging system may be a better approach to estimating medical risk of obesity

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

Edmonton Obesity Staging System (EOSS)Sharma AM & Kushner RF, Int J Obes 2009MedicalMentalFunctionalabsentabsentabsent

Edmonton Obesity Staging SystemStage 0: No obesity related risk factorsStage 1: Subclinical risk factors borderline HTN or DM, minor aches or psychopathologyStage 2: Established obesity-related disease HTN, DM, PCO, moderate limitations ADLStage 3: Established organ damage MI, CHF, DM comp, significant limitations of ADLStage 4: Severe disabilities end stage and limitations like wheelchair useSharma AM and Kushner RF. Int J Obes. 2009;33:289-95

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

EOSS Distribution Across BMI CategoriesNHANES III (1988-1994)OverweightClass IIIPadwal R, Sharma AM et al. CMAJ 201150 million23 million10 million6 million

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Obesity is Leveling in PrevalenceThe prevalence of obesity in 1961 was 10% in men and 15% in women defined as BMI >30Obesity prevalence started to rise in 1980The 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 yearsDiabetes prevalence started to rise in 1990

NHANES Prevalence of Obesity1961-2012

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

Fall in Energy Expenditure at WorkChurch TS et al. Plos One.2011;6(5):e19657

1960 1970 1980 1990 2000 2010YearMean Occupation Related METsOccupation Related Daily Energy Expenditure (calories)1960 1970 1980 1990 2000 2010Year

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

What is Causing the EpidemicPeople are less active and are eating moreThere are many causes. We cannot just scapegoat fast foodObesity virus Adenovirus D-36 is one causeEndocrine disruptors have been suggestedRegardless 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 ObesityAdenovirus of D group 36 (AD-36) causes obesity in non-human primates but one cannot intentionally infect humansAD-36 antibodies: 30% of obese and 11% leanIn identical twins discordant for antibodies, the positive twin had 2.1% more fat and had a BMI 1.4 units higher (p

Is Obesity Prevalence Important?Obesity is stigmatized especially in women and causes psychological distress. Obesity is associated with diabetesObesity is associated with hypertension and heart diseaseObesity is associated with cancerObesity is associated with osteoarthritis and much disability.

The Prevalence of Diabetes in the USCDC website

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DiabetesThe prevalence of diabetes has tripled since the 1980s and is increasingIt 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 20200.2% of the population have type 1 diabetes and 3.1% have undiagnosed diabetes28.4% of the US has pre-diabetes

Diabetes is ExpensiveIt 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 careThe 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

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Mortality Risk with Staging SystemKuk JL et al. Appl Physiol Nutr Metab. 2011;36:570-576HR for All CauseHR for All CVDRefRef****

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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 LossSjostrom L et al. N Engl J Med. 2007;357(8):741-52

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SummaryObesity can be diagnosed by class and stagePeople in the US are less active and eating more, but multiple causes for obesity existComplications of obesity include diabetes, heart disease, cancer and increased mortalityObesity is expensive and straining our health care delivery systemIt is of utmost importance to screen for obesity and intervene in its management

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 BalanceInvestigations Stratification Front Line Clinical ApplicationsROBERT J. MALCOLM, MDProfessor, Department of Psychiatry and Behavioral SciencesAssociate Dean for Continuing Medical Education, College of MedicineMedical University of South CarolinaCharleston, SC

Weight Regulating Mechanisms and Effect of Anti-obesity Drugs Its Complicated!Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652662. doi:10.1038/clpt.2010.57Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These PathwaysSlide:Dr. Caroline Apovian

High EnergyENERGYENERGYSedentary LifestyleDense Foods(sugar or fat)INTAKEEXPENDITUREGenetic &Biological Susceptibilities(Underlying basis)

ControlledSystemControllerFeedback ModelAfferent

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ControlsFat

ControlledSystemControllerAfferent

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ControlsFatAnatomyMonoaminesPeptidesCytokinesFeedback Model

Picture of Frohlichs Case of Hypothlamic Obesity

Location of Hypothalamic Centers That Affect FeedingLaThalamusMamillo-thalamicTrackDorsal HyopthalmusDorsomedial HypoLateral HypoSurap-optic nucleusVentromedial HypoLateral Hypothalamic Lesions Ventromedial Hypothalamic Lesions


SignalsEfferent


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

Serotonin Biology - ISerotonin is most concentrated in the hypothalamus, basal ganglia and brainstem7 groups of 14 serotonin receptors are known5HT-1 - Intronless, G-protein coupled receptor that inhibits adenylyl cyclase5HT-2Contains introns, that are coupled to G-protein receptors that activate phospholipase C5-HT2C is only in the brain 5HT-3 - Ligand-gated ion channel

Activation of 5-HT1A auto-receptor increases feedingActivation of 5-HT1B and 5-HT2C by any 5-HT agonist will reduce food intake5-HT receptors in PVN specifically decrease fat intakeKnock-out of 5-HT2C receptor produces obesity and convulsions. Serotonin reuptake inhibitors and releasers can precipitate weight loss or weight gain

Serotonin Biology - II

02468101214CarbohydrateFatProtein2-Hr Food Intake (kcal)SalineSerotoninSmith B et al AJP 1999Macronutrient ChoiceSerotonin (and Other Agonists) in PVN Reduce Food Intake

5-HT2CRs Expressed by Pro-opiomelanocortin Neurons Regulate Insulin Sensitivity in Liver Mice lacking 5-HT 2C receptors have hepatic insulin resistanceWhich 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 sensitivityMoreover, this 5-HT2C R-melanocortin circuit is sufficient to mediate the anti-diabetic effects of 5-HT2CR agonists.Xu Y, et al Nat Neurosci. 2010 Dec;13(12):1457-9. Epub 2010 Oct 31

Serotonin 2c Receptor and Diabetes

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. 2003 Jun;994:169-74.

Serotonin and Melancortin ReceptorsWe 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. 2003 Jun;1994:169-74.

INDEX Study CompletersMean Weight Loss (% Initial Weight)Guy-Grand et al INDEX study Lancet 1988

Phentermine: A Noradrenergic Drug Reduces Body WeightMunro JF et al BMJ 1968;1:352-4


SignalsEfferent


Agouti-related peptideDynorphinGhrelinMelanin-concentrating hormoneNeuropeptide YOrexin A (Hypocretin)RF-2 peptides (arginine phenylalanine amide-2)Galanin-like-peptide -MSHCorticotrophin-releasing hormoneCholecystokininCocaine-amphetamine regulated transcriptGlucagon-like peptide-1LeptinAmylinBombesin/GRPObestatin (part of ghrelin)Nesfatin-1 (NEFA-NUCB2)Peptides That Affect Food Intake

Peptides That Affect Food IntakeAgouti-related peptideDynorphinGhrelinMelanin-concentrating hormoneNeuropeptide YOrexin A (Hypocretin)RF-2 peptides (arginine phenylalanine amide-2)Galanin-like-peptide -MSHCorticotrophin-releasing hormoneCholecystokininCocaine-amphetamine regulated transcriptGlucagon-like peptide-1LeptinAmylinBombesin/GRPObestatin (part of ghrelin)Nesfatin-1 (NEFA-NUCB2)

Leptin the Ultimate Messenger of Fat StoresWeight Loss

POMC Serotonin 5-HT2c

Hypothalamus Leptin

Model of the Arcuate NucleusModel showing the afferentsignals from the periphery that modulate the activityof hypothalamic neurons ina reciprocal way to increaseor decrease food intakeBadman, Science 2005


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.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. 2012 Jan 3;122(1):153-62. Obesity Is Associated with Inflammatory Hypothalamic Injury

Hypothalamic Inflammatory Markers Increase on High Fat Diet0.51.01.52.02.0Il1-b Il-6 Tnf- Socs3 Nfkb IkBkb IkBk Inflammatory MarkersmRNA (fold increase)Thaler JP et al J Clin Invest 2012;122:153-162

.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. 2012 Jan 3;122(1):153-62. Obesity Is Associated with Inflammatory Hypothalamic Injury

Leptin Resistance and CytokinesTaking all of these phenomena into account, we think that it is possible that overconsumption of nutrients could be a reason for development of leptin resistanceThis 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 inflammationEvidence 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 obesityLoss 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 Its So Hard To Lose Weight?

Hypothetical Feed-forward, Positive Feedback Mechanism Drives Weight UpWang J, Diabetes, 2001; DiMarzo V pers commOzcan L et al Cell Metabolism; 2009 2012 Louis J. Aronne, MD

Food IntakeGut and LiverPancreasAutonomic Nervous SystemEnergy ExpenditureAdipose Tissue 2007 LJ Aronne MD. Adapted from Campfield LA et al. Science. 1998;280:1383-1387; Porte D et al. Diabetologia. 1998;41:863-881.Adrenal CortexEnergy Balance and Adipose StoresMeal SizeAdrenal SteroidsLeptinAmylinInsulinExternal Factors Food Availability, PalatabilityAdiponectinGhrelinGLP-1CCKVagusAfferent Signals EfferentNPYAGRPgalaninOrexin-ADynorphinCannabinoidsStimulate-MSHCRH/UCNGLP-ICARTNE5-HTInhibitCentral SignalsWhat is Causing the Epidemic of Obesity and Why Is It So Hard to Lose Weight?

Weight Regulating Mechanisms and Effect of Anti-obesity Drugs Its Complicated!Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652662. doi:10.1038/clpt.2010.57Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These PathwaysSlide:Dr. Caroline Apovian

Treatment Gap in the Management of ObesityPhysicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities0% 5%10%15%20%25%30%35%Current PharmacotherapyLap BandGastric BypassTreatmentGapToo risky for many people

New Frontiers and Treatment Paradigms for Pharmacologic Management of Obesity

Focus on Safety and Efficacy of Agents Affecting CNS Signaling Systems and Appetite RegulationInvestigations Stratification Front Line Clinical ApplicationsMARC-ANDRE CORNIER, MD - Program ChairmanAssociate Professor of MedicineDivision of Endocrinology, Metabolism and DiabetesAnschutz Health and Wellness CenterUniversity of Colorado School of MedicineDenver, CO

Overall Treatment StrategyTypical Algorithm(Progress through algorithm as clinically required)

Guide to Selecting Obesity Treatment

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

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

Chronic Disease Drug DevelopmentDiuretics salt in urineCNS drugs side effects eg. reserpine and depressionCombinations to lower side effects and increase efficacyPeripherally acting drugs eg. angiotensin receptor blockersOrlistat calories in stoolCNS drugs side effects eg. amphetamine and addictionCombinations to lower side effects and increase efficacy eg topiramate-phenterminePeripherally acting drugs (in development)

Obesity Pharmacotherapy A Bad Safety Record1893: Thyroid hormone -> hyperthyroidism1933: Dinitrophenol -> cataracts/neuropathy1937: Amphetamine -> addiction1967: Rainbow pills (digitalis & diuretics) -> CV sx 1997: Fenfluramine -> valvulopathy2000: Phenylpropanolamine -> stroke2004: Herbal caffeine & ephedra -> CV sx2010: Sibutramine -> MI and stroke

Weight Loss Drugs Approved by FDAPhentermine/TopiramateQsymiaLorcaserinBelviqOrlistat Xenical, Alli PhentermineAdipex, Fastin, Ionamin Diethylpropion Tenuate, Tenuate, DospanPhendimetrazine Bontril, Plegine, Prelu-2, X-TrozineMethamphetamine DesoxynBenzphetamine Didrex Mazindol Sanorex, Mazanor

Generic Name Trade Name

Efficacy of Currently Available Weight Loss Medications DrugPhentermineOrlistatLorcaserinPhentermine/TopiramateAverage Weight Loss 3.6% > placebo2.75% > placebo3.3% > placebo9% > placebo

PhentermineMechanism: Appetite suppressantInhibits NE and dopamine releaseDose: 15-37.5 mg daily (AM)FDA approved for short-term (3 months) useSide effects: Increased BP and HR, insomnia, agitation, dry mouth, headache, tremorEfficacy: More weight loss than placebo (~3-5%)

OrlistatMechanism: Inhibits lipases and blocks fat absorption by ~30% (reduction in absorbed fat)Dose: 60-120 mg TID (with meals)FDA approved for long-term useSide effects: mild to moderate GI events, potential for malabsorption of fat soluble vitamins, liver toxicity?, nephrolithiasisEfficacy: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 incidenceImprovements in glycemic control in T2D

Lorcaserin Brand name: BelviqApproved in 2012 (10 mg BID) for long-term weight managementMechanism:Selective 5-HT2C receptor agonistincreases satiety appetite suppressantBays HE. Expert Rev Cardiovasc Ther. 2009;7:1429-1445; Belviq [prescribing information]. Woodcliff Lake, NJ: Eisai; Inc. 2012.

BLOOM Study Body Weight Over Years 1 and 25.81 0.16%2.16 0.14%BLOOM = Behavioral Modification and Lorcaserin for Obesity. Smith SR, et al. N Engl J Med. 2010;363:245-256.

5.81 0.16%2.16 0.14%BLOOM = Behavioral Modification and Lorcaserin for Obesity. Smith SR, et al. N Engl J Med. 2010;363:245-256.BLOOM Study Body Weight Over Years 1 and 2

47.5%20.3%22.6%7.7%BLOOM = Behavioral Modification and Lorcaserin for Obesity. Smith SR, et al. N Engl J Med. 2010;363:245-256.BLOOM Study Body Weight Over Years 1 and 2

Fasting Plasma GlucoseBLOOM-DMChange in Glycemic ParametersHbA1C, -0.5%*P

Summary of EchocardiographicSafety MonitoringMore than 20,000 echocardiographsMore than 7,500 patientsLorcaserin did not increase the risk of valvulopathy above the pre-specified margin relative to placeboLorcaserin did not meaningfully affect regurgitant scores at any heart valveFDA defined valvulopathy relative risk: 1.16 (95% confidence interval (0.81, 1.67, NS)

Lorcaserin Most common AEs: Headache, nausea, dizziness, fatigue, dry mouth, constipationNotesDiscontinue if 5% weight loss is not achieved by week 12Discontinue for evaluation if signs or symptoms of valvular heart diseaseDEA Schedule CIVPregnancy category X Interesting effect on glycemia greater benefit than expected for degree of weight lossBays HE. Expert Rev Cardiovasc Ther. 2009;7:1429-1445; Belviq [prescribing information]. Woodcliff Lake, NJ: Eisai; Inc. 2012.

Phentermine and FenfluraminePhen - FenWeintraub M et al. Clin Pharmacol Ther. 51(5):586-94, 1992.

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Phentermine/Topiramate ERBrand name: QsymiaApproved in 2012 for long-term weight managementMechanism:Phentermine: inhibits NE and dopamine releaseTopiramate: mechanism on weight loss is not knownIncreases satiety appetite suppressantDosing:Start at 3.75/23mg daily x 2 weeks thento 7.5/46mgAfter 12 weeks canto 11.25/69mg and 15/92mg

Gadde KM et al. Lancet. 2011;377(9774):1314-52Phentermine/Topiramate Phase III Trial

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Phentermine/Topiramate Phase III TrialGadde KM et al. Lancet. 2011;377(9774):1314-52

Phentermine/Topiramate Phase III TrialGarvey, et al. Am J Clin Nutr 2012;95:297-308.

Phentermine/Topiramate ERMost 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,creatinineNotesDiscontinue if 5% weight loss is not achieved by week 12DEA Schedule Class IVPregnancy category X Safety: fetal cleft palate - pregnancy test q mo.

Obesity Drugs and CVD Risk FactorsBays HE. Specialty Corner: Investigational Anti-obesity Agents to Treat Adiposopathy and "Sick Fat. pages 22-23. 2011

Anti-Obesity AgentBPLDL-CTGHDL-CPhentermine/ Topirmate ERLorcaserinNo significant change

Whats in the Pipeline?New Frontiers and Treatment Paradigms for Pharmacologic Management of Obesity

Naltrexone/BupropionNot yet FDA approvedCVD safety study in progressDose: 3 week escalation to 16/180mg SR bidMechanism:Naltrexone: opioid receptor antagonistBuproprion: NE/dopamine reuptake inhibitorAppetite suppressant, reduces cravings?Adverse events : Nausea, headache, constipation, dizziness, vomiting, insomnia, dry mouth & hot flushes

Bupropion 360 & Naltrexone 32 mgITT-LOCFObservedPlacebo-subtracted weight lossWeek 56NB16: -3.7%NB32: -4.8%Placebo-subtracted weight lossCompletersNB16: -4.9%NB32: -6.2%P

Liraglutide 3 mg/d in Obese SubjectsAstrup A et al. Lancet 374(9701):1606-16, 2009

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Kg Weight Lost

N=300, P

Zonisamide 360 + Bupropion 360 mgWeight Loss at 1 Year of TreatmentPlacebo (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

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

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

Belornib Weight Loss in HumansImpact of 2-18 ug/kg/dose ZGN-433 treatment on body weight in obese womenValues are medians SEM (n=6-8) for the per protocol population.*** p

SummaryObesity is a chronic physiologically controlled disease that requires chronic treatmentWe have two new CNS acting drugs for obesity lorcaserin and phentermine/topiramateThere are 3 drugs in late stage development: naltrexone/bupropion, liraglutide, andzonisamide/bupropionPeripherally 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

Real World Challenges in Obesity ManagementCase Study-Based Learning Workshops and Clinical Simulations in Obesity Management

Investigations Stratification Front Line Clinical ApplicationsMARC-ANDRE CORNIER, MD - Program ChairmanAssociate Professor of MedicineDivision of Endocrinology, Metabolism and DiabetesAnschutz Health and Wellness CenterUniversity of Colorado School of MedicineDenver, CO

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

Case Study 1With a height of 66 inches and weight of 190 pounds, ERs 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 ERs history, you identify five obesity-related conditions:HypertensionGastroesophageal reflux disease (GERD)Impaired glucose tolerance (possible diabetes)Hypertriglyceridemia and low HDL-C levelsArthralgia

Case Study 1 - Question 1You decide to order additional tests to evaluate ERs hypertension and diabetes.

Based on the NHLBI algorithm, treatment for ERs obesity is indicated.

At this point you would:

Recommend diet and lifestyle changesInitiate orlistatInitiate lorcaserinInitiate phentermineInitiate phentermine HCl/topiramate CR

Case Study 1 - Question 2In 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 daysInitiate orlistatInitiate lorcaserinInitiate phentermineInitiate phentermine HCl/topiramate CR

Case Study 1 - Question 390 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.


Cease pharmacotherapy and recommend diet and lifestyle changesCease pharmacotherapy, recommend diet and lifestyle changes, and revisit in 90 daysMaintain current pharmacotherapySwitch to alternative pharmacotherapy

Case Study 1 - Question 490 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.


Cease pharmacotherapy and recommend diet and lifestyle changesCease pharmacotherapy, recommend diet and lifestyle changes, and revisit in 90 daysMaintain current pharmacotherapySwitch to alternative pharmacotherapy

42-year-old man with BMI 37Weight 242 lbs., up 5 lbs. from 6 months earlierGout well-controlled on allopurinolHyperlipidemia (on low-dose simvastatin); bilateral knee arthritisExaminationCentral obesity with waist circumference 44 in.BP 132/82Laboratory studiesFasting glucose 90Fasting triglycerides 260Cholesterol 220; LDL cholesterol 146; HDL cholesterol 38Other tests normalCase Study 2

Weight and lifestyle historyMildly heavy as a childGrew 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 agoSlowly progressive 55 lb. weight gain over last 10 yearsWorks as salesman with hectic lifestyle; irregular meals; frequent fast foods and snackingNo previous serious weight loss attempts; feels healthyHas exercised at gym 4x/week over the past year with only 4 lb. weight lossCase Study 2

Case Study 2 - Question 1You increase the dose of simvastatin.What would you do to treat the obesity?Recommend a healthier and more regular dietEncourage a more vigorous exercise programRefer him to a psychologist for behavior modificationInitiate orlistat therapyInitiate lorcaserin therapy42 MBMI 37Central distributionPre-DMDyslipidemiaGERD GoutOAChildhood onsetSteady adult gainIrregular eaterFast food dietRegular exerciserHectic lifestyle

Clinical progressHe listens to your dietary advice and stops snackingHis hectic lifestyle continues, but he eats more meals at home and is able to change from fast food to family style restaurants when travelingContinues to exercise regularlyLost 4 lbs. (to 238 lbs.) in the first month but none since, despite maintaining his new lifestyleAt follow-up 3 months later, his weight is 239 lbs., BP 128/84 and LDL and total cholesterol in the normal rangeCase Study 2

What would you do now?Continue to encourage a healthy dietRefer to dietitian for nutritional managementRefer to a stress management programInitiate phentermine therapyInitiate lorcaserin therapyCase Study 2 Question 2

Clinical progressHe sees a dietitian who recommends a specific dietary regimen, which he follows reasonably wellOver 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 normalHis fasting glucose is 114, and his triglyceride level is 222, and his HbA1c is 6.6%Case Study 2

What would you do now?Continue to encourage a healthy dietRefer back to the dietitian for additional counselingRefer to a stress management programInitiate phentermine therapyInitiate lorcaserin therapyCase Study 2 Question 3

Clinical progressYou begin phentermine at 15 mg/day, monitoring BP and pulse carefullyHe reports dry mouth that resolves after about 3 weeks; he otherwise tolerates the medication well, without tachycardia, hypertension or subjective adverse effectsAt 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 phentermineHe continues the recommended dietary changesTwo 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

Case Study 2 - Question 4What would you do now?Continue the phentermine at 15 mg/day and re-emphasize the recommended diet and lifestyle changesStop the phentermine and follow his clinical progressStop the phentermine and start orlistat at 120 mg tidIncrease the phentermine to 30 mg/dayRecommend consultation for bariatric surgery

Clinical progressHe tolerates the increased dose of phentermine well with only transient dry mouthAt 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 overallCase Study 2

Case Study 2 - Question 5What would you do now?Continue the phentermine at 30 mg/day and refer back to the dietitianStop the phentermine and follow his clinical progressStop the phentermine and start orlistat at 120 mg tidAdd topiramate by substituting the low-dose combination of phentermine (3.75 mg/day) and topiramate (23 mg/day) for the phentermine aloneRecommend consultation for bariatric surgery

Clinical progressHe tolerates the low-dose phentermine-topiramate combination (phen-top) well, without adverse effectsAfter 14 days, you increase the phen-top dose to 7.5 mg phentermine + 46 mg topiramate dailyIn 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 summaryInitial 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 earlierCase Study 2

Case Study 2 - Question 6What would you do now?Continue the phen-top at current dosingStop the phen-top, re-enforce lifestyle adjustments and follow his clinical progressIncrease the phen-top dosing to 15 mg phentermine + 92 mg topiramate daily (high dose)Add lorcaserin at 10 mg bidRecommend consultation for bariatric surgery

51-year-old woman with BMI 43.3Weight 252 lbs., height 54Well-controlled hypertension, hypothyroidism, Barretts esophagus, osteoarthritis (s/p knee replacement), colonic polyps, and depressionType 2 diabetes on pioglitazone, glimepiride and insulin (long- and short-acting to total of 65 units/day) no eye, neurological or vascular complicationsSleep apnea well-controlled on CPAPOther medications include losartan, hydrochlorthiazide, omeprazole, levothyroxine, omeprazole, aspirin and sertralineCase Study 3

ExaminationCentral obesity with waist circumference 41 in.Benign, protuberant abdomen; no signs of chronic liver diseaseNo signs of peripheral neuropathyBenign abdomenLaboratory studiesFasting glucose 111HbA1c 7.1%AST 43, ALT 51, alkaline phosphatase 120BUN 32; creatinine 1.2TSH 5.64Other tests normalCase Study 3

Weight and lifestyle historyNormal weight as a child; overweight in college and graduate school (weight 150-175; BMI 26-30)Progressive weight gain in adult life; insatiable appetite with frequent cravings and large portionsNumerous unsupervised, supervised and structured diets with variable weight loss (up to 30 lbs.); none maintainedAverage weight stable over the past few years; currently at highest lifetime weightMarried with grown children; works as financial plannerCooks regularly and well, and entertains oftenExercises three times a week with a physical trainerCase Study 3

Case Study 3 - Question 1You increase the dose of L-thyroxine. How would you initiate obesity treatment?Recommend a meal-replacement programSubstitute citalopram for sertralineRefer her to a psychologist for cognitive-behavior therapy for the depressionSubstitute metformin for glimepirideInitiate treatment with a combination of phentermine and topiramate51 FBMI 43.3Central distributionT2DM (55OSAHypothyroidismGERD / BarrettsOAColonic polypsDepressionAdult onsetHealthy dietOften hungryLarge portionsRegular exerciser

Clinical progressYou discontinue the sulfonylurea and start metformin at 500 mg bid, monitoring her glucose carefully and adjusting short-acting insulin as requiredIn the next 30 days, she loses 5 lbs. to a weight of 247 lbs. (BMI 42.4)You increase the metformin to 750 mg bidAt 3 months, she has lost a total of 14 lbs. (5.6%) to 238 lbs.She reports a noticeably diminished appetite and cravingsInsulin requirement falls from 65 to 52 units/day3 months later, her weight is stable at 235 lbs. (BMI 40.3), down 17 lbs. (6.7%)Case Study 3

Case Study 3 - Question 2What would you do now to treat the obesity?Refer to a commercial weight loss programSubstitute bupropion for sertralineInitiate therapy with a combination of phentermine and topiramateInitiate therapy with lorcaserinRefer for bariatric surgery

Clinical progressLow-dose phen-top (phentermine 3.75 mg + topiramate 23 mg daily) initiated and well-toleratedAfter 14 days, you increase the phen-top dose to phentermine 7.5 mg + topiramate 46 mg daily with no adverse consequencesIn 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

Case Study 3 - Question 3What would you do now?Continue the phen-top at current dosing and add orlistat at 120 mg tidStop the phen-top and start phentermine at 15 mg dailyStop the phen-top and start lorcaserin at 10 mg bidStop the phen-top and start orlistat at 120 mg tidStop the phen-top and substitute liraglutide s.c. for the pioglitazone

Clinical progressShe tolerates the new medication wellAfter 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

Case Study 3 - Question 4What would you do now?Stop all weight loss medications and refer to a dietitian to reinforce healthy eating habitsStop all weight loss medications and refer to a psychologist for behavioral therapyContinue the current regimen and restart a combination of phentermine and topiramateStop 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

Clinical progressShe 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 symptomsOne year after surgery, her weight is down 51 lbs. to 181 lbs. (BMI 31.1), which has been stable for more than 3 monthsShe 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

Case Study 3 - Question 5What would you do now?Indicate that there is no further therapy beyond surgery and reinforce the need to follow a healthy lifestyleRefer her to a psychologist to help address her expectationsEncourage her to extend post-operative weight loss with a low-calorie (calorie restricted) dietInstitute pharmacological therapy with lorcaserinRefer her back to the surgeon for consideration of revising the surgical procedure

Clinical progressLorcaserin at 10 mg/day is started and well-toleratedOver 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 summaryInitial 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 earlierCase Study 3

46-year-old woman with BMI 30.7Weight 190 lbs., up 5 lbs. from 6 months earlierHypertension, heartburn, weight-bearing joint pain ExaminationCentral obesity with waist circumference 36 in.BP 134/90Laboratory studiesGlucose 118; HbA1c 6.4%Triglycerides 255 mg/dL, LDL cholesterol 140HDL cholesterol 42 mg/dLOther tests normalCase Study 4

Weight and lifestyle historyNormal weight as child Progressive weight gain after college exacerbated after having children in late 20sPreviously on intermittent diets with up to 20 lb. weight loss, but invariable weight regainEats mostly home-prepared foodLittle or no snacking, but eats meals irregularlySingle mother of 2 teenagers, with steady boyfriendWorks as nursing assistant on evening and night shiftWalks extensively at work; no structured exerciseCase Study 4

Case Study 4 - Question 1What treatment would you initially recommend for this patient?1.Broad-based diet and lifestyle counseling2.Implementation of moderate structured exercise regimen3.Cooking classes4.Change jobs5.Initiate pharmacotherapy for obesity46 FBMI 30.7Central distributionPre-DMHTNDyslipidemiaGERD Joint painObesity onset 20sFailed dietsHome-cookerIrregular eaterWalks a lotNight shift workerStressful life

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

You recommend that she continue the exercise program.What else would you recommend now?Laud her success and encourage continuing a healthy lifestyleRefer to exercise trainer to help with exerciseEncourage a more regular eating patternSuggest that she change to day shiftInitiate pharmacotherapy for obesityCase Study 4 Question 2

Clinical progressContinued regular exercise programStopped grazing and began eating on regular scheduleChange in eating schedule resulted in stabilization of sleep patterns as wellAt 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-esteemCase Study 4

What would you recommend now?Encourage a healthy diet and reassess HbA1cRefer to dietitian for nutritional managementInitiate pharmacotherapy for obesityRecommend bariatric surgical evaluation for type 2 diabetesRefer to plastic surgeon for liposuctionCase Study 4 Question 3

Summary and Vision Statement

Near Term Challenges and Potential Strategies for Optimizing Obesity Management in the Primary Care SettingInvestigations Stratification Front Line Clinical Applications

SummaryObesity is a chronic physiologically controlled disease that requires chronic treatmentMust be approached like other chronic diseasesYes, there are still many barriers and challenges to overcome with the management of obesity But there are also many opportunitiesAwareness and education are critical!Lifestyle modification is at the core of all our therapeutic optionsWe have good pharmacotherapies and new agents on the horizon yet these are underusedWe must use all of the tools at our disposition

SummaryReasons Why You Should Treat Overweight-ObesityExcess adiposity adversely impacts healthObesity 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 helpIf you dont, then who will?

Questions and AnswersInvestigations Stratification Front Line Clinical Applications

*******Etiology of Obesity

Obesity occurs when the bodys 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.

**QNEXA_Core_06-16-10_v03_NO_HIDDEN.ppt*QNEXA*Between diet and exercise and the current pharmacotherapy on one hand, and bariatric surgery on the otherWe need more treatments to fill the treatment gap, treat people in whom surgery is not indicatedIn hypertension we have 100 medications in 9 categories,

**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.

References1. 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;339:713-718.2. Kernan WN et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000;343:1826-1832.

******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]Lets move now to the evaluation of possible CNS effects.**Confidential Draft - For Discussion Purposes Only***CP1074317 Hayes, SAU8-15-2002 ****

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