new perspectives and emerging treatment paradigms for individualizing obesity management

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New Perspectives and Emerging Treatment Paradigms for New Perspectives and Emerging Treatment Paradigms for

Individualizing Obesity ManagementIndividualizing Obesity Management

Focus on Maximizing Behavioral, Cardiometabolic, and Focus on Maximizing Behavioral, Cardiometabolic, and Weight Loss Outcomes with Pharmacologic Agents Targeting Weight Loss Outcomes with Pharmacologic Agents Targeting

the Central Nervous Systemthe Central Nervous System

Lee M. Kaplan, MD, PhD Lee M. Kaplan, MD, PhD Director, Obesity, Metabolism & Nutrition Director, Obesity, Metabolism & Nutrition InstituteInstitute | Massachusetts General Massachusetts General HospitalHospital | Associate Professor of Medicine Associate Professor of Medicine | Harvard Medical SchoolHarvard Medical School | Boston, Boston, Massachusetts Massachusetts

Investigations Investigations Stratification Stratification Front Line Clinical ApplicationsFront Line Clinical Applications

Ken Fujioka, MD Ken Fujioka, MD Director, Nutrition and Metabolic Research Director, Nutrition and Metabolic Research Center | Director, Center for Weight Center | Director, Center for Weight Management | Scripps ClinicManagement | Scripps ClinicSan Diego, CA San Diego, CA

Program Co-ChairsProgram Co-Chairs

CME-certified symposium CME-certified symposium jointly sponsored by the jointly sponsored by the University of Massachusetts University of Massachusetts Medical School and Medical School and CMEducation Resources, LLCCMEducation Resources, LLC

Commercial Support: Commercial Support: This CME This CME activity is supported by an activity is supported by an educational grant from Eisai, educational grant from Eisai, Inc.Inc.

Welcome and Program Overview Welcome and Program Overview Welcome and Program Overview Welcome and Program Overview

Distinguished FacultyDistinguished Faculty

Program Co-Chairman Program Co-Chairman Lee M. Kaplan, MD, PhD Lee M. Kaplan, MD, PhD Associate Professor of Medicine Associate Professor of Medicine Harvard Medical SchoolHarvard Medical SchoolDirector, Obesity, Metabolism &Director, Obesity, Metabolism & Nutrition InstituteNutrition InstituteMassachusetts General HospitalMassachusetts General HospitalBoston, Massachusetts Boston, Massachusetts

Louis J. Aronne, MDLouis J. Aronne, MDSanford I. Weill Professor of Metabolic Sanford I. Weill Professor of Metabolic ResearchResearchWeill-Cornell Medical CollegeWeill-Cornell Medical CollegeAttending PhysicianAttending PhysicianThe New York-Presbyterian Hospital, The New York-Presbyterian Hospital, Weill-Cornell Medical CollegeWeill-Cornell Medical CollegeNew York, NY New York, NY

Program Co-ChairmanProgram Co-ChairmanKen Fujioka, MDKen Fujioka, MDDirector, Nutrition and Metabolic Research Director, Nutrition and Metabolic Research Center Center Director, Center for Weight Management Director, Center for Weight Management Scripps Clinic Scripps Clinic San Diego, CASan Diego, CA

Robert F. Kushner, MDRobert F. Kushner, MDProfessor of MedicineProfessor of MedicineNorthwestern University Northwestern University Feinberg School of Medicine Feinberg School of Medicine Clinical Director, Northwestern Clinical Director, Northwestern Comprehensive Center on ObesityComprehensive Center on ObesityChicago, IllinoisChicago, Illinois

COI DisclosuresCOI Disclosures

Faculty Member Relationship Corporation/Manufacturer

Kenneth Fujioka, MD Consultant: Speaker’s Bureau:Grant/Research

Orexigen, Novo Nordisk, Zafgen, NPS, Eisai, Nazura, Pathway Genomics, IsisAbbott, NPS, Eisai, VivusOrexigen, Novo Nordisk, Enteromedics, NPS, Eisai, Weight Watchers

Lee Kaplan, MD, PhD Scientific Advisor: Grant/Research:

Ethicon, Astra Zeneca, Eisai, GI Dynamics, MedImmune, Novo Nordisk, Rhythm, Takeda, Vivus, ZafgenEthicon

Robert F. Kushner, MD Consultant: Grant/Research

Novo Nordisk, Vivus, RetrofitWeight Watchers, Aspire Bariatrics

Louis J. Aronne, MD Consultant: Grant/Research: Ownership Interest: Board of Directors:

Eisai, Ethicon Endo-Surgery, Novo Nordisk, Vivus, ZafgenMedical University of South Carolina, Novo Nordisk, GI Dynamics, Aspire BariatricsCardiometabolic Support Network, LLC, Myos Corporation, ZafgenMyos Corporation

Current Challenges and Barriers to Current Challenges and Barriers to Obesity Treatment in the Obesity Treatment in the

Primary Care SettingPrimary Care Setting

Ken Fujioka, MD – Program Co-ChairKen Fujioka, MD – Program Co-Chair Director, Nutrition and Metabolic Research Center | Director, Center Director, Nutrition and Metabolic Research Center | Director, Center

for Weight Management | Scripps Clinic in San Diego, CAfor Weight Management | Scripps Clinic in San Diego, CA

New Perspectives andNew Perspectives andEmerging Treatment ParadigmsEmerging Treatment Paradigms

Are you Biased Against Are you Biased Against Overweight Patients?Overweight Patients?

► Fat people are good and lazy; thin people are bad and motivatedFat people are good and lazy; thin people are bad and motivated

► Fat people are bad and motivated; thin people are good and lazyFat people are bad and motivated; thin people are good and lazy

► Fat people are bad and lazy; thin people are good and motivatedFat people are bad and lazy; thin people are good and motivated

► Fat people are good and motivated; thin people are bad and lazyFat people are good and motivated; thin people are bad and lazy

Are you Biased ?Are you Biased ?

► Anywhere from 30% to 40% of health care providers Anywhere from 30% to 40% of health care providers who specialized in obesity treatment answered:who specialized in obesity treatment answered:

Fat people are bad and lazy; thin people are good and Fat people are bad and lazy; thin people are good and motivated motivated ● Indicating bias or negative attitudes towards the Indicating bias or negative attitudes towards the

overweight and obese patientoverweight and obese patient● Much of this bias is related to a lack of knowledge Much of this bias is related to a lack of knowledge

Teachman BA, Brownell KD. Teachman BA, Brownell KD. Int J Obes Relat Metab DisordInt J Obes Relat Metab Disord. 2001;25(10):1525-1531.. 2001;25(10):1525-1531.

Knowledge of ObesityKnowledge of Obesity

► Lack of knowledge is cited by many studies as a Lack of knowledge is cited by many studies as a reason why health care professionals do not even reason why health care professionals do not even attempt obesity managementattempt obesity management

► Not surprisingNot surprising● Understanding the mechanism of why it is so hard to lose Understanding the mechanism of why it is so hard to lose

weight and keep it off is recentweight and keep it off is recent

Fujioka K, Bakhru N. Office based management of Obesity;. Mt Sinai J Med. 2010 Sep-Oct;77(5):466-71. Review.

Pathophysiology of ObesityPathophysiology of ObesityWhy is it So Hard to Lose Weight?Why is it So Hard to Lose Weight?

► Need to know how humans regulate weight to Need to know how humans regulate weight to understand the treatment optionsunderstand the treatment options

► Patient APatient A● 48-year-old with a sedentary job48-year-old with a sedentary job● Weight - 150 pounds Weight - 150 pounds ● Develops lower back pain and is placed on prednisone Develops lower back pain and is placed on prednisone

(steroids) to decrease inflammation in compressed nerve (steroids) to decrease inflammation in compressed nerve causing severe paincausing severe pain

● Patient on “the steroids” for 2 months and unable Patient on “the steroids” for 2 months and unable exercise for 6 months and gains 50 poundsexercise for 6 months and gains 50 pounds

The Patient has Gained 50 poundsThe Patient has Gained 50 pounds

The patient has gone from 150 pounds to 200 poundsThe patient has gone from 150 pounds to 200 pounds• With this weight gain his fasting blood sugar is now 105With this weight gain his fasting blood sugar is now 105

The patient is now a “pre-diabetic”The patient is now a “pre-diabetic”• If the patient is Asian or Hispanic, he will see pre-If the patient is Asian or Hispanic, he will see pre-

diabetes emerge with less weight gain (20 to 30 diabetes emerge with less weight gain (20 to 30 pounds)pounds)

The patient is now technically obeseThe patient is now technically obese

Motivated Patient Trying to Lose WeightMotivated Patient Trying to Lose Weight

► The patient recovers from the back injury and decides to The patient recovers from the back injury and decides to lose weightlose weight

► The patient begins a diet and exercise programThe patient begins a diet and exercise program► He loses about 20 pounds (over 3 months)He loses about 20 pounds (over 3 months)

● 200 down to 180200 down to 180

► Despite staying on the diet and exercising 2 to 3 days a Despite staying on the diet and exercising 2 to 3 days a week, the patient stops losing weightweek, the patient stops losing weight

► A few months later the patient notes that weight is A few months later the patient notes that weight is starting to slowly go up starting to slowly go up

Weight Regulation in HumansWeight Regulation in Humans

► The human body is hardwired to know how many fat cells are on board and to keep the The human body is hardwired to know how many fat cells are on board and to keep the body weight stable body weight stable

► At about 5% to 10% of weight loss the human body will respond by:At about 5% to 10% of weight loss the human body will respond by:● Lowering metabolic rate (more than 5%-10%)Lowering metabolic rate (more than 5%-10%)● Lower the hormones that signal satiety or fullness after eatingLower the hormones that signal satiety or fullness after eating● Increase thoughts and hormones to make humans seek out and eat more foodIncrease thoughts and hormones to make humans seek out and eat more food● All part of defense of body weight All part of defense of body weight

• This does not get better with time (always trying to get back to that highest weight)This does not get better with time (always trying to get back to that highest weight)

Sumithran P et al. N Engl J Med. 2011;365:1597-1604

The Good News on The Good News on 5% to 10% Weight Loss5% to 10% Weight Loss

► Sustained weight loss of 3%-5% is likely to result in Sustained weight loss of 3%-5% is likely to result in clinically meaningful reductions in triglycerides, blood clinically meaningful reductions in triglycerides, blood glucose, HbA1C, and the risk of developing type 2 glucose, HbA1C, and the risk of developing type 2 diabetesdiabetes

► Greater amounts of weight loss will reduce blood Greater amounts of weight loss will reduce blood pressure, improve LDL–C and HDL–C, and reduce the pressure, improve LDL–C and HDL–C, and reduce the need for medications to control blood pressure, need for medications to control blood pressure, blood glucose and lipids as well as further reduce blood glucose and lipids as well as further reduce triglycerides and blood glucosetriglycerides and blood glucose

Jensen MD, et al.2013 AHA/ACC/TOS Obesity Guideline

Treatment OptionsTreatment Options20122012

DietDiet• Meal replacements, VLCDs, standard low calorie dietsMeal replacements, VLCDs, standard low calorie diets

ExerciseExercise• Just figured out that a combination of cardio and Just figured out that a combination of cardio and

resistance training is betterresistance training is betterPhenterminePhentermine

• Short term medicationShort term medicationOrlistatOrlistat

• Fat blocker with limited efficacy and well known side Fat blocker with limited efficacy and well known side effectseffects

Bariatric surgeryBariatric surgery• Lap bandLap band• Gastric bypassGastric bypass

► Medications approved in 2013Medications approved in 2013● LorcaserinLorcaserin● Phentermine/Topiramate ERPhentermine/Topiramate ER

► Medications going to the FDA for possible Medications going to the FDA for possible approvalapproval● Liraglutide Liraglutide ● Bupropion SR/ Naltrexone SRBupropion SR/ Naltrexone SR

Treatment OptionsTreatment Options20142014

Proper Use of Obesity Medications Proper Use of Obesity Medications

► Recognizing non-respondersRecognizing non-responders● An obese patient is started on a weight loss An obese patient is started on a weight loss

medication and is not losing adequate medication and is not losing adequate amounts of weightamounts of weight

● STOP the medicationSTOP the medication• Lorcaserin patient should lose 5% or more of Lorcaserin patient should lose 5% or more of

their weight by 3 months, otherwise stoptheir weight by 3 months, otherwise stop• Phentermine/topiramate patient should lose Phentermine/topiramate patient should lose

3% by 3 months or 5% by 6 months3% by 3 months or 5% by 6 months

REMs REMs Risk Evaluation Mitigation Strategy Risk Evaluation Mitigation Strategy

► Phentermine/Topiramate ERPhentermine/Topiramate ER● Possible cleft lip or palate in fetus Possible cleft lip or palate in fetus

exposed to topiramateexposed to topiramate

► REMSREMS● Physicians and pharmacies trained on use Physicians and pharmacies trained on use

of the medicationof the medication● Only certified pharmacies can dispenseOnly certified pharmacies can dispense

• Help to ensure the patient is educated to Help to ensure the patient is educated to not get pregnant while on the medicationnot get pregnant while on the medication

Bariatric SurgeryBariatric Surgery

► Bariatric surgeryBariatric surgery● Sleeve gastrectomy comes of ageSleeve gastrectomy comes of age

• Procedure between an adjustable band Procedure between an adjustable band and gastric bypassand gastric bypass

• Excellent weight lossExcellent weight loss• Fewer nutritional problems after Fewer nutritional problems after

(compared to bypass)(compared to bypass)

FinancialFinancial

► AMA – Obesity defined as a “disease”AMA – Obesity defined as a “disease”► CMS – Primary care practitioners (includes NPs and CMS – Primary care practitioners (includes NPs and

PAs) can get reimbursed for “obesity treatment”PAs) can get reimbursed for “obesity treatment”● They have specific guidelines on how to treatThey have specific guidelines on how to treat

► Weight loss medicationsWeight loss medications● More insurance companies are now starting to More insurance companies are now starting to

reimburse for weight loss medicationsreimburse for weight loss medications• The overall number is still low (less than 50%)The overall number is still low (less than 50%)

► Bariatric surgeryBariatric surgery● Vast majority of insurances cover Vast majority of insurances cover

Treating Patients with Obesity:Treating Patients with Obesity:

Who, Why, How and to What EndsWho, Why, How and to What Ends

Lee M. Kaplan, MD, PhDLee M. Kaplan, MD, PhDObesity, Metabolism & Nutrition InstituteObesity, Metabolism & Nutrition InstituteMassachusetts General HospitalMassachusetts General HospitalHarvard Medical SchoolHarvard Medical School

[email protected]@partners.org

April 11, 2014April 11, 2014

New Perspectives and Emerging Treatment Paradigms New Perspectives and Emerging Treatment Paradigms for Individualizing Obesity Managementfor Individualizing Obesity Management

DisclosuresDisclosures

I may discuss the off-label / unapproved use of several drugs or I may discuss the off-label / unapproved use of several drugs or devices, including: bupropion, canagliflozin, EndoBarrier, devices, including: bupropion, canagliflozin, EndoBarrier, exenatide, liraglutide, metformin, naltrexone, phentermine, exenatide, liraglutide, metformin, naltrexone, phentermine, pramlintide, topiramate, zonisamidepramlintide, topiramate, zonisamide

I am a member of scientific advisory boards for the following I am a member of scientific advisory boards for the following companies:companies:

Astra-ZenecaAstra-Zeneca EisaiEisai EthiconEthicon FractylFractylGelesisGelesis GI DynamicsGI Dynamics MedImmuneMedImmune MetavisionMetavisionNovo NordiskNovo Nordisk RhythmRhythm Second GenomeSecond Genome TakedaTakedaUSGI MedicalUSGI Medical VivusVivus ZafgenZafgen

I receive funding for basic research from the U.S. National I receive funding for basic research from the U.S. National Institutes of Health and Ethicon Surgical Care. Institutes of Health and Ethicon Surgical Care.

I have equity in the following companies:I have equity in the following companies:

FractylFractyl GelesisGelesisGI DynamicsGI Dynamics RhythmRhythm

Why is weight regain after dieting so common? Why is weight regain after dieting so common?

1.1. Exercise, not diet, is the most effective means of losing Exercise, not diet, is the most effective means of losing weightweight

2.2. The body reacts to weight loss by decreasing daily The body reacts to weight loss by decreasing daily energy expenditureenergy expenditure

3.3. Diet foods are boring and patients stop eating themDiet foods are boring and patients stop eating them

4.4. Dieting increases the body’s set point for fat massDieting increases the body’s set point for fat mass

5.5. Weight loss often leads to unwanted effects that cause Weight loss often leads to unwanted effects that cause patients to sabotage their effortspatients to sabotage their efforts

Question 1Question 1

Please Enter Your Response On Your Keypad

Which of the following is Which of the following is NOTNOT a demonstrated a demonstrated benefit of modest regular exercise? benefit of modest regular exercise?

1.1. Enhances weight loss effect of other lifestyle Enhances weight loss effect of other lifestyle changeschanges

2.2. Causes weight loss directlyCauses weight loss directly

3.3. Alters appetite to favor healthier foodsAlters appetite to favor healthier foods

4.4. Stimulates fat to burn more caloriesStimulates fat to burn more calories

5.5. Decreases cardiovascular riskDecreases cardiovascular risk



Which of the following comorbidities of Which of the following comorbidities of obesity has obesity has NOT NOT been shown to improve with been shown to improve with

modest (5-10%) weight loss?modest (5-10%) weight loss?

1.1. Type 2 diabetesType 2 diabetes

2.2. HypertensionHypertension

3.3. DyslipidemiaDyslipidemia

4.4. Cardiovascular riskCardiovascular risk

5.5. Fatty liver diseaseFatty liver disease



If a patient with prediabetes and obesity maintains a If a patient with prediabetes and obesity maintains a 4% weight loss over 4 years, how much do they lower 4% weight loss over 4 years, how much do they lower

their risk of developing diabetes?their risk of developing diabetes?

1.1. <10%<10%

2.2. ~25%~25%

3.3. ~50%~50%

4.4. ~75%~75%

5.5. >90%>90%



Which of the following medications is Which of the following medications is NOTNOT currently currently approved by the FDA for the treatment of obesity? approved by the FDA for the treatment of obesity?

1.1. OrlistatOrlistat

2.2. LiraglutideLiraglutide

3.3. PhenterminePhentermine

4.4. LorcaserinLorcaserin

5.5. Phentermine / Topiramate ER combination Phentermine / Topiramate ER combination



Which of the following weight loss Which of the following weight loss medications do medications do NOTNOT work through central work through central

nervous system mechanisms?nervous system mechanisms?

1.1. BupropionBupropion



4.4. Topiramate ERTopiramate ER




Which of the following is Which of the following is NOTNOT a primary a primary mechanism of weight loss from centrally-mechanism of weight loss from centrally-

acting weight loss medications?acting weight loss medications?

1.1. Change in food preferences Change in food preferences

2.2. Decrease in appetiteDecrease in appetite

3.3. Increase in resting and post-meal energy expenditureIncrease in resting and post-meal energy expenditure

4.4. Demonstrating the value of a healthier weight to the patientDemonstrating the value of a healthier weight to the patient

5.5. Lower physiologically defended body weightLower physiologically defended body weight



Medical Complications of ObesityMedical Complications of Obesity

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome

Gallstones

Gout

Diabetes

Osteoarthritis

Fatty liver diseasesteatosissteatohepatitiscirrhosis

Hypertension

Dyslipidemia

Cataracts

Skin disorders

Pancreatitis

Intracranial hypertensionCognitive dysfunction

Cancerbreast, uterus, cervix, ovary, prostate, kidney, colon, esophaguspancreas, gallbladder, liver

Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome

Stroke

Complications of ObesityComplications of Obesity

PsychologicalPsychological

NeoplasticNeoplastic

InflammatoryInflammatory

StructuralStructural

MetabolicMetabolic

DegenerativeDegenerative 6565

Complications of ObesityComplications of Obesity

Several of these complications exacerbate the Several of these complications exacerbate the underlying obesity, creating a vicious cycle:underlying obesity, creating a vicious cycle:

Diabetes Diabetes Many diabetes drugs Many diabetes drugs cause weight gaincause weight gain

PCOSPCOS Insulin resistance Insulin resistance promotes lipogenesispromotes lipogenesis

Sleep apneaSleep apnea Disrupted sleepDisrupted sleepcan cause weight gaincan cause weight gain

ArthritisArthritis Limit exercise capacityLimit exercise capacityBack painBack pain

InflammatoryInflammatory Steroids often causeSteroids often causedisordersdisorders weight gainweight gain

DepressionDepression Eating disorders andEating disorders andPsychologicalPsychological many psychotropic agents many psychotropic agents

cause weight gaincause weight gain

PsychologicalPsychological

NeoplasticNeoplastic

InflammatoryInflammatory

StructuralStructural

MetabolicMetabolic

DegenerativeDegenerative

Benefits of Modest Intentional Weight LossBenefits of Modest Intentional Weight Loss

• Improvement in comorbid Improvement in comorbid diseasesdiseases

• Type 2 diabetesType 2 diabetes• HypertensionHypertension• DyslipidemiaDyslipidemia• Fatty liver diseaseFatty liver disease• Obstructive sleep apneaObstructive sleep apnea• AsthmaAsthma• OsteoarthritisOsteoarthritis• Cancer riskCancer risk

• Improved quality of lifeImproved quality of life• Decreased health care costsDecreased health care costs• Decreased surgical Decreased surgical

complication rates complication rates • Orthopedic surgeryOrthopedic surgery• Heart surgeryHeart surgery• General and thoracic General and thoracic

surgerysurgery

• The effect on cardiovascular risk is less clearThe effect on cardiovascular risk is less clear

Relationship Between BMI and Relationship Between BMI and Risk of Type 2 DiabetesRisk of Type 2 Diabetes

Chan J et al. Diabetes Care 1994;17:961.Colditz G et al. Ann Intern Med 1995;122:481.

Age-A

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Age-A

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Body Mass index (kg/mBody Mass index (kg/m22))

Men

Women

<22 <23 23-24 24-25 25-27 27-29 29-31 31-33 33-35 >35

1.0

2.91.0

4.31.0

5.01.5

8.12.2

15.8

4.4

27.6

40.3

54.0

93.2

6.711.6

21.3

42.1

-22

-18

-14

-10

-6

-2

2

6

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Year

Ch

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PlaceboMetforminLifestyle

DPP Research Group, N Engl J Med, 2002DPP Research Group, N Engl J Med, 2002

Benefits of Intensive Medical InterventionBenefits of Intensive Medical Intervention

Diabetes Prevention ProgramDiabetes Prevention Program

Diabetes PreventionDiabetes Prevention

Diabetes Prevention Program Research GroupDiabetes Prevention Program Research GroupN Engl J Med, 2002N Engl J Med, 2002

Cum

ulat

ive

Inci

denc

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Dia

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s (%

)40

30

20

10

00 1 2 3 4

PlaceboPlacebo

MetforminMetformin

LifestyleLifestyle

Year

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

Obesity: A Failure of Weight RegulationObesity: A Failure of Weight Regulation

Genetics

Development

EnvironmentAdipose tissue

Leptin

HT

Food intakeEnergy expenditureNutrient handling

Cortex

GI Tract

The current obesity epidemic results primarily from changes in the environment

Macroenvironmental Influences*Macroenvironmental Influences*

•24-hour lifestyle

•Economic structure

•Time pressures

•Workload

•Loss of downtime

•Speed of life

•Global stressors

*Amenable only to societal intervention

Microenvironmental Influences*Microenvironmental Influences*

•Types of nutrients

•Eating schedules

•Physical activity

•Sleep health

•Drugs and medications

•Local stressors

*Amenable to individual action

The goal of lifestyle-based therapies is toThe goal of lifestyle-based therapies is tonormalize the patient’s microenvironmentnormalize the patient’s microenvironment

Overall Treatment StrategyOverall Treatment Strategy

Typical AlgorithmTypical Algorithm(progress through algorithm as clinically required)(progress through algorithm as clinically required)

Post-surgical Combination TherapiesPost-surgical Combination Therapies

Weight Loss SurgeryWeight Loss Surgery

Add MedicationsAdd Medications

Professionally-directed Lifestyle ChangeProfessionally-directed Lifestyle Change

Self-directed Lifestyle ChangeSelf-directed Lifestyle Change

• Healthy diet – to change the nutrient environment by changing the diet chemistry• Improves nutrient signaling to the brain

• Emphasize unprocessed foods

• Encourage complexity

• Number of calories is MUCH less important

• Regular exercise• To improve muscle health, not to burn calories acutely

• Long-term exercise more important than type or intensity

• Stress reduction• Reduce both perceived and “invisible” stresses

• Restore sleep

• Regularize circadian rhythms

Lifestyle Treatment of the Patient with ObesityLifestyle Treatment of the Patient with Obesity

Pharmacological TherapiesPharmacological Therapies

Medication-induced Weight Gain Medication-induced Weight Gain

Medications account for 5-10% of obesity in Medications account for 5-10% of obesity in

the U.S.the U.S.

In each relevant category, remove or substitute In each relevant category, remove or substitute

weight gain-promoting medications with weight weight gain-promoting medications with weight

neutral or weight loss-promoting alternativesneutral or weight loss-promoting alternatives

Weight Loss from Other MedicationsWeight Loss from Other Medications

MedicationMedication Indicated UsesIndicated Uses CommentsComments

BupropionBupropion DepressionDepression Avoid in bipolar diseaseAvoid in bipolar disease

TopiramateTopiramateSeizuresSeizuresMigrainesMigraines

Mood disordersMood disorders

May produce neurological side May produce neurological side effectseffects

ZonisamideZonisamideSeizuresSeizures

Mood disordersMood disordersFew studiesFew studies

MetforminMetforminType 2 diabetesType 2 diabetes

PCOSPCOSRare liver toxicityRare liver toxicity

Liraglutide. ExenatideLiraglutide. Exenatide Type 2 diabetesType 2 diabetes InjectableInjectable

PramlintidePramlintide Type 2 diabetesType 2 diabetes InjectableInjectable

PramlintidePramlintide Type 2 diabetesType 2 diabetes InjectableInjectable

Strategy: Aim for Double Benefits when PossibleStrategy: Aim for Double Benefits when Possible

Medications Approved for ObesityMedications Approved for Obesity

MedicationMedication Average Average Weight Loss*Weight Loss*

Mechanism of Mechanism of ActionAction Potential Side EffectsPotential Side Effects

Phentermine (short-Phentermine (short-term treatment)term treatment) ~ 5%~ 5% AdrenergicAdrenergic Tachycardia, hypertensionTachycardia, hypertension

Phentermine / Phentermine / TopiramateTopiramate 10%10% Adrenergic, CNSAdrenergic, CNS

Tachycardia, hypertension,Tachycardia, hypertension,cognitive dysfunction, cognitive dysfunction,

neuropathy, teratogenicityneuropathy, teratogenicity

LorcaserinLorcaserin 3.5%3.5%Serotonergic Serotonergic

(5HT(5HT2C2C)) HeadacheHeadache

OrlistatOrlistat 3%3% Lipase inhibitorLipase inhibitor Steatorrhea, incontinenceSteatorrhea, incontinence

* Beyond placebo

Practical Use of Weight Loss MedicationsPractical Use of Weight Loss Medications

• Understand risks, cautions and monitoring essentialsUnderstand risks, cautions and monitoring essentials

• Start when weight is stable (within 3% over 3 months)Start when weight is stable (within 3% over 3 months)

• Aim for weight stability with lifestyle managementAim for weight stability with lifestyle management

• Assess effects at 1 and 3 monthsAssess effects at 1 and 3 months

• Continue medication beyond 3 months if ≥ 5% total weight lossContinue medication beyond 3 months if ≥ 5% total weight loss

• Some use “4x3” rule - ≥ 4 lbs. weight loss/month x 3 monthsSome use “4x3” rule - ≥ 4 lbs. weight loss/month x 3 months

• Weight plateau with increased hunger is expectedWeight plateau with increased hunger is expected

• Medication still working if substantial weight regain absentMedication still working if substantial weight regain absent

Foundational Role of the Central Nervous System in Appetite Regulation

Robert Kushner, MD, FACPProfessor of Medicine

Northwestern University Feinberg School of Medicine

[email protected]

DisclosuresI am a consultant, speaker, advisor, or receive research support from:

Aspire Bariatrics

Novo Nordisk

Retrofit

Takeda Pharmaceuticals

VIVUS Inc.

Weight Watchers

Zafgen Inc.

Clinical Application

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

Woods, S. C. et al. J Clin Endocrinol Metab 2008;93:s37-s50

Model summarizing the 3 levels of control over energy homeostasis

Gut Peptides that Regulate Appetite

Murphy KG, Bloom SR. Nature 2006;444:854-859

Ghrelin Signals Hunger

BR LU DI

(24 hour clock)

GhrelinLevel

Adapted from Williams DL, Cummings DE. J Nutr 2005;135:1320-1325

Gut peptides and regulation of appetite

Peptide Where synthesized

Effect on feeding

Ghrelin Stomach Orexigenic

CCK Duodenum Anorexigenic

PYY Distal small intestine

Anorexigenic

GLP-1 Small intestine Anorexigenic

Amylin Pancreas Anorexigenic

CCK = cholecystokinin; PYY = polypeptide YY;GLP-1 = glucagon-like peptide 1; [exenatide, liraglutide]; Amylin [pramlintide]

Leptin is reduced in response to reduction in calories and weight loss; increasing appetite

Wadden TA et al. J Clin Endocrinol Metab 1998;83:214-218

BDD = balanced deficit diet (1200 kcal/d week 2 – 20, then 1200 – 1800 kcal/d week 21 – 40)

LCD = low calorie diet (1000 kcal/d week 2 – 13, 1200 kcal/d week 14-20, then 1200 – 1800 kcal/d weeks 21-40)

Fat Cells obgene

obgene

Hypothalamusobgene

Anorexigenic• CART• POMC• MSH

Orexigenic• Neuropeptide Y• Agouti-related protein

Leptin

Effector Signaling Molecules

Adapted from: L. A. Campfield, F. J. Smith, P. Burn, Horm. Metab. Res. 28, 619 (1996); Endocrinol. Metab. 4, 81 (1997).

Neuron Populations in the ARC

Suppress food intake•POMC (proopiomelanocortin) •CART (cocaine- and amphetamine-regulated transcript)

Two neuron populations with opposing effects on food intake in the hypothalamic arcuate nucleus (ARC):

Stimulate food intake•NPY (neuropeptide Y)•AgRP (agouti-related peptide)

Suzuki K, Jayasena CN, Bloom SR. J Obes. 2011; 2011: 528401. doi: 10.1155/2011/528401.

The Pivotal Role of Leptin

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

University of Edinburgh http://www.diabesity.eu/Leptin.htm

Increase hungerReduce hunger

Hypothalamic Appetite Regulation

Farooqi S. Cell Metab 2006;4:260-262

Increased hunger

Reduced hunger


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

Farooqi et al. NEJM 341, 1999

A Case of Congenital Leptin Deficiency



3% of subjects with severe early onset obesity had a LEPR mutation

6% children withsevere obesity hada mutation in theMC4 receptor


• Can we target some of these signals for pharmacological intervention?



Increased hunger

Reduced hunger

Adrenergic R

Topiramate

5-HT 2c R


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

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

Regulation of Eating: Homeostatic versus Hedonic Signaling Pathways

AN = arcuate nucleus. PVN = paraventricular nucleus, LHA = lateral hypothalamic areaVTA = ventral tegmental areas, SN = substantia nigra, DS = dorsal striatum, NAc = nucleus accumbens

Wang GJ et al. J Addict Med 2009;3:8-18

Activation of Regional Brain Areas by Visual Images of Foods

Mehta S et al. Am J Clin Nutr 2012;96:989-999

Key Learning Take Away’s from the Presentation

The ‘ying-yang’ hypothalamic system is balanced between 2 primary neurons: NYP/AGRP (hunger) and POMC/CART (satiety)

There are 2 peripheral signals that inform the brain about energy balance

Satiation signals arise from gut hormones and indicate meal-to-meal hunger (ghrelin) and fullness (GLP-1, PYY)

Adiposity signals arise from fat cells (leptin) and monitor longer-term energy balance

Two new pharmacological agents (phentermine-topiramate and lorcaserin) act on the primary neurons to alter neurotransmission

The hedonic signaling pathway is responsible to ‘liking or craving’ food

Results and Implications of Multicenter Trials Evaluating the Safety and Efficacy of Centrally Acting Agents as part of Multimodal Management for Obesity

A Review of Metabolic Benefits, Side Effects, and Rationale for Achieving Moderate Weight Loss Through

Drug Based Therapy

March 2014

Louis J. Aronne, MD, FACPSanford I. Weill Professor of Metabolic Research

Weill Medical College of Cornell University

Medical Director, Center for Weight Management and Metabolic Clinical Research

New York Presbyterian HospitalNew York, NY

March 2014

Disclosures

Ownership Interest:BMIQ

Cardiometabolic Support Network

Myos Corporation

Zafgen, Inc.

Board of Directors:Myos CorporationJamieson Laboratories

I am a consultant, speaker, advisor, or receive research support from:Aspire BariatricsAmylin Pharmaceuticals IncArena PharmaceuticalsEisai Inc.Ethicon Endo-Surgery Inc.GlaxoSmithKline Consumer Healthcare LPGI DynamicsHigh Point Pharmaceuticals LLCMedical University of South Carolina Novo NordiskPfizerTakeda PharmaceuticalsUSGIVIVUS Inc.Zafgen Inc.

As faculty of Weill Cornell Medical College, we are committed to providing transparency for any and all external relationships prior to giving an academic presentation.

Obesity Pharmacotherapy

Obesity Pharmacotherapy

An adjunct to lifestyle modification – not a substitute

Can increase chances of meaningful weight loss

76

Anti-obesity MedicationsRationale and Criteria

• Non-drug interventions should be attempted for at least 6 months before considering pharmacotherapy1

• For patients with BMI > 30

• For patients with BMI > 27 or above with concomitant risk factors or diseases (hypertension, dyslipidemia, CHD, type 2 diabetes, sleep apnea)1

1. NIH Clinical Guidelines Evidence Report, Sept 1998. 77

Lets think about for a minute:>120 drugs in 10 categoriesUp to triple drug combinations available

Hypertension Treatment

78

Diuretics

Beta-blockers

ACE inhibitors

Angiotensin II receptor blockers

Calcium channel blockers

Alpha blockers

Alpha-2 Receptor Agonist

Combined alpha and beta-blockers

Central agonists

Peripheral adrenergic inhibitors

Source: L. Aronne

Potential Anti-obesity Drugs and Their PathwaysComplex System with Redundancy-That’s Why It’s Hard to Lose

Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi:10.1038/clpt.2010.57Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways 79

Anti-obesity Drugs Presently on the Market and Pending Approval

80Modified from Zhi-yun Zhang Z-y and Wang M-w. Acta Pharmacologica Sinica 2012;33:145–147.

New!

New!

90%!

Expected Weight Loss with Newly Approved and Investigational Anti-obesity Medications

Modified from Powell AG, Apovian CM, Aronne LJ. Clin Pharmacol Ther. 2011 Jul;90(1):40-51. 81

Pending

Pending

Pending for obesity

Recently Approved Pharmacotherapy

*2 year extension data available.

821. Gadde KM, et al. Lancet. 2011;377:1341-1352. 2. Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308. 3. Smith SR, et al. N Engl J Med. 2010;363:245-256. 4. O’Neil PM, et al. Obesity. 2012;20:1426-1436.

Emerging Pharmacotherapy

83

Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors (The Light Study). 2012.; Clinicaltrials.gov.

Effect of Liraglutide on Body Weight in Non-diabetic Obese Subjects or Overweight Subjects With Co-morbidities: SCALE - Obesity and Pre-diabetes. 2011.

Phentermine/Topiramate

2012

Indications Indications and Doseand Dose

•Approved by FDA, July 2012, schedule IV

•Indication Weight loss in pts with BMI ≥30 kg/m2

or BMI ≥27 kg/m2 with weight-related co-morbid condition(s)

•Treatment Dose Dailyphentermine 7.5 mgtopiramate ER 46 mg

•Max Dose Dailyphentermine 15 mg topiramate ER 92 mg

Phentermine/Topiramate ER

Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012. 85

Mechanism of Mechanism of ActionActionPhentermine• Sympathomimetic

amine, NE release

• Blunts appetite

Topiramate

•Increases GABA activity, antagonize AMPA/ kainate glutamate receptor, carbonic anhydrase inhibitor

• Prolongs satiety

Contraindications Contraindications and and WarningsWarnings

Contraindications Pregnancy, glaucoma,

hyperthyroidism, MAOIs

Warnings• Fetal toxicity• Increased heart rate• Suicide and mood

and sleep disorders• Acute myopia and

glaucoma• Cognitive impairment• Metabolic acidosis• Creatinine elevations• Hypoglycemia with

diabetes meds

• Once-a-day, oral, extended release topiramate• Low doses of previously approved medications to minimize side effects

0 400 mg400 mg200100

30050 150 250 350

Topiramate ERTopiramate ER

0 30mg30mg(free base)(free base)155 10 253.75 7.5

PhenterminePhentermine

Maximum Maximum Approved Approved

DosesDoses

20

23 46 92

Low Mid Full

DOSING•Begin with low dose for 2 wks phentermine 3.75/ topiramate ER•Advance to treatment dose phentermine 7.5/ topiramate ER 46 •If <3% weight loss after 12 wks, either discontinue or advance to full dose phentermine 15/ topiramate ER 92 (transition dose phentermine 11.25/ topiramate ER 69 for 2 wks) •If <5% weight loss after 12 wks on full dose, discontinue (take every other day for one wk)

DOSING•Begin with low dose for 2 wks phentermine 3.75/ topiramate ER•Advance to treatment dose phentermine 7.5/ topiramate ER 46 •If <3% weight loss after 12 wks, either discontinue or advance to full dose phentermine 15/ topiramate ER 92 (transition dose phentermine 11.25/ topiramate ER 69 for 2 wks) •If <5% weight loss after 12 wks on full dose, discontinue (take every other day for one wk)

Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.

Phentermine/Topiramate ER

86

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

Phentermine/TopiramateTrials

87

EQUIP

CONQUER

www.qsymia.com/hcp/conquer-trial.aspx

Effect of Phentermine/Topiramate ER on Weight Loss in Obese Adults Over 2 Years

Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.

-9.3%

-10.5%

-1.8%

Data are shown with least squares mean (95% CI).

SEQUEL Study

Placebo

Phentermine/topiramate CR 7.5/46

Phentermine/topiramate CR 15/92

88

Phentermine/Topiramate ER Improves Risk Factors and Manifestations of Cardiometabolic Disease CONQUER Study

Changes from baseline to week 56 in secondary endpoints

Gadde KM, et al. Lancet. 2011;377(9774):1341-1352. 89

Metabolic Effects of Phentermine/Topiramate ER in Non-Diabetic Patients: SEQUEL Study

Glucose Insulin

*P≤0.005 vs placebo.Phen/TPM CR, phentermine/topiramate controlled release.

*

*

*

*

*

Placebo Phen/TPM ER 7.5/46 mg Phen/TPM ER 15/92 mg

*

90Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.

Weill Cornell Medical College

check if this is this from day 1 to day 730, 2 years?

Phentermine/Topiramate ER: EQUIP and CONQUERMost Commonly Reported Treatment Emergent Adverse Events

Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012. 91

Summary of Phentermine and Topiramate Neuropsychiatric Safety

• No serious AEs related to depression, anxiety or cognition

• No increase in the risk of suicidality(C-SSRS*, PHQ-9**, and AE reporting) in a population where 20% had a prior historyof depression

• Can be prescribed in patients with stable depression and patients on SSRIs

*Columbia Suicide Severity Rating Scale** Patient Health Questionnaire 9-item depression scale

92Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012.

Phentermine/Topiramate ERREMS Program

FDA Pregnancy Category X: Contraindicated

• Topiramate monotherapy for epilepsy in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

Risk Evaluation and Mitigation Strategy (REMS)• Inform patients about increased risk of orofacial

clefts, in infants exposed to phentermine/ topiramate during the first trimester of pregnancy

• Importance of contraception in women of child-bearing potential and pregnancy checks

• Need to discontinue phentermine/topiramate immediately if pregnancy occur

Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.Phentermine and topiramate extended-release capsules CIV Healthcare Provider Training Program. Vivus; 08/2012. 93

Lorcaserin

2012

Lorcaserin

Lorcaserin hydrochloride [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012. 95

Mechanism of Mechanism of ActionAction• Selective 5-HT2C

receptor agonist

• Stimulates α-MSH production from POMC neurons resulting in activation of MC4R

• Increases satiety

Indications and Indications and DoseDose• Approved by FDA

June 2012

• Indication: Weight loss in patients with BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with weight-related co-morbid condition(s)

• 10 mg po bid

• Schedule IV

• Discontinue if 5% weight loss is not achieved in 12 wks

Contraindications Contraindications and Warningsand WarningsContraindications • Pregnancy

Warnings•Co-administration with other serotonergic or anti-dopaminergic agents

•Valvular heart disease

•Cognitive impairment

•Psychiatric disorders (euphoria, suicidal thoughts, depression)

•Priapism

•Risk of hypoglycemia with diabetes meds

96

Increase in serotonin bioavailability (due to food intake or pharmacological compounds such as sibutramine and fenfluramine) or direct agonism of 5HT2CRs and 5HT1BRs modulates firing of POMC/CART and AgRP NPY neurones within the arcuate nucleus of the ARC

Anorectic POMC neurones expressing 5HT2CR depolarize on receptor activation and release α-melanocyte-stimulating hormone (α-MSH), which in turn activates second-order melanocortin 4 receptor (MC4R) expressing neurones, principally within the paraventricular nucleus of the hypothalamus (PVH; Balthasar et al. 2005)

Concomitant activation of 5HT1BRs expressed on orexigenic AgRP/NPY neurones within the ARC causes membrane hyperpolarization and subsequent inhibition of neuropeptide release

Inhibitory 5HT1BR activation also attenuates inhibitory postsynaptic currents onto POMC/CART neurones further potentiating anorexigenesis

Subsequent downstream neuroendocrine signalling promotes satiety and the cessation of food intake

Garfield A S , and Heisler L K. J Physiol. 2009;587:49-60.

Proposed Model of a Serotonergic Pathway Modulating Food Intake

Lorcaserin Phase 3 Trials

• n=3,182 • 2 years tx• Dosage 10 mg QD1

1. Smith SR, et al. N Engl J Med 2010;363:245-56.2. Fidler MC, et al. J Clin Endocrinol Metab, October 2011, 96(10):3067–3077.3. O’Neil PM, et al. Obesity (16 March 2012) | doi:10.1038/oby.2012.66Arena Pharmaceuticals

• n=4,008 • 1 year tx• Dosage 10 mg QD2

• n=604 obese/ overweight with type 2 DM

• 1 year+ tx• Dosage 10 mg BID or 10 mg QD3

97

Lorcaserin: Those Who Lost ≥ 4.5% Total Body Weight by Week 12 Were Week 52 Responders

0 4 8 12 16 20 24 28 32 36 40 44 48 52-15

-10

-5

0

Responder:Lorcaserin BID

Non-Responder:Lorcaserin BID

Week

%Change

Studies 009 and 011, MITT

-10.22%

STOP -2.46%

Responder: Lorcaserin BID

Non-responder: Lorcaserin BID

Slide courtesy Dr. Steve Smith; May 10, 2012 FDA Advisory Committee Meeting 98

Lorcaserin ─ BLOOM Study:Key Secondary Endpoints

Intention-to-Treat Analysis with LOCF Imputation

99Smith SR, et al. NEJM. 2010;363:245-256.

Randomized Placebo‐Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 DM BLOOM‐DM Study - HbA1c

O’Neil PM, et al. Obesity (Silver Spring). 2012 Jul;20(7):1426-36.

101

Randomized Placebo‐Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 DM BLOOM‐DM StudyWeight Loss

O’Neil PM, et al. Obesity (Silver Spring). 2012 Jul;20(7):1426-36.

Lorcaserin: Adverse Events Reported by >5% in Any Group

102Smith SR, et al. NEJM. 2010;363:245-256.

Intention-to-Treat Analysis with LOCF Imputation

Naltrexone SR/Bupropion

Target of

2014

2011

Naltrexone/Bupropion

• Mechanism of Action– Naltrexone ─ Opioid receptor antagonist

– Bupropion ─ Dopamine/noradrenaline reuptake inhibitor

• Approved by FDA committee but FDA did not approve until a CVD outcome study is performed due to concerns about blood pressure and pulse in some patients

• The Light Study (CVD outcomes) is under way; estimated completion: July 2017

Apovian C, et al. Obesity. 2013.Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors (The Light Study). 2012. http://clinicaltrials.gov/show/NCT01601704 104

Mean Weight Loss

Greenway FL, et al. Lancet 2010 Aug 21; 376:595. DOI:10.1016/S0140-6736(10)60888-4.

Naltrexone/ Bupropion

56 Weeks – Completer PopulationCOR-I Phase 3

105

A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II)

Apovian CM, Aronne L, et al. Obesity (Silver Spring). 2013 May;21(5):935-43.

Naltrexone SR / Bupropion SR Phase 3 Trial (COR-II)

106

Improvement in risk factors with use of Naltrexone SR / Bupropion SR

107Apovian CM, Aronne L, et al. Obesity (Silver Spring). 2013 May;21(5):935-43.

Side Effects

Most frequent events:– Nausea

• N=171 (29.8%) naltrexone 32 mg plus bupropion

• N=155 (27.2%) naltrexone 16 mg plus bupropion

• N=30 (5.3%) placebo

– Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups vs. placebo

– Transient increase of ~1·5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups

– Combination treatment was not associated with increased depression or suicides vs. placebo

Naltrexone/Bupropion

Greenway FL, et al. Lancet. 2010 Aug 21;376(9741):595-605.PMID: 20673995. 108

Liraglutide

2010for Type 2 DM

for anti-obesity

Liraglutide

• Glucagon-Like Peptide 1 (GLP-1) receptor agonist approved in 2010 for treatment of type 2 diabetes (1.8 mg/day)

• Appetite effect mediated by both the activation of GLP-1 receptors expressed on vagal afferents and hypothalamus

• Affects visceral fat adiposity, appetite, food preference, and cardiovascular biomarkers in patients with type 2 diabetes

• Suppresses appetite, and delays gastric emptying

• Phase III trials assessing effects of doses as high as 3.0 mg/day submitted to FDA

110

Effects of Liraglutide and Orlistat on Body Weight in Nondiabetic Obese Adults

Data are mean (95% CI) for the ITT population111Astrup A, et al. Lancet. 2009 Nov 7;374(9701):1606-16.

Liraglutide Weight Loss: One Year

112

Supplementary Information Table 3: Mean changes in body weight

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

Liraglutide Weight Loss: Two Years

113

Liraglutide 3.0 mg for 1 year (and then maintained on 2.4/3.0 mg for the second year) maintained a mean weight loss of 10.3±7.1 kg from screening over 2 years

3.0 mg10.3±7.1 kgweight loss

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

• Generally well tolerated and improved quality of life• Adverse events mostly mild or moderate• Gastrointestinal events (particularly nausea and

vomiting), consistent with the known physiological effects of GLP-1, were more frequent than with placebo

• At year 1, nausea and/or vomiting was associated with greater weight loss with liraglutide 3.0 mg, but even those who did not experience these events lost more weight than those on placebo or orlistat

• Injection regimen did not impair adherence or cause significant withdrawal during treatment or run-in

Liraglutide: Adverse Events

114Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.

Obesity Drugs in the Pipeline

Beloranib

• N=19 obese women

• Mean BMI 38 kg/m2

• Dosage at 0.9 mg/m2 associated with a 42% reduction in triglycerides 18% reduction in LDL-cholesterol

– Improvement in C-reactive protein and reduced sense of hunger

• Most frequent AE’s: headache, infusion site injury, nausea, and diarrhea

• Nausea and infusion site injury occurred more with beloranib vs placebo

• Loss of venous access most common reason for discontinuation

Beloranib: Phase 1 Trial Results – 4 weeks

116

Fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor

Hughes TE, et al. Obesity (Silver Spring). 2013 Mar 20. doi: 10.1002/oby.20356. [Epub ahead of print]

No evidence of major tolerability or safety issues (Phase 1 trials)

• Completers: n=19

• Mean BMI 37.9 kg/m2

• Administered through subcutaneous injections 2x weekly over 12 weeks

• Patients ate normally; not counseled to change exercise habits

• Beloranib-patients showed improvements in cardiometabolic risk factors including reduced triglycerides, LDL cholesterol and C-reactive protein (an inflammatory marker) versus placebo

Beloranib: Phase 2 TrialInterim Analysis - 12 Weeks

117

Fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor

ADA Poster Session 19-B Abstract #188-LB June 22, 2013

No evidence of major tolerability or safety issues (Phase 1 trials)

Anti-obesity Medications in Development

Kim GW, et al. Clin Pharmacol Ther. 2013 Oct 8. doi: 10.1038/clpt.2013.204. [Epub ahead of print] 118

• Few choices of anti-obesity medications• Two new medications approved in 2012• Two more are pending approval• Medications can enhance weight loss for

select candidates and improve cardiometabolic outcomes

• Medications are always only adjunct to diet and exercise

• When we have more medications, we will treat obesity more frequently.

Summary

119

Case Based Learning, Front-Line Practice Strategies, Case Based Learning, Front-Line Practice Strategies, and Real World Implementation of Obesity and Real World Implementation of Obesity Management in the Primary Care SettingManagement in the Primary Care Setting

When, In Whom, Why, and How to Treat ObesityWhen, In Whom, Why, and How to Treat Obesity

New Perspectives andNew Perspectives andEmerging Treatment ParadigmsEmerging Treatment Paradigms

Ken Fujioka, MD – Program Co-ChairKen Fujioka, MD – Program Co-Chair Director, Nutrition and Metabolic Research Center | Director, Center Director, Nutrition and Metabolic Research Center | Director, Center

for Weight Management | Scripps Clinic in San Diego, CA for Weight Management | Scripps Clinic in San Diego, CA

Case Study 1Case Study 1Metabolically Healthy ObeseMetabolically Healthy Obese

► 43-year-old male accountant43-year-old male accountant● 6 feet tall, weight 225 pounds6 feet tall, weight 225 pounds

● Gained about 35 pounds after college (played Gained about 35 pounds after college (played basketball in college)basketball in college)

● Still plays recreational basketball and lifts weightsStill plays recreational basketball and lifts weights

● Wants to lose weight so he can dunk a basketballWants to lose weight so he can dunk a basketball

● And his much younger wife sent him in for his snoringAnd his much younger wife sent him in for his snoring

● No known medical problems No known medical problems

Case Study 1Case Study 1Physical ExamPhysical Exam

BP: 124/72 Pulse 74BP: 124/72 Pulse 74► BMI = 30BMI = 30► Waist is 35 inchesWaist is 35 inches► ENT: normal ENT: normal ● Upper airway looks OK maybe a little narrowedUpper airway looks OK maybe a little narrowed► Skin normalSkin normal► The rest of the exam is completely normalThe rest of the exam is completely normal► What tests do you order?What tests do you order?

Which test is not needed in the work up Which test is not needed in the work up of the obese male ?of the obese male ?

1)1) Comprehensive metabolic panelComprehensive metabolic panel

2)2) Thyroid functionThyroid function

3)3) Overnight oximetryOvernight oximetry

4)4) Total testosteroneTotal testosterone

5)5) A1cA1c

6)6) Lipids Lipids

7)7) Vitamin D level (25 OH)Vitamin D level (25 OH)

Case Study 1 - Question 1Case Study 1 - Question 1


Case Study 1Case Study 1The Basketball PlayerThe Basketball Player

► Comprehensive metabolic panelComprehensive metabolic panel● Completely normalCompletely normal● Fasting glucose 84Fasting glucose 84● TSH 2.8 normalTSH 2.8 normal● Total testosterone 402Total testosterone 402● Lipids all with in normal parametersLipids all with in normal parameters

► Overnight oximetry : Sleep apnea work upOvernight oximetry : Sleep apnea work up● NormalNormal

Which lipid parameter has very little Which lipid parameter has very little improvement with weight loss?improvement with weight loss?

1)1) TriglyceridesTriglycerides

2)2) LDL LDL

3)3) HDLHDL

4)4) All lipid parameters are dramatically improved with All lipid parameters are dramatically improved with weight loss and made worse by obesity weight loss and made worse by obesity



Classify or stage the severity of this patient’s obesity:Classify or stage the severity of this patient’s obesity:

1)1) Stage 0Stage 0

2)2) Stage 1Stage 1

3)3) Stage 2Stage 2

4)4) Stage 3Stage 3

5)5) Stage 4 Stage 4



What would be the best treatment option for this What would be the best treatment option for this patient? patient?

1)1) Do nothing and reassure him he is healthy Do nothing and reassure him he is healthy

2)2) Diet and lifestyle modification Diet and lifestyle modification

3)3) Medications plus diet and lifestyleMedications plus diet and lifestyle

4)4) Bariatric surgery Bariatric surgery



Case Study 2Case Study 2Hispanic Male Hispanic Male

► 46-year-old Hispanic male born and raised in Florida 46-year-old Hispanic male born and raised in Florida ► Presents for his annual physical Presents for his annual physical

● Not good about getting an annual physical but got moved up to a vice president job Not good about getting an annual physical but got moved up to a vice president job and needs a physical for life insurance and needs a physical for life insurance

► BMI is 27BMI is 27► No history of medical problemsNo history of medical problems► He has no complaints and feels great He has no complaints and feels great

► BMI 27BMI 27► Waist 38 inchesWaist 38 inches

► Fasting blood sugar 104Fasting blood sugar 104► A1c 5.9A1c 5.9► LipidsLipids

● TGs 289TGs 289● HDL 27HDL 27● LDL 109LDL 109

► The rest of his labs are all normalThe rest of his labs are all normal

Case Study 2Case Study 2Hispanic Male Hispanic Male

Does this patient meet the definition of obesity ?Does this patient meet the definition of obesity ?

1.1. No (not obese just overweight) No (not obese just overweight)

2.2. Yes (obese)Yes (obese)

3.3. It depends on what which definition of obesity It depends on what which definition of obesity you use (International vs. American)you use (International vs. American)

4.4. It depends on what country you are in It depends on what country you are in



Classify or Stage the severity of this patient’s obesity:Classify or Stage the severity of this patient’s obesity:

1)1) Stage 0Stage 0

2)2) Stage 1Stage 1

3)3) Stage 2Stage 2

4)4) Stage 3Stage 3




Which medications would you consider ?Which medications would you consider ?

1)1) MetforminMetformin

2)2) OrlistatOrlistat

3)3) LorcaserinLorcaserin

4)4) Phentermine/Topiramate ERPhentermine/Topiramate ER

5)5) PhenterminePhentermine



Case Study 3 Case Study 3

► 37-year-old newly married Caucasian female 37-year-old newly married Caucasian female

► Has known polycystic ovarian syndromeHas known polycystic ovarian syndrome

► Told by her Ob-gyn to lose weight to improve her Told by her Ob-gyn to lose weight to improve her chances of getting pregnantchances of getting pregnant

► The patient specifically asks for a “weight loss” The patient specifically asks for a “weight loss” medication to kick start her weight lossmedication to kick start her weight loss

► She also wants her thyroid tested and says a doctor in She also wants her thyroid tested and says a doctor in the past gave her thyroid meds the past gave her thyroid meds

Case Study 3Case Study 3PCO PatientPCO Patient

► BMI 34BMI 34► Skin: acne scars with 6 inflammatory acne lesions on Skin: acne scars with 6 inflammatory acne lesions on

the facethe face► Hair: some lose on the scalpHair: some lose on the scalp► Waist 44 inches Waist 44 inches ► A1c 6.5A1c 6.5► Fasting glucose 138Fasting glucose 138► TSH is normal (1.8) and not on thyroid replacementTSH is normal (1.8) and not on thyroid replacement


1)1) Stage 0Stage 0

2)2) Stage 1Stage 1

3)3) Stage 2Stage 2

4)4) Stage 3Stage 3




Should you start thyroid replacement therapy?Should you start thyroid replacement therapy?

1)1) Give her low dose replacement since she Give her low dose replacement since she was on it beforewas on it before

2)2) Her TSH is normal and she does not need Her TSH is normal and she does not need replacementreplacement

3)3) Give her low dose replacement as she will Give her low dose replacement as she will need more thyroid hormone when she is need more thyroid hormone when she is pregnantpregnant




1)1) Do nothing and reassure the patient she is healthy Do nothing and reassure the patient she is healthy






Which diabetic medications would you consider ?Which diabetic medications would you consider ?1) Metformin

2)2) SulfonylureaSulfonylurea

3) DPP-4 inhibitor

4) GLP-1

5) SGLT-2 inhibitor inhibitor

6)6) Pioglitazone Pioglitazone

7)7) InsulinInsulin



Which weight loss medication would you consider ?Which weight loss medication would you consider ?

1)1) 1. Orlistat1. Orlistat

2)2) 2. Phentermine2. Phentermine

3)3) 3. Phentermine/topiramate ER3. Phentermine/topiramate ER

4)4) 4. Lorcaserin4. Lorcaserin



Case Study 4Case Study 4

► 55-year-old morbidly obese male 55-year-old morbidly obese male ► Had a myocardial infarction 8 months ago and is Had a myocardial infarction 8 months ago and is

finishing up cardiac rehabfinishing up cardiac rehab► No CHF and had a CABG with excellent resultsNo CHF and had a CABG with excellent results► Has bilateral degenerative joint disease and the Has bilateral degenerative joint disease and the

orthopedic surgeon will not operate until he loses orthopedic surgeon will not operate until he loses weightweight

► Due to his weight and knees he now has trouble just Due to his weight and knees he now has trouble just walking from room to roomwalking from room to room● Can’t go up and down stairsCan’t go up and down stairs

Case Study 4Case Study 4Morbidly Obese MaleMorbidly Obese Male

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

Patient is on the following medications:Patient is on the following medications:which medication will make weight loss more difficultwhich medication will make weight loss more difficult

1)1) HCTZHCTZ

2)2) ARBARB

3)3) Beta-blockerBeta-blocker

4)4) MetforminMetformin




1)1) Stage 0Stage 0

2)2) Stage 1Stage 1

3)3) Stage 2Stage 2

4)4) Stage 3Stage 3





► 48-year-old depressed female48-year-old depressed female► Peri-menopausal Peri-menopausal ► Wants to lose weight to feel better about herselfWants to lose weight to feel better about herself

● “ “ I am depressed about being fat”I am depressed about being fat”► I follow a gluten free diet and exercise 1 to 2 hours a I follow a gluten free diet and exercise 1 to 2 hours a

day and can’t lose weightday and can’t lose weight► It has to be my thyroid or some hormonal problem It has to be my thyroid or some hormonal problem

Case Study 5Case Study 5Obese Peri-menopausal FemaleObese Peri-menopausal Female

► Medications: 30 mgs paroxetine Medications: 30 mgs paroxetine ► No health problemsNo health problems► BMI 32BMI 32► LabsLabs

● TSH 1.3 (WNLs)TSH 1.3 (WNLs)● Lipids normalLipids normal● Glucose normalGlucose normal

Classify or stage the severity of this patient’s obesityClassify or stage the severity of this patient’s obesity



1)1) Stage 0Stage 0

2)2) Stage 1Stage 1

3)3) Stage 2Stage 2

4)4) Stage 3Stage 3



1)1) Do nothing and reassure her she is healthy Do nothing and reassure her she is healthy






Which medication changes would you consider ?Which medication changes would you consider ?

1)1) Wean off paroxetineWean off paroxetine

2)2) Start bupropionStart bupropion

3)3) OrlistatOrlistat

4)4) LorcaserinLorcaserin

5)5) Phentermine/topiramate ERPhentermine/topiramate ER

6)6) PhenterminePhentermine



Case Study 6Case Study 6► A 49-year-old female with severe obesity presents for assistance with weight lossA 49-year-old female with severe obesity presents for assistance with weight loss

● T2DM x 4 yearsT2DM x 4 years• Metformin 500 mg BID, liraglutide 1.8 mg sc q dMetformin 500 mg BID, liraglutide 1.8 mg sc q d

● HypertensionHypertension• Losartan 100 mg q d, diltiazem 360, chlorthalidone 50 mg q dLosartan 100 mg q d, diltiazem 360, chlorthalidone 50 mg q d

● HyperlipidemiaHyperlipidemia• Simvastatin 20 mg q dSimvastatin 20 mg q d

● GERDGERD• Lansoprazole 30 mg q dLansoprazole 30 mg q d

● OSA – nightly CPAPOSA – nightly CPAP● Arthralgias of kneesArthralgias of knees


► Weight historyWeight history● Overweight since high school followed by progressive, ratcheting weight gain since entering the work Overweight since high school followed by progressive, ratcheting weight gain since entering the work

force to highest weight of 340 lbs.force to highest weight of 340 lbs.● Attributes obesity to work and family stress, and providing care to family membersAttributes obesity to work and family stress, and providing care to family members● Previously participated in commercial programs (Jenny Craig and Weight Watchers) and saw RD when Previously participated in commercial programs (Jenny Craig and Weight Watchers) and saw RD when

she was diagnosed with T2DMshe was diagnosed with T2DM

► Social historySocial history● Single, living with brother and Labrador retriever ‘Bear’, works as quality assurance analyst for BCBSSingle, living with brother and Labrador retriever ‘Bear’, works as quality assurance analyst for BCBS

► Diet historyDiet history● Skips breakfast, first meal at 11:00 AM is left-overs Skips breakfast, first meal at 11:00 AM is left-overs

or fast food. Second meal is 6:30 PM, either fast or fast food. Second meal is 6:30 PM, either fast food or easy prep foods [although appetite food or easy prep foods [although appetite reduced since starting on liraglutide, selection of reduced since starting on liraglutide, selection of foods and portions have not changed].foods and portions have not changed].

► Physical activity historyPhysical activity history• Limited to ADLs. Has stationary bike and treadmill Limited to ADLs. Has stationary bike and treadmill

in home but seldom usedin home but seldom used


► ExaminationExamination● Weight 352 lbs, height 66.25 in, BMI 52.1 kg/mWeight 352 lbs, height 66.25 in, BMI 52.1 kg/m22

● BP 128/62, HR 92BP 128/62, HR 92● Heart – Grade 2/6 SEMHeart – Grade 2/6 SEM● Extremities – dystrophic skin changes, 1+ edemaExtremities – dystrophic skin changes, 1+ edema

► LabsLabs● Glucose 95 mg/dl, HbA1c 6.5%Glucose 95 mg/dl, HbA1c 6.5%● BUN 19 mg/dl, eGFR 73 ml/min/1.73BUN 19 mg/dl, eGFR 73 ml/min/1.73● TC 152 mg/dl, LDLc 70 mg/dl, HDLc 46, TG 181 mg/dlTC 152 mg/dl, LDLc 70 mg/dl, HDLc 46, TG 181 mg/dl


What would you recommend regarding weight What would you recommend regarding weight management?management?

1)1) Refer to commercial programRefer to commercial program2)2) Refer to registered dietitianRefer to registered dietitian3)3) Initiate lifestyle counseling yourself Initiate lifestyle counseling yourself 4)4) One of the above + pharmacotherapyOne of the above + pharmacotherapy5)5) Refer for bariatric surgeryRefer for bariatric surgery



Case Study 6Case Study 6RD VisitRD Visit

► Further assessmentFurther assessment● Brother does the grocery shopping – will not buy Brother does the grocery shopping – will not buy

healthier foods since he believes it is too expensivehealthier foods since he believes it is too expensive● Eats out often, choosing fast foodsEats out often, choosing fast foods● Eats out of boredom and anxietyEats out of boredom and anxiety

► CounselingCounseling● Make small changes, do not skip breakfastMake small changes, do not skip breakfast● Track diet [patient response “is not going to happen”]Track diet [patient response “is not going to happen”]● Healthy ‘budget conscious’ itemsHealthy ‘budget conscious’ items● Snack and meal ideasSnack and meal ideas

Case Study 6Case Study 6Follow Up at 7 WeeksFollow Up at 7 Weeks

► Implemented some changes from RD visit: not Implemented some changes from RD visit: not skipping meals, less ‘junk food’skipping meals, less ‘junk food’

► 6 lbs. weight loss initially, no change in past 3 6 lbs. weight loss initially, no change in past 3 weeks. weeks.

► Went to bariatric surgery seminar at my request Went to bariatric surgery seminar at my request but considers surgery a ‘mutilation’ and is not but considers surgery a ‘mutilation’ and is not interestedinterested

► Perceives lifestyle changes to be very hard. Perceives lifestyle changes to be very hard. Difficult of focus on self-care and is feeling Difficult of focus on self-care and is feeling pessimisticpessimistic

Weight Graph from EHRWeight Graph from EHR

What would your approach be at this time?What would your approach be at this time?1)1)Stay the course and reinforce importance of adherenceStay the course and reinforce importance of adherence

2)2)Refer to mental health professionalRefer to mental health professional

3)3)Prescribe a very-low-calorie diet (VLCD) to reduce Prescribe a very-low-calorie diet (VLCD) to reduce caloric intake furthercaloric intake further

4)4)Emphasize need to start an exercise programEmphasize need to start an exercise program

5)5)Initiate pharmacotherapyInitiate pharmacotherapy

6)6)Revisit her negative view of bariatric surgeryRevisit her negative view of bariatric surgery



Rationale for Prescribing Rationale for Prescribing Anti-Obesity MedicationsAnti-Obesity Medications

► Weight loss, and maintenance of lost Weight loss, and maintenance of lost weight, is difficult for many patientsweight, is difficult for many patients

► The primary function of anti-obesity The primary function of anti-obesity medication is to assist with weight loss and medication is to assist with weight loss and maintenance of lost weight by reducing maintenance of lost weight by reducing hunger and/or increasing satiety, thus hunger and/or increasing satiety, thus allowing patients to follow a calorie-reduced allowing patients to follow a calorie-reduced diet with more resolvediet with more resolve

*an anti-obesity medication may have independent effects, e.g., orlistat on LDLc, liraglutide on glucose

Case Study 6Case Study 6Follow UpFollow Up

► The addition of pharmacotherapy was The addition of pharmacotherapy was discussed and patient’s attitudes assessed.discussed and patient’s attitudes assessed.

► Use and side effects of Use and side effects of phentermine/topiramate ER were discussed phentermine/topiramate ER were discussed and asked her to review the company website and asked her to review the company website [lorcaserin was not available at the time][lorcaserin was not available at the time]

► Patient elected to try medication and a Patient elected to try medication and a prescription was providedprescription was provided

Weight Graph from EHRWeight Graph from EHR

46 lbs = 14%

Case Study 6Case Study 6BiomarkersBiomarkers

ValueValue BaselineBaseline 3 3 monthsmonths

7 7 monthsmonths

10 10 monthsmonths

14 14 monthsmonths

Weight, lbs, (% wt loss) 325.2325.2 303.5303.5

(6.6%)(6.6%)290 290

(10.7%)(10.7%)282 282

(13.2%)(13.2%)280280

(13.8%)(13.8%)

Glucose, mg/dl 9595 9393 8989 8585 8888

HbA1c, % 6.56.5 6.36.3 6.06.0 5.95.9 6.06.0

TC, mg/dl 182182 175175 183183 176176 175175

LDL-c, mg/dl 110110 103103 107107 105105 104104

HDL-c. mg/dl 4646 4545 5151 5454 5151

TG, mg/dl 181181 135135 127127 8383 9898

New Perspectives and Emerging Treatment Paradigms New Perspectives and Emerging Treatment Paradigms for Individualizing Obesity Managementfor Individualizing Obesity Management

Optimizing Weight Loss in the Primary Care Optimizing Weight Loss in the Primary Care Setting: Where Are We Now, and Where Are Setting: Where Are We Now, and Where Are We Going?We Going?

Lee M. Kaplan, MD, PhDLee M. Kaplan, MD, PhDObesity, Metabolism & Nutrition InstituteObesity, Metabolism & Nutrition InstituteMassachusetts General HospitalMassachusetts General HospitalHarvard Medical SchoolHarvard Medical School

[email protected]@partners.org

April 11, 2014April 11, 2014

What is Obesity?What is Obesity?

• The presence and severity of obesity can be The presence and severity of obesity can be estimatedestimated by a variety of biomarkers by a variety of biomarkers• Body mass index (BMI)Body mass index (BMI)• Body compositionBody composition• Body fat distributionBody fat distribution• Risk scoresRisk scores• ComorbiditiesComorbidities

• But these markers should not But these markers should not definedefine obesity obesity

Excessive fat accumulation Excessive fat accumulation that presents a risk to healththat presents a risk to health

• Calling it a disease would define one-third of Americans Calling it a disease would define one-third of Americans as being ill and could lead to more reliance on costly as being ill and could lead to more reliance on costly drugs and surgery rather than lifestyle changesdrugs and surgery rather than lifestyle changes

• Some people might be overtreated because their BMI Some people might be overtreated because their BMI was above a line designating them as having a disease, was above a line designating them as having a disease, even though they were healthyeven though they were healthy

Why Obesity is Why Obesity is NOTNOT a Disease a Disease

• It is a lifestyle choiceIt is a lifestyle choice

• No specific symptoms associated with itNo specific symptoms associated with it

• It is a It is a risk factor risk factor for disease, not a disease itself*for disease, not a disease itself*

* What about high cholesterol or hypertension?

Why Obesity Why Obesity ISIS a Disease a Disease

• It is associated with impaired body functionIt is associated with impaired body function

• Like other diseases, it results from physiological Like other diseases, it results from physiological dysfunction (precipitated by numerous forces in modern dysfunction (precipitated by numerous forces in modern society)society)

• It causes, exacerbates or accelerates more than 65 It causes, exacerbates or accelerates more than 65 significant comorbid diseasessignificant comorbid diseases

• It is associated with a substantial burden of morbidity It is associated with a substantial burden of morbidity and premature deathand premature death

Obesity Complications – Targets of TherapyObesity Complications – Targets of Therapy

• DiabetesDiabetes• HypertensionHypertension• HyperlipidemiaHyperlipidemia• Fatty liver diseaseFatty liver disease• Sleep apneaSleep apnea• GERDGERD• ArthritisArthritis• Inflammatory and autoimmune diseasesInflammatory and autoimmune diseases• Cancer (12 types)Cancer (12 types)• Cognitive dysfunctionCognitive dysfunction

OverallOverall TreatmentTreatment StrategyStrategy

Typical AlgorithmTypical Algorithm(progress through algorithm as clinically required)(progress through algorithm as clinically required)

Post-surgical Combination TherapiesPost-surgical Combination Therapies

Weight Loss SurgeryWeight Loss Surgery

Add MedicationsAdd Medications

Professionally-directed Lifestyle ChangeProfessionally-directed Lifestyle Change

Self-directed Lifestyle ChangeSelf-directed Lifestyle Change

There is broad variability in the weight loss There is broad variability in the weight loss response to response to ALLALL therapies for obesity therapies for obesity

The Heterogeneity of ObesityThe Heterogeneity of Obesity

Core Principle of Obesity Treatment

• Lifestyle interventions

• Medications

• Surgery

• Lifestyle interventions

• Medications

• Surgery

Weight Loss Variability after Gastric BypassWeight Loss Variability after Gastric Bypass

Bessler et al., 2008

Bessler et al., 2008

Weight Loss Variability after Gastric BandingWeight Loss Variability after Gastric Banding

Adapted from Hansen DL et al., IJO 2001; 25:496

Responder Tail

Sibutramine-induced Weight Loss

Weight Loss Variability with SibutramineWeight Loss Variability with Sibutramine

Lorcaserin-induced Weight Loss

% Weight Loss

% o

f Pati

en

ts

Weight Loss Variability with LorcaserinWeight Loss Variability with Lorcaserin

Weight Loss Variability on Different DietsWeight Loss Variability on Different Diets

Atkins DietAtkins Diet Zone DietZone Diet

LEARN ProgramLEARN Program Ornish DietOrnish Diet

Weight ChangeWeight Change Weight ChangeWeight Change

Weight ChangeWeight Change Weight ChangeWeight Change

No.

of

Subje

cts

No.

of

Subje

cts

No.

of

Subje

cts

No.

of

Subje

cts

Adapted from Gardner et al, JAMA 2007Adapted from Gardner et al, JAMA 2007

Wide variability in therapeutic response is best explained by clinically important

subtypes

Prader- Willi syndromeBardet-Biedl syndromeAlström syndrome HypothalamicHyperphagicThermogenesis deficientCircadian-disruptedStress-inducedCentralPeripheralDiffuseNeonatalEarly childhoodPeripubertalGestationalMenopausal“Healthy”MetabolicInflammatory

The Obesities – A Plethora of Discrete DisordersThe Obesities – A Plethora of Discrete Disorders

Multiple Subtypes = Variation in Treatment Response

Leptin deficiencyLepR deficiencyMC4R deficiencyMSH deficiencySim-1 deficiencyPC-1 deficiencyKSR2 deficiencyMRAP2 deficiencySH2B1 deficiencyBDNF deficiencytrkB deficiencyCarpenter syndromeCohen syndromeAyazi syndromeMOMO syndromeRubenstein-Taybi syndromeFragile X syndromeBFL syndromeAlbright osteodystrophy

Diet-dependentExercise-sensitiveSleep-sensitiveInsulin-inducedSteroid-inducedProgesterone-inducedPsychotropic-inducedAntibiotic-inducedEndocrine disruptor Phentermine-responsiveLorcaserin-responsiveTopiramate-responsiveMetformin-responsiveBupropion-responsiveGLP-1 responsiveBypass-responsiveBypass-resistantGastric band-responsive

What Differs Among Different Obesity Subtypes

• Timing of obesity onset• Fat location and distribution• Metabolic consequences• Phenotypic differences

• Hunger• Satiety• Reward-based eating• Energy expenditure

• Response to environmental causes• Eating

• Exercise• Stress• Sleep deprivation• Circadian disruption

• Response to therapies

Weight LossWeight Loss00

Num

ber

of

Subje

cts

Num

ber

of

Subje

cts

Heterogeneity of Response

Highly responsive subgroup

Highly responsive subgroup

ConclusionsConclusions

• Obesity Obesity ISIS a disease, regardless of its designation a disease, regardless of its designation

• There are implications (to all of us) of thinking about it this wayThere are implications (to all of us) of thinking about it this way

• Physiologically based therapiesPhysiologically based therapies• Heterogeneity of causeHeterogeneity of cause• Variable treatment responseVariable treatment response• Opportunity to benefit selected subpopulations – value of predictive markersOpportunity to benefit selected subpopulations – value of predictive markers

• Attitudes about obesity underlie the major barriers to its treatmentAttitudes about obesity underlie the major barriers to its treatment

• Education and (evidence-based) participation by all stakeholders is the key Education and (evidence-based) participation by all stakeholders is the key to ultimate successto ultimate success

Take-home MessagesTake-home Messages

Obesity TreatmentObesity Treatment

• Lifestyle adjustment is the mainstay of therapyLifestyle adjustment is the mainstay of therapy

• Medications can be effectiveMedications can be effective

• In selected patientsIn selected patients

• Medications work differently in different patients – requires ‘trial Medications work differently in different patients – requires ‘trial and error’ approachand error’ approach

• Combination therapies look particularly promisingCombination therapies look particularly promising

Go Slow and Try Different ApproachesGo Slow and Try Different Approaches

• Test therapies sequentiallyTest therapies sequentially

• Pursue combination therapies – including combinations of specific Pursue combination therapies – including combinations of specific lifestyle changes with more classical medical approacheslifestyle changes with more classical medical approaches

• Be supportiveBe supportive

• Be persistentBe persistent• Be there for the patientBe there for the patient

Practical GuidancePractical Guidance

Aim for “cure,” but always provide care.

Why is all this so important?Why is all this so important?

• The current standard of care for obesity is:The current standard of care for obesity is:

00• For ultimate success, this needs to changeFor ultimate success, this needs to change

• Ignoring obesity needs to become no more acceptable Ignoring obesity needs to become no more acceptable than ignoring other disordersthan ignoring other disorders

• There needs to be incentive to embrace obesity There needs to be incentive to embrace obesity treatmenttreatment

A Call to ActionA Call to Action

Determine BMI at each visitDetermine BMI at each visit

Counsel patients with obesity on the risks of excess weight and the Counsel patients with obesity on the risks of excess weight and the benefits of weight loss benefits of weight loss

Identify the medical comorbidities of obesity in each patientIdentify the medical comorbidities of obesity in each patient

Pursue a step-wise strategy for weight loss – lifestyle, medications and Pursue a step-wise strategy for weight loss – lifestyle, medications and surgery as neededsurgery as needed

Help patients maintain weight loss by optimizing the patients lifestyle – Help patients maintain weight loss by optimizing the patients lifestyle – healthy diet, regular exercise, adequate sleep, stress reductionhealthy diet, regular exercise, adequate sleep, stress reduction

184

Why is weight regain after dieting so common? Why is weight regain after dieting so common?

1.1. Exercise, not diet, is the most effective means of losing weightExercise, not diet, is the most effective means of losing weight

2.2. The body reacts to weight loss by decreasing daily energy The body reacts to weight loss by decreasing daily energy expenditureexpenditure

3.3. Diet foods are boring and patients stop eating themDiet foods are boring and patients stop eating them

4.4. Dieting increases the body’s set point for fat massDieting increases the body’s set point for fat mass

5.5. Weight loss often leads to unwanted effects that cause Weight loss often leads to unwanted effects that cause patients to sabotage their effortspatients to sabotage their efforts



Which of the following is Which of the following is NOTNOT a demonstrated a demonstrated benefit of modest regular exercise? benefit of modest regular exercise?

1.1. Enhances weight loss effect of other lifestyle Enhances weight loss effect of other lifestyle changeschanges

2.2. Causes weight loss directlyCauses weight loss directly

3.3. Alters appetite to favor healthier foodsAlters appetite to favor healthier foods

4.4. Stimulates fat to burn more caloriesStimulates fat to burn more calories

5.5. Decreases cardiovascular riskDecreases cardiovascular risk



Which of the following comorbidities of Which of the following comorbidities of obesity has obesity has NOT NOT been shown to improve with been shown to improve with

modest (5-10%) weight loss?modest (5-10%) weight loss?1.1. Type 2 diabetesType 2 diabetes

2.2. HypertensionHypertension

3.3. DyslipidemiaDyslipidemia

4.4. Cardiovascular riskCardiovascular risk

5.5. Fatty liver diseaseFatty liver disease



If a patient with prediabetes and obesity maintains a If a patient with prediabetes and obesity maintains a 4% weight loss over 4 years, how much do they lower 4% weight loss over 4 years, how much do they lower

their risk of developing diabetes?their risk of developing diabetes?

1.1. <10%<10%

2.2. ~25%~25%

3.3. ~50%~50%

4.4. ~75%~75%

5.5. >90%>90%



Which of the following medications is Which of the following medications is NOTNOT currently currently approved by the FDA for the treatment of obesity? approved by the FDA for the treatment of obesity?

1.1. OrlistatOrlistat




5.5. Phentermine / Topiramate ER combination Phentermine / Topiramate ER combination



Which of the following weight loss Which of the following weight loss medications do medications do NOTNOT work through central work through central

nervous system mechanisms?nervous system mechanisms?

1.1. BupropionBupropion



4.4. Topiramate ERTopiramate ER




Which of the following is Which of the following is NOTNOT a primary a primary mechanism of weight loss from centrally-mechanism of weight loss from centrally-

acting weight loss medications?acting weight loss medications?

1.1. Change in food preferences Change in food preferences

2.2. Decrease in appetiteDecrease in appetite

3.3. Increase in resting and post-meal energy expenditureIncrease in resting and post-meal energy expenditure

4.4. Demonstrating the value of a healthier weight to the patientDemonstrating the value of a healthier weight to the patient

5.5. Lower physiologically defended body weightLower physiologically defended body weight



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