MedicalManagementofObesityinthe

OutpatientSetting:

WhatthePCPNeedstoKnow

JodyDushay,MDMMScAssistantProfessorofMedicine

HarvardMedicalSchool

DivisionofEndocrinology,BILH

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Outline/Objectives

• InitialMDconsultationforweightloss

• Guidelinesforthemedicaltreatmentofobesity

• Pharmacotherapyforweightloss– Indications,efficacy,sideeffects

• Beyondthescale:Additional importantlifestylechangesforimprovinghealthCO

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Disclosures

• None

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Why(andhow)doweeat?

• Whatregulatesourappetite?

• Ourfoodchoices?

• Whenweeat?

• Howmuchweeat?

• Whenwestopeating?COPYRIGHT

Weeatforsurvivalandpleasure

• Homeostatic/survival

(metabolic)

• Hedonic/pleasure

(emotional)

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Homeostatic:eattosurvive

• Hunger(centraland

peripheralsignals)

• Seekfoodsource

• Hormonesignalsfromthe

GIsystemtothebrainthat

energystoresincreased

• Brainreleasessatietysignals

(neurotransmitters)

• Stopeating

Hedonic:eatforpleasure

• +/- hungersignal

• Desireapleasurableactivity

• Foodsource

– Sight,smell,thought

• Eatingisreinforcedby

neuropeptiderelease

– Differentcircuitryfrom

homeostaticdrive

• Ignoresatietysignals

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Hhypothalamic nuclei

involved infeeding

HOMEOSTATIC

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Itisdifficulttoloseweightand

maintainweightloss!

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Metabolicchangesdonotfavor

weightlossormaintenance

• Weightlossisusuallyassociatedwith

decreaseintotalenergyexpenditureoutof

proportiontochanges inleanbodymass

– Thispersistsaslongasreducedweightis

maintained

• Increasedhungeranddecreasedsatietyoccur

afterweightloss

– Increasesecretionofhungerhormonesand

perceptionofhunger

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Sumithran NEJM 2011

50 overweight adults, BMI 27-40

10 weeks of very low calorie diet

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Sumithran NEJM 2011

Hungerhormonesincreaseandsatiety

hormonesdecreaseafterweightloss

HUNGER

SATIETY

SATIETY

SATIETY

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Sumithran NEJM 2011

Hungeranddesiretoeatareincreased

afterweightloss

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Howcanwehelpourpatients

improvetheirhealth

andloseweight?

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Ourenvironmentisnotconducivewellnessorweightloss

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Obesity-FocusedHistory

WeightLossReadiness

• Motivation andsocialsupport

• Psychiatricstatus

• Presenceof stressful lifecircumstances

• Timeconstraints

• Goalsandexpectations

Kushner RF. Circulation. 2012;126:2870-2877.

ReviewofSystems

• Checklist ofobesity-related

complications

• smoking cessation

• medication initiation

• pregnancyormenopause

• lifestressors

• majorlifestyle change

(surgeryà sedentary)

• Extent ofdailyphysicalactivity

• Sleep habits anddifficulties

• Foodpreferences and

frequency/quantity ofmeals

• Psychological assessment

– Mood/anxietydisorders,ADD,PTSD

– Eatingdisorders

LifeEventsandWeightGain DietandActivity

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Whatistheroleof

pharmacotherapyinthe

treatmentofobesity?

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Whyusepharmacotherapytotreatobesity?

• Obesityisachronicmetabolicandneurobehavioral disease

• Weusemedicationstotreatchronicdiseases– Withoutnearlyasmuchhesitation

• Medicationcanhelp…– Improveadherencetolifestylechange

– Achieveclinicallysignificantweightloss

– Butto“jumpstartweightloss”?– Notsomuch

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EndocrineSocietyClinicalPracticeGuidelines

• Patientsunabletosuccessfullyloseandmaintainweightandwhomeetlabelindicationsarecandidatesforweightlossmedication(strongevidence)

• Appropriatetouseapprovedweightlossmedicationovernopharmacologictherapytoamelioratecomorbiditiesandamplifyadherencetobehavioralchange

• BMI≥30,or≥27withcomorbidities

• Lowqualityevidenceforthesecutoffs

• ONLYasadjunctivetreatmenttolifestylechange

Apovian et al, JCEM 2015

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Generalguidelinesforallobesitymedications

• Assessefficacyandsafetyeverymonthforfirst3mos,thenatleastevery3mos

• Currentlyavailablemedicationsdonotchangeunderlyingphysiologyofweightregulationinanypermanentway

• Nopermanenteffectonappetite/satiety

– Effectslastonlyaslongasmedicationiscontinued

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DrugsfortheTreatmentofObesity

• Phenterminemonotherapy (short term)

• Orlistat

• Lorcaserin

• Phentermine- Topiramate

• Bupropion– Naltrexone

• Liraglutide

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Phentermine

DEA = Drug Enforcement Agency; T2D = type 2 diabetes.

Adipex-P prescribing information. Sellersville, PA: Teva Pharmaceuticals.; 2013.

§ 15,30,or37.5mgoncedaily,in

themorning

MechanismofAction

§ Sympathomimeticamine

anorectic

Indications

§ Short-termadjuncttodietand

exerciseinpatientswith

§ Treatment duration≤12weeks

§ BMI≥30kg/m2

§ BMI≥27kg/m2 with≥1weight-

related comorbidity

§ Hypertension

§ T2D

§ Hyperlipidemia

§ DEAScheduleIVControlled

Substance

Dosing

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Orlistat

T2D = type 2 diabetes.

Xenical prescribing information. South San Francisco, CA: Genentech USA, Inc.; 2013.

MechanismofAction

§ Reversiblegastrointestinal

lipaseinhibitor

Indications

§ Weightlossandweight

maintenanceinconjunction

withareducedcaloriediet

§ BMI≥30kg/m2

§ BMI≥27kg/m2 with≥1

weight-relatedcomorbidity

§ Hypertension

§ T2D

§ Dyslipidemia

Dosing

§ 120mgTIDwitheachmain

mealcontainingfatCOPYRIGHT

Lorcaserin

DEA = Drug Enforcement Agency; T2D = type 2 diabetes.

Belviq prescribing information. Woodcliff Lake, NJ: Eisai Inc.; 2012.

MechanismofAction

§ Specific5-HT2C(serotonin)

receptoragonist

Indications

§ Adjuncttodietandexercisein

patientswith

§ BMI≥30kg/m2

§ BMI≥27kg/m2 with≥1weight-

related comorbidity

§ Hypertension

§ T2D

§ Dyslipidemia

§ ScheduleIVControlledSubstance

Dosing

§ 10mgtwicedaily

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LorcaserinWeightLoss

Bohula et al NEJM 2018

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Phentermine/TopiramateER

T2D = type 2 diabetes.

Qsymia prescribing information. Mountain View, CA: Vivus, Inc.; 2012.

MechanismofAction

§ Central noradrenergic effects

§ Phentermine: immediate-release

sympathomimetic

§ Topiramate ER: delayed-release gabanergic

Indications

Dosing

§ Once daily in morning§ Start: phentermine 3.75/topiramate ER

23 mg

§ Usual dose: 7.5/46 mg

§ Maximum dose: 15/92 mg

§ If <3% weight loss after 12

weeks, discontinue or advance to

next dose

§ If <5% weight loss after 12

weeks on maximum dose,

discontinue

§ Schedule IV Controlled Substance

§ Adjunct to diet and exercise in

patients with

§ BMI ≥30 kg/m2

§ BMI ≥27 kg/m2 with ≥1 weight-related comorbidity

§ Hypertension§ T2D§ Dyslipidemia

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CONQUER Trial

WeightLosswithPhentermine/Topiramate in

ObeseAdults

29

Data are shown with mean (95% CI).

Phen/TPM ER = phentermine/topiramate extended release.

Garvey WT, et al. Am J Clin Nutr. 2012;95(2):297-308.

SEQUEL Extension

SEQUEL Study

(CompleterAnalysis)

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

LS

mean

weig

ht

loss (

%)

-2

-4

-6

-8

-10

-12

-14

-160 12 20 92

0

Weeks

28 36 44 52 60 68 76 84 100 108 LOCF

Placebo n: 227 227 227 208 197 227

Phen/TPM 7.5/46 n: 153 152 153 137 129 153

Phen/TPM 15/92 n: 295 295 295 268 248 295

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Naltrexone/BupropionSR

32T2D = type 2 diabetes.

Contrave prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2014.

MechanismofAction

§ Naltrexone:opioidreceptor

antagonist

§ Bupropion:norepinephrine-

dopaminereuptakeinhibitor

Indications

§ Adjuncttodietandexercisein

patientswith

§ BMI≥30kg/m2

§ BMI≥27kg/m2 with≥1

weight-relatedcomorbidity

§ Hypertension

§ T2D

§ Dyslipidemia

§ Other

Dosing

§ Eachtabletis8mg

naltrexone/90mgbupropion

§ Titrateupto2tabletsbid

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Naltrexone-Bupropion:WeightLoss

Greenway FL et al. Lancet 2010; 376:696-605

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DIYislessexpensive

• Phentermineavailableas8mgtablet

• Topiramateavailable25,50,100mg

• Startwith4mgphentermine,25mg

topiramate

• Canalsoprescribebupropionandnaltrexone

independently

– Contrave:360mgbuproprion,32mgnaltrexone

(8mgnaltrexone/90mgbuproprionpertablet)

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Liraglutide

T2D = type 2 diabetes.

Saxenda prescribing information. Plainsboro, NJ: NovoNordisk Inc.

MechanismofAction

§ GLP-1receptoragonist

Indications

§ Adjuncttodietandexercisein

patientswith

§ BMI≥30kg/m2

§ BMI≥27kg/m2with≥1

weight-related

comorbidity

§ Hypertension

§ T2D

§ Dyslipidemia

Dosing

§ Titratefromto1.8to3mgonce

dailysubcutaneousinjectionCOPYRIGHT

LiraglutideandBodyWeightOver3Years

37

All arms included lifestyle intervention: −500 kcal/day hypocaloric diet + 150 min/week increased physical activity.

Full analysis set, fasting visit data only. Line graphs are observed means ( SE). Points (sqaure, triangle) are observed means

with last observation carried forward (LOCF).

Fujioka K, et al. ENDO 2016, April 1-4, 2016; Abstract 24365.

778

320

DW

eig

ht

(%)

-2.1

-5.2

1467 1295 1223 1161 1100 1030 971 885 849 830 780805911

734 635 576 544 508 465 436 375 365 354 327336399

n=

n=

747

322

-2.7

-7.1

Week

-3.5

-9.2

-3.4

-8.5

Off-drug follow-up

Liraglutide 3.0 mg Placebo

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Orlistat1,2 Lorcaserin3-5Phentermine/

topiramate6-8Naltrexone/

bupropion9,10Liraglutide

3mg11,12

Study(no.weeks),

no.ITTpatientsin

treatmentgroup

Davidson

etal(52),

n=657

XENDOS

(208),

n=1640

BLOSSOM

(52),

n=1602

BLOOM

(52),

n=1538

BLOOM-

DM(52),

n=256

EQUIP

(56),

n=512

CONQUER

(56),

n=995

SEQUEL

(108),

n=295

CORI

(56),

n=583

CORII

(56),

n=1001

SCALE-

Main(56),

n=212

SCALE

(56),

n=2487

Baselineweight(kg) 100.7 110.4 100.1 100.4 106.0 115.2 103.0 101.9 99.7 100.3 100.4 106.2

ComparisonofWeight-LossMedications

ApprovedforLong-TermUse

40

Placebo-SubtractedChangesfromBaseline,HighestApprovedDose

(NotHead-to-HeadTrials)

DW

eig

ht

(%)

ITT = intent to treat.

1. Davidson MH, et al. JAMA. 1999;281:235-242. 2. Torgerson JS, et al. Diabetes Care. 2004;27:155-161. 3. Fidler MC, et al. J Clin

Endocrinol Metab. 2011;96:3067-3077. 4. Smith SR, et al. N Engl J Med. 2010;363:245-256. 5. O’Neil PM, et al. Obesity.

2012;20:1426-1436. 6. Allison DB, et al. Obesity (Silver Spring). 2012;20:330-342. 7. Gadde KM, et al. Lancet. 2011;377:1341-1352.

8. Garvey WT, et al. Am J Clin Nutr. 2012;95(2):297-308. 9. Greenway FL, et al. Lancet. 2010;376:595-605. 10. Apovian CM, et al.

Obesity (Silver Spring). 2013;21:935–943. 11. Wadden TA, et al. Int J Obes (Lond). 2013;37:1443-1451. 12. Pi-Sunyer X, et al. N Engl

J Med. 2015;373:11-22.

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Week

DW

eig

ht

(%)

Week

DW

eig

ht

(%)

Yancy WS, et al. Arch Intern Med. 2010;170:136-145.

OrlistatPlusLow-FatDietLow-CarbohydrateKetogenicDiet

HeterogeneityofTreatmentEffect

forWeightLoss

41

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Heterogeneity isalsotruefor

pharmacotherapy

Earlyweightlosspredicts

longtermweightloss

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ClinicalCase

• 53yofemale,BMI36

– 50+lbweightgainwithlastpregnancy,lost10lbs

postpartum

– Steadyweightgainsincemenopause

• PMHnotableforIBS,chronicbloating,

depression,andelevatedcholesterol

– Hasbeenonbupropioninthepast,noweightloss

• BP118/60,HR70s

• Medications:MVI,SSRI

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ClinicalCase

• Startedpharmacotherapy forweightloss

193

167 Weight (lbs)

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ClinicalCase

• 44yomale,BMI33

• Medicalhistory:HTN,

OSA,HIV+,depression,

compulsiveeating,

voraciousappetite

• Medications:ART,SSRI

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ClinicalCase

• 51yomale,BMI46

• HistoryofGraves’ disease,nowinremission

• Impairedglucosetolerance(A1c5.8%),NAFLD

withNASscore5/8,moderatefibrosis,

elevatedcholesterol

• Nighttimeeatingisamajorproblem

• Travelsforwork,eatsoutoften

• Nomedications

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ClinicalCase

Weight, lbs

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ClinicalCase

• 41yo female

• T2DM,NAFLD,PCOS,ADD,anxiety

• Medications:metformin, spironolactone

– Prefersasfewmedicationsaspossible

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Weight, lbs

241 lbs

190 lbs

ClinicalCase

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Summary

• Manyfactorscontrolappetiteandfoodintake

– Redundantsystemsprotectourbodyweight/body

fatsetpoint

• Obesityisachronicdiseaseresultingfrom

dysregulationofenergyhomeostasis

• Attentiontolifestyle isthecornerstoneof

obesity treatment

• Thereisaroleforpharmacotherapy totreat

obesity

– Considerrisk/benefitandpatientpreference

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Myapproach

• Detailedhistoryincludingweight,diet,meds

• Secondarycausesforobesity

– Usuallyunrevealing,don’tgooverboard

• Riskstratify

• Patient’sconcern,goals,levelofmotivation

• Patient’sviewon

– meds/nomeds

– newmeds/oldmeds

– Pills/injections

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Myapproach

• Remember contraindications

• Orderlabsyouneedatbaseline

– Repeatdependingonmedication

• Planwhenwillyoufollowupandhow

– Thisisahightouchundertaking!

– 3moswon’tdothejob

• Remember taperoffphentermine/topiramate

• NOmedications approvedwithout lifestyle

change

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