Canadian Adult Obesity Clinical Practice Guidelines 1

KEY MESSAGES FOR HEALTHCARE PROVIDERS

• Therearethreemedications indicatedforchronicobesitymanagement in Canada in addition to health behaviourchanges: liraglutide (Saxenda®) 3.0 mg, naltrexone/bu-propion (Contrave®) ina combination tablet, andorlistat(Xenical®).All threemedicationshavebeen shown tobeeffectiveinproducingweightlossgreaterthanplaceboforadurationofatleastoneyear.

• Medicationsthatarenotapprovedaspharmacotherapyforobesitymanagementshouldnotbeusedforthispurpose.

• The individual response to obesity management pharma-cotherapy is heterogeneous; the response tomedicationscandifferfrompatienttopatient.Inchoosingthemostap-propriateobesitypharmacotherapy,considermechanismofaction,safety,potentialsideeffects/tolerability,contraindica-tions,druginteractions,modeofadministrationandcost.

Pharmacotherapy in Obesity Management SueD.PedersenMDi,PriyaManjooMDii,SeanWhartonMDPharmDiii

i) C-ENDODiabetes&EndocrinologyClinicii) DepartmentofEndocrinology,UniversityofBritish

Columbiaiii) DepartmentofMedicine,McMasterUniversity

Cite this Chapter

PedersenSD,ManjooP,WhartonS.CanadianAdultObesityClinicalPracticeGuidelines:PharmacotherapyinObesityManagement.Availablefrom: https://obesitycanada.ca/guidelines/pharmacotherapy. Accessed [date].

Update History

Version1,August4,2020.AdultObesityClinicalPracticeGuidelinesarealivingdocument,withonlythelatestchapterspostedatobesitycanada.ca/guidelines.

RECOMMENDATIONS

1.PharmacotherapyforweightlosscanbeusedforindividualswithBMI≥30kg/m2orBMI≥27kg/m2withadiposity-relatedcomplications,inconjunctionwithmedicalnutritiontherapy,physical activity and psychological interventions (liraglutide3.0mg[Level2a,GradeB)],1–3naltrexone/bupropioncombi-nation[Level2a,GradeB],4orlistat[Level2a,GradeB]).5

2.Pharmacotherapy may be used to maintain weight lossthathasbeenachievedbyhealthbehaviourchanges,andto prevent weight regain (liraglutide 3.0 mg or orlistat)(Level2a,GradeB).6

3.Forpeoplelivingwithtype2diabetesandaBMI≥27kg/m2, pharmacotherapy can be used in conjunction withhealthbehaviourchangesforweightlossandimprovementinglycemiccontrol:liraglutide3.0mg(Level1a,GradeA);7 naltrexone/bupropion combination (Level 2a; Grade B),8

orlistat(Level2a,GradeB).9

4.We recommend pharmacotherapy in conjunction withhealthbehaviourchangesforpeoplelivingwithprediabetesandoverweightorobesity(BMI>27kg/m2)todelayorpre-venttype2diabetes.(Liraglutide3.0mg(Level2a,GradeB);2,orlistat(Level2a,GradeB).10

5.We do not suggest the use of prescription or over-the-counter (OTC)medicationsother than thoseapproved forweightmanagement(Level4,GradeD,Consensus).

6.For people livingwith overweight or obesitywho requirepharmacotherapy forotherhealth conditions,we suggestchoosing drugs that are not associatedwithweight gain(Level4,GradeD,Consensus).

Canadian Adult Obesity Clinical Practice Guidelines 2

Introduction

Modestandsustainedweightloss(5%–10%)isassociatedwithimprovementsincomorbiditiesassociatedwithobesity.11–13Healthbehaviourmodificationsarethecornerstoneofobesitymanage-ment;however,healthbehaviourchangesaloneareoftennotsuf-ficientforachievingobesitymanagementgoals.Healthbehaviourmodificationgenerallyachievesonlya3%–5%weightloss,whichismostoftennotsustainedoverthelongterm(seethechapterEffective Psychological and Behavioural Interventions inObesityManagement).Pharmacotherapyforobesityshouldbeconsideredtodecreaseweightandimprovemetabolicand/orhealthparam-eterswhenhealthbehaviourchangealonehasbeenineffective,insufficientorwithoutsustainedbenefit.

ThischapterprovidesareviewoftheliteraturepertainingtotheefficacyoftheobesitymedicationscurrentlyapprovedbyHealthCanada. It is intended to informprimary carepractitioners andspecialistsontheappropriateuseofobesitypharmacotherapy.

HealthCanadahasestablishedthefollowingcriteriathatmustbesatisfied for a pharmacotherapeutic agent to receive regulatoryapprovalforchronicobesitymanagement:

1.Theagentmustbestudiedinclinicaltrialsofatleastoneyearinduration.

2.Theagentmustinduceaplacebo-adjustedmeanweightlossof≥5%ormustdemonstratea≥5%weightlossinatleast35%ofpatients,withthisproportionbeingmorethandoublethatinplacebo.

3.Theagentshoulddemonstrateanimprovementinobesity-relatedcomorbidities.

PharmacotherapyisindicatedforchronicobesitymanagementinCanadaforindividualswithabodymassindex(BMI)≥30kg/m2,or≥27kg/m2withcomorbiditiesassociatedwithexcessbodyfat(e.g.type2diabetes[T2DM],hypertension,dyslipidemia).

TherearethreemedicationsapprovedforobesitymanagementinCanada: orlistat, liraglutide 3.0mg and naltrexone/bupropion. It

isrecognizedthatothermedications,availableinCanadabutnotapproved forobesitymanagement,areusedoff-label forobesitymanagement.Asaresult,ourliteraturesearchemployedanopenstrategy to capture all pharmacotherapy agents that have beenstudiedforobesitymanagement.However,withtheexceptionofmetformin for prevention of antipsychotic-induced weight gain(see: TheRoleofMentalHealth inObesityManagement for themetforminrecommendation),wediscouragehealthcareprovidersfromusingagentssolelyforchronicobesitymanagementiftheydonothave regulatoryapproval for this indication.Non-prescriptiontreatments/supplementsarereviewedseparatelyintheCommercialProductsandProgramsforObesityManagementchapter.

Thischapterwilladdressclinicalquestionspertainingtotheeffi-cacyofpharmacotherapy inpeoplewithoverweightorobesity.Itwillalsosummarizeevidenceforpharmacotherapyforobesityamongpersonswithselectedcomorbidities,includingT2DM,pre-diabetes,hepaticsteatosis,polycysticovarysyndrome,obstructivesleep apnea and osteoarthritis. Randomized controlled trials ormeta-analysesofatleastsixmonthsdurationwereincludedintheliteraturereview.

Considerations in the use of pharmacotherapyfor obesity management

Thereareseveralfactorstobetakenintoconsiderationindeter-mining theappropriate choiceofpharmacotherapy forpatientswithoverweightorobesity.Theetiologyofobesityiscomplexandheterogeneous.Psychosocial,emotionalandhedoniccontributorsofobesityshouldbediagnosedandmanagedwherepossible.Themechanismofaction,adversesideeffects,safety,andtolerabilityofeachagentmustbeconsideredinthecontextofeachpatient’scomorbiditiesandexistingmedications.Thecostofmedicationsaswellasthemode(oralversussubcutaneous)andfrequencyofadministrationcanbeabarriertopatientadherenceandshouldbediscussed. It is important toassess concomitantmedicationsthatapatientistakingaspossiblecontributorstoweightgainandtoconsideralternativeswhereappropriate.

Ifclinicallysignificantweightlossisnotachievedwithpharmaco-therapy,otherfactorscontributingtoperceivedpharmacotherapyfailureshouldbeassessed,includinginappropriatedosingorad-

KEY MESSAGES FOR PEOPLE LIVING WITH OBESITY

• Obesitymedicationcanhelpyouinyourobesitymanage-mentjourneywhenhealthbehaviourchangesalonehavenotbeeneffectiveorsustainable.

• There are threemedications approved for long-termobesitymanagement in Canada: liraglutide 3.0 mg (Saxenda®),naltrexone/bupropioninacombinationtablet(Contrave®) andorlistat(Xenical®).Thesemedicationscanhelpyoutoachieveandmaintaina5%–10%weightlossandimprove

healthcomplicationsassociatedwithexcessweight.Thesemedications are approved by Health Canada and havebeenproveninrobustclinicaltrialstobeeffectiveforobesitymanagement.

• Medications thatarenotapproved forobesity treatmentmaynotbesafeoreffectiveforobesitymanagementandshouldbeavoided.

Canadian Adult Obesity Clinical Practice Guidelines 3

herence, barriers to health behaviour change, andpsychosocialormedicalissues.Itshouldalsoberecognizedthatthereiscon-siderableheterogeneityintheresponsetopharmacotherapywithanypharmacotherapeuticagent.Considerationshouldbegivento trying another obesity medication or obesity managementtherapy if clinically significant obesitymanagement success hasnotbeenachievedafterthreemonthsonfull/maximumtolerateddoseandnootherevidentetiologiesof the lackof successareapparent.Currently,wehavenoabilitytopredictwhichmedica-tionwillbenefitapatientmost.Withtheevolutionofprecisionmedicine,includinghormonalandgeneticprofiling,itmayinthefuturebecomepossible topredictwhichpharmacotherapymaybenefitanindividualpatientthemost.

Regulatoryagenciesrecommenddiscontinuingpharmacotherapyforobesity ifweight lossof≥5%hasnotbeenachievedafterthreemonths on therapeutic dose. However, pharmacotherapycanalsobeused tomaintainweight lossachievedwithapriorhealthbehaviourchangeoraverylowenergydiet.3,6

Obesitymedicationsareintendedaspartofalong-termtreatmentstrategy. Clinical trials for obesity pharmacotherapy consistentlydemonstrateregainofweightwhenactivetreatmentisstopped.2,14

Theuseofobesitypharmacotherapyisnotrecommendedinpreg-nantorbreastfeedingwomen,orinwomenwhoaretryingtocon-ceive. There is no data available to informon the timing of thediscontinuationofobesitypharmacotherapypriortoconception.

Mechanism and efficacy of approved pharmacotherapy for obesity management

Orlistat

Orlistat,a semisyntheticderivativeof lipstatin,wasapprovedaspharmacotherapy for obesity management in Canada in 1999(seeTable1). It is apotentand selective inhibitorofpancreaticlipase, thereby inhibiting thebreakdownofdietary triglyceridesintoabsorbablefreefattyacids.Asaresultofthis,approximately30%ofingestedtriglyceridesareexcreted,primarilyinthefeces,creatingacaloricdeficit.15

Todate,orlistatistheonlyavailableobesitymedicationthatdoesnotspecificallytargetappetiteorsatietymechanisms.

Orlistatatadoseof120mgthreetimesdaily(takenduringoruptoonehouraftermeals)isapprovedbyHealthCanadaforweightreductionorreducingtheriskofweightregainafterpriorweightlossinpatientswithaBMI≥30kg/m2,orBMI≥27kg/m2inthepresenceofcomorbidities(e.g.hypertension,T2DM,dyslipidemia,excessvisceralfat).16

Asystematicreviewandmeta-analysisofrandomizedcontrolledtrialsoforlistat120mgthreetimesadayreportedameanplacebosubtractedweightlossof-2.9%atoneyear.5Additionally,54%and 26% of patients achieved ≥ 5% and ≥ 10%weight loss,

respectively,comparedto33%and14%forplacebo.5Orlistathasbeenshowntobeeffectiveinmaintainingweightlossafteraverylowenergydietforeightweeks,withlessweightregainintheorli-statarmcomparedtoplacebooverthreeyears(4.6kgvs.7.0kg).6

Orlistattherapyisassociatedwithsignificantadversegastrointesti-naleffects,includingoilyspottingandstool,flatuswithdischarge,fecal urgency and increased defecation.5 These adverse effectsmaycausepatientswhodonotlowertheirdietaryfatintaketodiscontinuetherapy.Along-termanalysisofobesitymedicationsinCanadademonstratedsix-month,oneyearandtwo-yearper-sistence ratesof18%,6%and2%withorlistat, respectively.17 Orlistattherapymayinterferewiththeabsorptionoffat-solublevitamins(A,D,EandK),andpatientsshouldthusbecounselledtotakeamultivitaminat least twohoursbeforeorafter takingorlistat.5,16Orlistatiscontraindicatedinpatientswithchronicmal-absorptionsyndromeorcholestasis.Somepatientsmaydevelopincreasedlevelsofurinaryoxalateonorlistat;casesofoxalatene-phropathywithrenalfailurehavebeenreported.18Therehavealsobeenrarecasesofsevereliverinjuryoracuteliverfailure.19

AsorlistatmayinterferewithvitaminKabsorption,internationalnormalized ratioshouldbemonitoredcloselywhenoralantico-agulants are co-administered. Orlistatmay affect absorption oflevothyroxineand/oriodinesalts;patientsonlevothyroxineshouldbemonitoredforchangesinthyroidfunction.Areductioninplas-macyclosporinelevelshasbeenobservedwhenorlistatisco-ad-ministered;thus,itisrecommendedtomonitorcyclosporinelevelsmorefrequently.Orlistatmayaffectabsorptionofanticonvulsants,sopatientsonanticonvulsantsshouldbemonitoredforpossiblechangesinthefrequencyand/orseverityofseizure.16

Theminimalweightlosswithorlistataboveplaceboaswell,asitsfrequentgastrointestinalsideeffects, limit itsuseastherapyforobesitymanagement.

Liraglutide

Liraglutide is a daily, subcutaneously administered, human glu-cagon-like peptide 1 (GLP-1) analog that acts centrally on thepro-opiomelanocortin(POMC)/CARTneuronstoimprovesatiationandsatietyandreducehunger,withatransienteffecttodecreasegastricemptying.24,25

Liraglutide increases insulin release and suppresses glucagonduringtimesofglucoseelevation.LiraglutideisapprovedinCan-adaforthemanagementofT2DMatadoseof1.2mgor1.8mgdaily,withnearmaximaltherapeuticefficacyforA1Cloweringatthe1.8mgdose.LiraglutidewasapprovedinCanadain2015forchronicobesitymanagementatadoseof3.0mgdaily,inpeoplewithorwithouttype2diabetes.Therecommendedstartingdoseof liraglutide is 0.6mgdaily,with up-titration by 0.6mg eachweekuntilthe3.0mgtargetdoseisachieved.

Amongpeoplewithnormoglycemiaorprediabetes,liraglutide3.0mgwithhealthbehaviourmodificationresultedinan8.0%weightlossatoneyear,comparedto2.6%onplacebo(healthbehaviour

Canadian Adult Obesity Clinical Practice Guidelines 4

Table 1. Pharmacotherapy for Obesity*

Naltrexone/Bupropion LiraglutideOrlistat

Modeofadministration

Dose/frequency

Effecton%weightlossat1year,placebosubtracted

Effectonweightoverlongerterm,placebosubtracted

%ofpatientsachieving≥5%weightlossat1year

%ofpatientsachieving≥10%weightlossat1year

Effectonmaintenanceofpreviousweightloss

Effectonprediabetes

EffectonBPat1year, placebosubtracted

Effectonlipidsat1year,placebosubtracted

EffectonHRat1year,placebosubtracted

EffectonA1Cinpatientswithdia-betesat1year,placebosubtracted

EffectonNASH

EffectonPCOS

EffectonOA

EffectonOSA

Cost

Contraindications

Commonsideeffects

Raresideeffects

Druginteractions

Oral

120mgTID

-2.9%5

-2.8kgat4years10

54%(vs33%inplacebo)5

26%(vs14%inplacebo)5

2.4kglessweightregainvs placeboover3years6

37.3%reductioninriskof developingT2DMover4years10

-1.9mmHgSBP-1.5mmHgDBP20

-0.27mmol/Ltotalchol-0.21mmol/LLDL-0.02mmol/LHDL-0.00mmol/LTG20

Nochange

-0.4%9

Noimprovement

Notstudied

Notstudied

Notstudied

$$

•Cholestasis•Chronicmalabsorptionsyndrome16 •Pregnancy

Loose,oilystools,flatus

•Liverfailure•Nephrolithiasis•Acutekidneyinjury

•Fat-solublevitamins•Levothyroxine•Cyclosporine•Oralanticoagulants anticonvulsants16

Subcutaneous

3.0mgdaily

-5.4%1

-4.2%at3years2

63.2%(vs27.1%inplacebo)1

33.1%(vs10.6%inplacebo)1

-6.0%additionalplacebo-subtractedweightlossat1year3

79%reductioninriskofdevelopingT2DMover3years2

-2.8mmHgSBP-0.9mmHgDBP1

-2.3%totalchol-2.4%LDL+1.9%HDL-3.9%nonHDL-9.3%TG1

+2.4BPM1

-1.0%7

Improvement21

-5.2kgplacebosubtractedweightlossat6mo;nodataonmenstrualcyclicity22

Notstudied

ReducesAHIby6/hr23

$$$$

•Pasthistoryofpancreatitis•Personalorfamilyhistoryof medullarythyroidcancer

•PersonalhistoryofMEN2 syndrome

•Pregnancy

Nausea,constipation,diarrhea,vomiting

PancreatitisCholelithiasis

Mayaffectabsorptionofmedi-cationsduetoslowingofgastricemptying

Oral

16/180mgBID

-4.8%4

Notstudied

48%(vs16%inplacebo)4

25%(vs7%inplacebo)4

Notstudied

Notstudied

+1.8mmHgsBP+0.9mmHgdBP4

-1.5%LDL+7.2%HDL-9.6%TG4

+1.1BPM4

-0.5%8

Notstudied

Notstudied

Notstudied

Notstudied

$$$

•Uncontrolledhypertension•Anyopioiduse•Historyof,orriskfactorsfor,seizure•Abruptdiscontinuationofalcohol•Concomitantadministrationofmonoamineoxidaseinhibitors(MAOI)

•Severehepaticimpairment•End-stagerenalfailure•Pregnancy

Nausea,constipation,headache,drymouth,dizziness,diarrhea

•Seizure•Worseningofdepression

Yes:Seechaptertext

Canadian Adult Obesity Clinical Practice Guidelines 5

modificationalone).1 Intermsofcategoricalweightloss,63.2%ofpatientsonliraglutidelost≥5%bodyweightatoneyear,com-paredwith27.1%ofpatientsintheplacebogroup;133.1%and10.6%ofparticipantslostmorethan10%oftheirbodyweightonliraglutide3.0mgandplacebo,respectively.Patientswithpre-diabeteswerefollowedtothreeyears,withsustainedweightlossof-6.1%intheliraglutidegroupvs.-1.9%inplacebo.2

Followinga-6.0%weightlosswithalow-caloriediet,liraglutide3.0mgplus health behaviour counselling reducedweight by afurther -6.2% at one year comparedwith -0.2% in the place-bo group (ongoing health behaviour counselling alone). Morepatientson liraglutide3.0mgwereable tomaintain the≥5%run-inweightloss(81.4%)comparedwiththosereceivingplace-bo(48.9%).Fewerpatientsonliraglutide3.0mgregained≥5%bodyweight(1.9%)comparedtoplacebo(17.5%).3

Themost common side effect of liraglutide is nauseadue to atransient decrease in gastric emptying. Patientsmay also expe-rience constipation, diarrhea, heartburn and/or vomiting.Moregradual titration can helpmitigate gastrointestinal side effects,shouldtheseoccur.Liraglutideuseisassociatedwitha1.4%high-erriskofgallstonescomparedtoplacebo.26

Thereisasmallincreasedriskofpancreatitiscomparedtoplacebo,withthemajorityofthesecasesseeninassociationwithgallbladderdisease.2Liraglutideiscontraindicatedinpatientswithapersonalorfamilyhistoryofmedullarythyroidcancerorapersonalhistoryofmultipleendocrineneoplasiatype2becauseofanincreasedriskofmedullarythyroidcancerseeninrodentstudies.Therehavebeennocasesofmedullarythyroidcancer inhumanstudiesof liraglu-tide.Liraglutidedelaysgastricemptying,whichmayimpactabsorp-tionofconcomitantlyadministeredoralmedications.

Naltrexone/Bupropion

Naltrexone hydrochloride/bupropion hydrochloride is a combina-tionof twomedications.Naltrexone isanopioid receptorantag-onistthathasbeenusedfordecadesforthetreatmentofalcoholandopioiddependence.Bupropionisawidelyusedantidepressantthat inhibits the reuptakeof dopamine andnorepinephrine. Thenaltrexone/bupropionsustainedreleaseformulationwasapprovedfor chronic obesity management in Canada in 2018, at a totaldailydoseof32mgnaltrexoneand360mgbupropion.Bupropi-on inducessatietycentrallybyenhancingproductionandreleaseofα-melanocyte stimulating hormone (α-MSH) andβ-endorphin fromthepro-opiomelanocortincellsinthearcuatenucleusofthehypothalamus. Naltrexone disrupts the auto-inhibitory effect ofβ-endorphin on the pro-opiomelanocortin cells by blocking theμ-opioid receptors.Naltrexone/bupropionalso influences theme-solimbicrewardsystemtoreducecravings.27Thissynergisticmodeofactionissupportedbytheevidencethattheuseofbupropionornaltrexonealonedonotleadtoclinicallymeaningfulweightloss.28

Eachtabletofthenaltrexone/bupropioncombinationcontains8mgofnaltrexoneand90mgofbupropion.Therecommendedtitration

scheduleisonetabletdailyforthefirstweek,withanincreasebyonetableteachweekuntilthemaintenancedoseoftwotabletstwicedaily(totaldailydose32mg/360mg)isreached.

Amongpatientswithoverweightorobesitywithoutdiabetes,nal-trexone/bupropion32mg/360mgwith ahypocaloricdiet (500kcal/daydeficit)andexercisewasassociatedwithweightlossof-6.1%versus-1.3%inplacebo.4A≥5%weight losswasseenin48%ofpatients,and≥10%weightlosswasseenin25%ofpatients, comparedwith 16% and 7% in the placebo groups,respectively.4Acombinedanalysisofthreenaltrexone/bupropiontrialsfoundthatearlyimprovementsincravingswerepredictiveofgreaterweightlosssuccess.29

Themostcommonsideeffectsofnaltrexone/bupropion includenausea,constipation,headache,vomiting,insomnia,drymouth,dizzinessanddiarrhea.Mostnauseaeventsoccurduringthedoseescalationperiodandaretransient.

Naltrexone/bupropioniscontraindicated inpatientswithuncon-trolledhypertension(seeothercardiovascularriskfactors,below).Anyopioiduseisanabsolutecontraindicationtotheuseofnal-trexone/bupropion. Opioid therapy should be discontinued forseven to 10 days prior to initiation of naltrexone/bupropion toprevent the precipitation of opioidwithdrawal.30 As bupropionisassociatedwithaslightlyincreasedriskofseizure,naltrexone/bupropion is contraindicated in seizure disorders, anorexia ner-vosa, bulimia or patients undergoing abrupt discontinuation ofalcohol,benzodiazepines,barbituratesorantiepilepticdrugs.Nal-trexone/bupropionshouldbedosedwithcautionwithanydrugsthatlowerseizurethreshold.Monoamineinhibitors(MOAIs)canincreasetheriskofhypertensivereactions,andnaltrexone/bupro-pionshouldthereforenotbeusedwithin14daysoftakingmono-amineinhibitors.Naltrexone/bupropionshouldnotbetakenwithahighfatmeal(≥55%fat),asthissignificantlyincreasessystemicexposuretothemedication.31

There are multiple potential drug interactions with naltrexone/bupropion,whichstemfromtheeffectofbupropionanditsme-tabolitestoinhibitthehepaticCYP2D6enzymesystem.Physiciansandpharmacistsmustbeawareoftheimportanceofevaluatingpotentialdruginteractionspriortoinitiatingnaltrexone/bupropi-on.Amongpatientsalreadyreceivingnaltrexone/bupropion,med-icationsmetabolizedbyCYP2D6shouldbestartedatthe lowerendoftheirrecommendeddosagerangewithcautioustitration(e.g. selective serotonin reuptake inhibitors,betablockers,anti-psychotic agents, type 1C antiarrhythmic agents andmany tri-cyclic antidepressants, e.g. citalopram, metoprolol, risperidone,propafenoneanddesipramine,respectively).32Forpatientsalreadyreceiving these medications, consideration should be given fordose reductionwhen starting naltrexone/bupropion. Bupropionmayresultinreducedefficacyoftamoxifenandshouldthereforenotbeusedincombinationwithit.

BupropionisprimarilymetabolizedbytheCYP2B6enzymesystem.Therefore,naltrexone/bupropiondosingshouldnotexceedonetab-lettwicedailywhenusedwithCYP2B6inhibitors(e.g.ticlopidine,

Canadian Adult Obesity Clinical Practice Guidelines 6

clopidogrel).33Naltrexone/bupropion shouldbeavoided inpatientstakingCYP2B6inducersasthesemayreduceefficacyofnaltrexone/bupropionbyreducingbupropionexposure(e.g.ritonavir,lopinavir,efavirenz,carbamazepine,phenobarbital,phenytoin).32 Central ner-voussystemtoxicitycanoccurwhennaltrexone/bupropion isusedconcomitantlywithdopaminergicdrugs(e.g.levodopa,amantadine).

Efficacy of pharmacotherapy on health parameters

Type 2 diabetes mellitus prevention

T2DM is a common complication of obesity, andprevention ofdiabetes is an important goal in chronic obesity management.PeoplewithprediabetesareathighriskofdevelopingT2DM,withabout25%ofindividualswitheitherimpairedfastingglucoseorimpaired glucose tolerance progressing to T2DM over three tofiveyears.34Amongindividualswithprediabetes,onekilogramofweightlossisassociatedwitha16%relativeriskreductioninthedevelopmentofT2DM.35

Pharmacotherapyforobesitycanbeofbenefittopreventordelaythe development of T2DM.Orlistatwas evaluated for diabetespreventioninatrialof3305patientswithobesityandeithernor-mal (79%) or impaired (21%) glucose tolerance. Patientswererandomized to health behaviour changes plus either orlistat orplacebo.10Afterfouryearsoftreatment,thecumulativeincidenceofdiabeteswas6.2%intheorlistatgroupcomparedwith9.0%inplacebo,withacorresponding37.3%decreaseinriskofpro-gressiontoT2DM.PeoplewithimpairedglucosetolerancederivedthegreatestbenefitintermsofdecreasedrateofprogressiontoT2DM, compared to study participants with normoglycemia. Asecondary analysis demonstrated greaterweight loss to be theprimaryreasonfordiabetesprevention.10

Liraglutide3.0mghasdemonstratedefficacytopreventandde-layT2DMamongstpeoplewithprediabetes.TheSCALEObesityandPrediabetestrialrandomized2254patientstoreceiveliraglu-tide3.0mg(n=1505)orplacebo(n=749), inadditiontohealthbehaviourchange.ThetimetoonsetofT2DMoverathree-yeartreatmentperiodinthisstudywas2.7timeslongerwithliraglu-tide3.0mgvs.healthbehaviouralone,andtheriskofdevelopingT2DMwasreducedby79%.2Theseimprovementsarelikelyduetoacombinedeffectoftheantihyperglycemiceffectsofliraglu-tideaswellasliraglutide-mediatedweightloss.

Currently,therearenopublishedstudiesevaluatingtheefficacyofnaltrexone/bupropionondiabetesprevention.

Oursystematicreviewidentifiedonerandomizedcontroltrialeval-uatingtheefficacyofexenatide(ashortactingGLP-1analog)ver-susplaceboonbodyweightandglucosetoleranceamongpeoplewithobesitywithnormoglycemia,impairedglucosetoleranceorimpairedfastingglucose,onabackgroundofhealthbehaviourin-terventionovera24weekperiod.29Theexenatidegroupdemon-strateda-5.1kgweightlosscomparedwith-1.6kgonplacebo.

Impairedfastingtolerancenormalizedin77%ofexenatidetreat-edpatientscomparedwith56%intheplacebogroup.Exenatideisnotindicatedforobesitymanagement,norforthepreventionofT2DM.

Type 2 diabetes mellitus

ObesityinT2DMisassociatedwithpoorerglycemiccontrol,bloodpressureandlipidprofiles,andincreaseduseoflipidloweringandantihypertensivedrugs,comparedwithpeoplewithdiabeteswhodonothaveobesity.36

Theeffectofantidiabeticpharmacotherapyonweightshouldbeconsidered in choosing the most appropriate medication(s) forglycemic control. GLP1 receptor agonists and sodium/glucosecotransporter2 inhibitorsareassociatedwithweight loss inad-ditiontoimprovingglycemiccontrol.Metformin,dipeptidylpep-tidase-4 inhibitorsandacarboseare typicallyweightneutral. In-sulin,insulinsecretagoguesandthiazolidinedionesareassociatedwithweightgain.37Pharmacotherapyforobesitycanbeofbenefitforweightlossandimproveddiabetescontrol.

Orlistathasbeendemonstratedtoimproveglycemiccontrolinpa-tientswithT2DM.Ameta-analysiscomprising2550patientswithT2DMandobesity randomized toorlistat120mgtidorplacebofound thatpatients treatedwithorlistathad significantlygreatermeandecreases in fastingplasmaglucoseandHbA1ccomparedwithplacebo(1.39mmol/lvs.0.47mmol/land0.74%vs.0.31%,respectively).9Weight loss intheorlistatgroupwas-3.8kgcom-paredto-1.4kgonplacebo.Theprimaryreasonforimprovementinglycemiccontrolwithorlistatisweightloss,althoughorlistatmayprovidebeneficialmetaboliceffectsindependentofweightloss.Forpatientswithminimalweightloss(1%ofbaselinebodyweight),or-listatprovidedasignificantlygreaterdecreaseinfastingplasmaglu-cose(0.83mmol/lvs.0.02mmol/l)andHbA1c(0.29%vs.0.14%).9

IntheSCALEdiabetestrial,liraglutide3.0mgwascomparedtolira-glutide1.8mgandplacebo,inadditiontohealthbehaviourchang-es,inpeoplewithobesityandT2DMmanagedwithoralagentsorhealthbehavioursalone.Atoneyear, liraglutide3.0mgreducedweightby -6.0% (n=423) compared to -4.7%on liraglutide1.8mg(n=211)and-2.0%onplacebo(n=212).Aclinicallysignificantweight lossof≥5%wasachievedby54.3%ofpatientson lira-glutide3.0mg,versus40.4%onliraglutide1.8mgand21.4%onplacebo.Weightloss≥10%occurredin25.2%ofpatientsonlira-glutide3.0mgversus15.9%withliraglutide1.8mgversus6.7%ofpeoplereceivinghealthbehaviourmodificationalone.Liraglutide3.0mgreducedHbA1cby1.3%comparedwith1.1%onliraglu-tide1.8mgand0.3%onplacebo.Inaddition,moreparticipantstreatedwithliraglutide3.0mgand1.8mgreducedtheirnetuseoforalantihyperglycemicagentscomparedwithplacebo.7

TheContraveObesityResearchDiabetes(COR-DM)trialevaluatedthesafetyandefficacyofnaltrexone/bupropion32mg/360mginadditiontohealthbehaviourchangesamongstadultswithaBMIof27–45kg/m2andT2DMmanagedwithoral agentsordiet.8

Canadian Adult Obesity Clinical Practice Guidelines 7

Naltrexone/bupropiontreatedpatientsachieveda5%weightre-ductioncomparedwith1.8%intheplacebogroup.Additional-ly,44.5%ofpatientsachieved≥5%weightlosscomparedwith18.9% in theplaceboarm,and18.5%ofpatients lost≥10%weightlosscomparedwith5.7%ofpatientsintheplaceboarm.Patientstreatedwithnaltrexone/bupropiondemonstrateda-0.5%greaterimprovementinA1CcomparedtoplaceboandweremorelikelytoachieveanA1C<7%(44.1%inthenaltrexone/bupro-piongroup versus 26.3% in placebo). The change inA1Cwascorrelatedwith thechange inbodyweight inboth studyarms.However,fewerpatientsreceivingnaltrexone/bupropionrequiredan increase indoseor theadditionofanotheroral antidiabeticagentcomparedwithplacebo(22.3%vs.35.2%,respectively).

Other cardiovascular risk factors

Pharmacotherapy-inducedweight loss can be of benefit to im-provecardiovascularriskfactorsinadditiontoglycemiccontrol.

Ameta-analysisdemonstratedthatorlistatproducedamodestim-provementinlipidprofileandsmallreductionsinbloodpressure(seeTable1)20

Liraglutide reduced systolicbloodpressureby -2.8mmHgcom-paredwithplacebo,withmodestimprovementsinlipidparame-ters.Aheartrateincreaseoftwobeatsperminute(BPM)wasnot-edamongstpeoplewithobesityandprediabetesatthreeyears.2

Naltrexone/bupropion is associated with modest improvementsin lipid parameters.4,8,38,39 Naltrexone/bupropion attenuates thebloodpressurereductionassociatedwithweightloss,whichmaybeduetoitsactiontoinhibitreuptakeofnorepinephrine.Naltrex-one/bupropion is contraindicated in patients with uncontrolledhypertension and shouldbeusedwith caution inpatientswithcontrolledhypertension.31

Regulatoryrequirementsforobesitypharmacotherapydonotin-cludeastandardrequirementforcardiovascularoutcometrialstoassess the cardiovascular safety of thesemedications.However,cardiovascular outcome studies may be required by regulatoryagencies,particularlyifthereisanyconcernforpotentialadverseeffectonanycardiovascularriskfactor.Sibutramine,whichisnolongeravailable inCanada,wasstudiedinacardiovascularout-come trial becauseof reported increases in bloodpressure andheart rate. This study found an increased risk of cardiovasculareventsinpeoplewithpreexistingcardiovasculardisease.

Liraglutidehasbeenshowntoreducecardiovasculareventsandmor-talityinpeoplewithT2DM38ata1.2–1.8mgdose.ThesedatahavebeenacceptedassufficientsafetydatabytheUSFoodandDrugAd-ministrationtoreassurethecardiovascularsafetyofliraglutideinpeo-plewithobesitywithoutT2DM,atthetherapeuticdoseof3.0mg.

TheCardiovascularOutcomesStudyofNaltrexoneSR/BupropionSR in Overweight andObese Subjectswith Cardiovascular RiskFactors (LIGHT) studywasacardiovascularoutcometrialunder-taken toassess the cardiovascular safetyofnaltrexone/bupropi-

on.Interimresultswerereleasedafter25%oftheplannednumberofmajoradversecardiovascularevents(MACE)occurred,compromisingtheintegrityofthetrial.Althoughthetrialwasterminatedupontherecommendationoftheleadinvestigator,theresultsofthepreplanned50%interimanalysiswerereleasedanddemonstratedahazardratioforthetimetothefirstmajoradversecardiaceventof0.88(95%CI:0.57–1.34) in favour of naltrexone/bupropion.40 These results couldnotbeusedtoestablishnon-inferiorityduetothecompromiseofthetrial.Anewcardiovascularoutcometrialisinplanningstages.

Therearenocardiovascularoutcometrialsfororlistat.

Todate,norandomizedclinicaltrialofobesitypharmacotherapyhasdemonstratedareductionincardiovasculareventsormortalityamongstpeoplewithoutdiabetes.

Other obesity-related comorbidities

Weight loss can improve health comorbidities associated withobesity, including hepatic steatosis, polycystic ovary syndrome,obstructivesleepapneaandosteoarthritis.

Nonalcoholic steatohepatitis (NASH)

In a small study (n=41), individuals with BMI >27 kg/m2withbiopsy-proven nonalcoholic steatohepatitis were randomized toreceivea1400Kcal/daydietplusvitaminE(800IU)dailywithorwithoutorlistatfor36weeks.Bothgroupshadsimilarlyimprovedliverenzymesandnonalcoholicfattyliverdiseaseactivityscores,andtherewasnosignificantdifferenceinweightlossbetweengroups(-8.3%onorlistatvs.-6.0%onplacebo).Orlistatdidnotenhanceweightlossorimproveliverenzymes,measuresofinsulinresistanceorhistopathology.SubjectswithgreaterweightlosshadimprovedNASHscoresinboththeorlistatandplacebogroups.41

Inasmallstudyof52patients,liraglutidetreatmentatadoseof1.8mgdailyresultedinresolutionofnonalcoholicsteatohepatitisin39%ofpatients comparedwith9%ofpatientsonplacebo.Theseresultsarebasedonliverbiopsiesperformedafter48weeksoftreatmentandmaybetheresultofthecombinationofweightlossandadirectbeneficialhepaticeffect.21

Naltrexone/bupropionhasnotbeenspecificallystudiedinregardtohepaticsteatosis.

Though data is conflicting, some small studies have suggestedthatmetforminmaycauseasmalldecreaseinBMIof-0.5to-1.3kg/m2withanimprovementinaminotransferasesand/orliverhis-tologyinpatientswithnonalcoholicfattyliverdisease.42,43

Polycystic ovary syndrome

Amongwomenwithpolycysticovarysyndrome,liraglutide1.8mghasbeenshowninasmallstudytoinduceplacebosubtractedweight

Canadian Adult Obesity Clinical Practice Guidelines 8

lossof-5.2kgandreducedliverfatcontent,visceralfatandthepres-ence of nonalcoholic fatty liver disease over 26 weeks.22,44 Thesestudiesdidnotevaluatemenstrual frequency, fertilityorhirsutism.Therearenostudiesofsufficientqualityevaluatingorlistatornaltrex-one/bupropioninpatientswithpolycysticovarysyndrome.

Metforminwithhealthbehaviourchangesmaybeassociatedwithasmall reduction inBMI (-0.73kg/m2)and improvedmenstruation inwomenwithpolycysticovary syndromeover sixmonths, comparedwithhealthbehaviouralone,45accordingtoonesystematicreviewandmeta-analysis.However,anothersystematicreviewandmeta-analysisshowednoeffectofmetforminonweightinthispopulation.46

Ina small studycomparingexenatide,metforminand thecom-binationof exenatide andmetformin inwomenwithpolycysticovary syndrome andoverweight,weight loss in both exenatidearmswassuperiortometforminwithweightlossof-6.0kgonthecombinationofexenatideandmetformin,-3.2kgwithexenatidealoneand-1.6kgonmetforminalone.Thecombinationofexen-atideandmetforminwassuperiortoeitherdrugasmonotherapytoimprovemenstrualcyclicityandovulationrate.47

Obstructive sleep apnea

TheonlyobesitypharmacotherapyavailableinCanadawhichhasbeenspecificallystudiedintheobstructivesleepapneapopulationisliraglutide.Amongpatientswithmoderateorsevereobstructivesleepapneawhowereunableorunwilling touseacontinuouspositive airway pressure machine, liraglutide 3.0mg combinedwithhealthbehaviourmodificationsignificantlyreducedthenum-ber of apnea-hypopnea index events by -12.2 events per hour,comparedwitha reductionof -6.1eventsperhourwithhealthbehaviourmodificationalone.23

Osteoarthritis

Theeffectofobesitypharmacotherapyonosteoarthritishasnotbeenadequatelystudied.

Mental health and quality of life

Thechoiceofagentstotreatmentalhealthconcerns(e.g.depres-sion,psychosis)musttakeeffectonweightintoconsideration(seeTheRoleofMentalHealth inObesityManagement. Pharmaco-therapy forbingeeatingdisorderandattentiondeficithyperac-tivitydisordermustalsotakeeffectonweightintoconsideration.

Whiletherelationshipbetweenmentalhealthandobesityiscom-plex,most studies show that successful obesitymanagement isassociated with an improvement in mental health parameters.Weightlossisassociatedwithimprovedqualityoflifeinsome,butnotall,weightlosstrials.Asmostobesitymedicationsareactiveinthebrain,itisimportanttoascertaintheireffectandsafetyonmentalhealthparameters.

Liraglutide 3.0 mg has been shown to improve health-relat-ed quality of life in peoplewith obesity and prediabetes48 and weight-relatedqualityoflife(QoL)inpeoplewithT2DM,7aswellasdemonstratingneuropsychiatricsafety.49

Naltrexone/bupropionhasdemonstratedagreater improvementinweight-relatedQoL compared to placebo. Study participantslosingthemostweightexperiencedthegreatestimprovementinweight-relatedQoLregardlessofwhethertheweightwaslostonnaltrexone/bupropion or placebo, suggesting that the improve-mentinQoLwasrelatedtotheweightlossratherthanthemed-icationitself.50Therehasbeenalong-standingconcernthatan-tidepressantscanrarely,paradoxically,worsendepressionand/orcauseworseningoremergenceofsuicidalideationorbehaviourduring the early phases of treatment. In theplacebo-controlledclinicaltrialswithnaltrexone/bupropionforthetreatmentofobe-sityinadultpatients,nosuicidesorsuicideattemptswerereport-edinstudiesupto56weeksduration. Inthesestudies,suicidalideationwasreportedbythree(0.20%)of1515patientstreatedwithplacebocomparedwithone(0.03%)of3239treatedwithnaltrexone/bupropion. The sameprecautions pertaining to anti-depressants should be considered when treating patients withnaltrexone/bupropion, including screening patients for suicidalbehavioursandideation.

Weightgainisacommonsideeffectofsomeantipsychoticmedi-cations.Asystematicreviewandmeta-analysiswasconductedof12double-blind,randomized,placebo-controlledtrialsof12–24weeks’duration,includingatotalof743patientswithschizophre-niaor schizoaffectivedisorder. The study found thatmetforminwas effective for the management of antipsychotic inducedweightgaininthispopulation,withameanweightlossinadultsof-3.2kgcomparedwithplacebo.Metforminismostimpactfulearlierinthecourseofantipsychotictreatmentorwithinitiationofantipsychoticmedication,withameandifferenceinweightof-5.9kgcomparedwithplacebo,versus -2.1kg inpatientswhohadbeenonantipsychoticmedicationlongertermbeforestartingmetformin.51

Medications with insufficient data for obesity management

Itisrecognizedthatavarietyofunapprovedpharmacotherapeu-ticapproachesaresometimesbeingutilizedintheclinicalsettinginanattempttoassistwithobesitymanagement.Basedonourreviewofthe literature,there is insufficientevidencetosupporttheuseofpharmacotherapiesorhormonal treatmentstrategies(e.g.,testosterone,thyroidhormone)thatarenotdiscussedinthisdocument.

Twoseparaterandomized,placebo-controlledtrialsevaluatedtheefficacyoftopiramateonweightlossamongpatientswithobesityandT2DMover24–40weeks.Thesetrialsdemonstratedclinicallymeaningfulweight lossof4.5%–6.6%and6.5%–9.1% in the96mg/daygroupand192mg/daydoses,respectively,comparedwith weight losses of 1.7%–2.5% in the placebo groups.52,53

Canadian Adult Obesity Clinical Practice Guidelines 9

Whiletopiramateisnotintendedaspharmacotherapyforobesity,itcouldbeconsideredinpatientswhorequiretopiramateforoth-erindications(e.g.anti-seizureormigrainetherapy)forpatientsinwhomweightgainisaclinicallyrelevantconcern.

Asystematic reviewandmeta-analysisevaluating themetaboliceffectsandweight lossoffluoxetine60mgdaily in215adultswith overweight or obesity and T2DMdemonstrated a -4.3 kgweightlosscomparedwithplacebo.Thesepatientsdidnothavedepression.Follow-upwassixtotwelvemonths infourstudies,butonlytwomonthsinthefifthstudyincluded.Fluoxetineshouldnotbeprescribedforweightlossbutcouldbeconsideredinpa-tientswhorequireitforotherindications,suchasdepression,forpatientsinwhomweightgainisaclinicallyrelevantconcern.

ArecentreviewsummarizesmedicationsavailableinCanadathatcauseweightgain,aswellasalternativechoices.54

Emerging treatments and future directions

TherearemedicationsapprovedforobesitymanagementinothercountriesthatarenotcurrentlyavailableinCanada.Therearealsoseveralagentsunderdevelopmentthatmayprovetobebeneficialforthetreatmentofobesity.

Lorcaserin is a5HT2c receptoragonist that is available in somecountries. It works by stimulation of the pro-opiomelanocortin(POMC)/CART neurons (see The Science of Obesity chapter) toinducesatietyandprovidesa -3.0%placebosubtractedweightlossatadoseof10mgBIDforoneyear.55Lorcaserinhasdemon-stratedcardiovascularsafetyintheCardiovascularSafetyofLorca-serininOverweightorObesePatientscardiovascularoutcometrial(CAMELLIA)butdidnotreducetheriskofcardiovascularevents.56

Phentermineandtopiramate(controlledrelease)areapprovedascombinationtherapyforobesityinsomecountries.PhentermineisanappetitesuppressantthatworksbyinhibitingtheneuropeptideY/agouti-relatedpeptideneuronsandincreasingenergyexpendi-ture.Themechanismbywhichtopiramateinducesweightlossisunclearandmayinvolvemultiplepathways.Atoneyear,-6.6%placebo subtractedweight losswas seenon the lowerdoseof7.5mg/46mg,and-8.6%onthehigherdoseof15mg/92mg.57

Emerging obesity pharmacotherapy

Semaglutide,whichisapprovedfortreatmentofT2DMinCanada,iscurrentlyunderevaluationinclinicaltrialsasapotentialpharmaco-therapeuticagentforchronicobesitymanagement.IntheSemaglu-tideandCardiovascularOutcomesinPatientswithType2Diabetes(SUSTAIN)clinicaltrialprogram,weightlossinpeoplewithT2DMonsemaglutide1.0mgSCweeklyover30–56weeksrangedfrom-4.5to-6.5kg,withupto-5.0kgplacebosubtractedweightloss.58Upto65.7%ofparticipantsinbothsemaglutidedosegroups(0.5mgand1.0mgweekly)achievedweightlossresponsesof≥5%,comparedwithup to11.3%ofpatientsonplacebo.Among patientswith

T2DMwithestablishedcardiovasculardiseaseorathighcardio-vascularrisk,semaglutide0.5mgand1mgweeklywasassoci-atedwith-2.9kgand-4.3kgplacebosubtractedweightlossattwo years, respectively.59 Semaglutide also decreased cardiovas-culareventsamongpatientswithT2DMaged50orgreaterwithestablishedcardiovasculardiseaseorathighriskofcardiovasculardiseasecomparedwithplacebo(heartrate,0.74(95%CI,0.58–0.95)overtwoyears.59Amongpeoplewithobesitywithoutdiabe-tes,semaglutideatadoseofupto0.4mgsubcutaneousperdaydemonstratedweightlossofupto-13.8%comparedwith-2.3%on placebo.60 A cardiovascular outcome trial of semaglutide inpeoplewithobesitywithoutdiabetesbutwithapriorhistoryofcardiovasculareventsiscurrentlyunderway.

Multipletreatmentoptionsarebeingstudied,whichincludemono-therapy or combinations of various hormones (e.g. GLP-1, GIP,glucagon,oxyntomodulin,amylin,PYY3-36). It isanticipatedthatadministering combinationsof thesehormoneswill bebeneficialtoaddressthehighlyredundanthormonalphysiologythatdefendsbodyweight.

Canadian Adult Obesity Clinical Practice Guidelines 10

Figure 1. Algorithm: Choice of Obesity Pharmacotherapy

BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2

plus obesity-related co-morbidities

Consider co-morbidities or specific features

Assess after 3 months on therapeutic dose

Diabetes, prediabetes, HTN, OSA, PCOS

Liraglutide 1st choice (for DM level 1, grade A;

preDM level 2, grade B)

Naltrexone/bupropion 2nd (for DM level 2, grade B)

Orlistat 3rd (for DM level 2, grade B)

Not successful for weight management

Discontinue medication and try second line OR

continue medication and add second-line agent

Craving, depression, smoking

Naltrexone/bupropion 1st choice

Liraglutide 2nd

Orlistat 3rd

Successful for weight management

Continue medication

Consider stopping or changing meds associated

with weight gain if possible

Canadian Adult Obesity Clinical Practice Guidelines 11

Correspondence:guidelines@obesitynetwork.ca

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