Canadian Adult Obesity Clinical Practice Guidelines 1 KEY MESSAGES FOR HEALTHCARE PROVIDERS • There are three medications indicated for chronic obesity management in Canada in addition to health behaviour changes: liraglutide (Saxenda ® ) 3.0 mg, naltrexone/bu- propion (Contrave ® ) in a combination tablet, and orlistat (Xenical ® ). All three medications have been shown to be effective in producing weight loss greater than placebo for a duration of at least one year. • Medications that are not approved as pharmacotherapy for obesity management should not be used for this purpose. • The individual response to obesity management pharma- cotherapy is heterogeneous; the response to medications can differ from patient to patient. In choosing the most ap- propriate obesity pharmacotherapy, consider mechanism of action, safety, potential side effects/tolerability, contraindica- tions, drug interactions, mode of administration and cost. Pharmacotherapy in Obesity Management Sue D. Pedersen MD i , Priya Manjoo MD ii , Sean Wharton MD Pharm D iii i) C-ENDO Diabetes & Endocrinology Clinic ii) Department of Endocrinology, University of British Columbia iii) Department of Medicine, McMaster University Cite this Chapter Pedersen SD, Manjoo P, Wharton S. Canadian Adult Obesity Clinical Practice Guidelines: Pharmacotherapy in Obesity Management. Available from: https://obesitycanada.ca/guidelines/pharmacotherapy . Accessed [date]. Update History Version 1, August 4, 2020. Adult Obesity Clinical Practice Guidelines are a living document, with only the latest chapters posted at obesitycanada.ca/guidelines. RECOMMENDATIONS 1. Pharmacotherapy for weight loss can be used for individuals with BMI ≥ 30 kg/m 2 or BMI ≥ 27 kg/m 2 with adiposity-related complications, in conjunction with medical nutrition therapy, physical activity and psychological interventions (liraglutide 3.0 mg [Level 2a, Grade B)], 1–3 naltrexone/bupropion combi- nation [Level 2a, Grade B], 4 orlistat [Level 2a, Grade B]). 5 2. Pharmacotherapy may be used to maintain weight loss that has been achieved by health behaviour changes, and to prevent weight regain (liraglutide 3.0 mg or orlistat) (Level 2a, Grade B). 6 3. For people living with type 2 diabetes and a BMI ≥ 27 kg/ m 2 , pharmacotherapy can be used in conjunction with health behaviour changes for weight loss and improvement in glycemic control: liraglutide 3.0 mg (Level 1a, Grade A); 7 naltrexone/bupropion combination (Level 2a; Grade B), 8 orlistat (Level 2a, Grade B). 9 4. We recommend pharmacotherapy in conjunction with health behaviour changes for people living with prediabetes and overweight or obesity (BMI > 27kg/m 2 ) to delay or pre- vent type 2 diabetes. (Liraglutide 3.0 mg (Level 2a, Grade B); 2 , orlistat (Level 2a, Grade B). 10 5. We do not suggest the use of prescription or over-the- counter (OTC) medications other than those approved for weight management (Level 4, Grade D, Consensus). 6. For people living with overweight or obesity who require pharmacotherapy for other health conditions, we suggest choosing drugs that are not associated with weight gain (Level 4, Grade D, Consensus).
12
Embed
Cite this Chapter Pharmacotherapy in Obesity Clinical ...obesitycanada.ca/.../Pharmacotherapy-v3-with-links... · Pharmacotherapy is indicated for chronic obesity management in Canada
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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.
• 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
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:
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.
• 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.
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
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
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.
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
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
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
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.
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
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
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.
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.
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.
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
Though data is conflicting, some small studies have suggestedthatmetforminmaycauseasmalldecreaseinBMIof-0.5to-1.3kg/m2withanimprovementinaminotransferasesand/orliverhis-tologyinpatientswithnonalcoholicfattyliverdisease.42,43
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
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
Asystematic reviewandmeta-analysisevaluating themetaboliceffectsandweight lossoffluoxetine60mgdaily in215adultswith overweight or obesity and T2DMdemonstrated a -4.3 kgweightlosscomparedwithplacebo.Thesepatientsdidnothavedepression.Follow-upwassixtotwelvemonths infourstudies,butonlytwomonthsinthefifthstudyincluded.Fluoxetineshouldnotbeprescribedforweightlossbutcouldbeconsideredinpa-tientswhorequireitforotherindications,suchasdepression,forpatientsinwhomweightgainisaclinicallyrelevantconcern.
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
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.
2. RouxCW,AstrupA,FujiokaK,etal.3yearsofliraglutideversusplacebofortype 2 diabetes risk reduction and weight management in individuals withprediabetes:arandomised,double-blindtrial.Lancet.2017;389(10077):1399-1409.doi:10.1016/S0140-6736(17)30069-7
3. Wadden TA,Hollander P, Klein S, et al.Weightmaintenance and additionalweight loss with liraglutide after low-calorie-diet-induced weight loss: TheSCALEMaintenance randomized study. Int J Obes. 2013;37(11):1443-1451.doi:10.1038/ijo.2013.120
4. Greenway FL, FujiokaK, Plodkowski RA, et al. Effect of naltrexoneplus bu-propion on weight loss in overweight and obese adults ( COR-I ): a multi-centre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet.2010;376(9741):595-605.doi:10.1016/S0140-6736(10)60888-4
5. Rucker D, Padwal R, Li SK, Curioni C, Lau DCW, Janeiro R De. Long termpharmacotherapy for obesity and overweight: updatedmeta-analysis. BMJ.2007;335(7631):1194-1199.doi:10.1136/bmj.39385.413113.25
11. KnowlerWC,Barrett-ConnorE, FowlerSE, et al.Reduction in the incidenceof type 2 diabetes with lifestyle intervention or metformin. N Engl J Med.2002;346(6):393-403.doi:10.1056/NEJMoa012512
12. PromratK,KleinerDE,NiemeierHM,etal.RandomizedControlledTrialTest-ing the Effects ofWeight Loss onNonalcoholic Steatohepatitis. Hepatology.2010;51(1):121-129.doi:10.1002/hep.23276
20. ZhouY,MaX,WuC,etal.EffectofAnti-ObesityDrugonCardiovascularRiskFactors: A Systematic Review andMeta-Analysis of Randomized ControlledTrials.PLoSOne.2012;7(6):e39062.doi:10.1371/journal.pone.0039062
27. Greenway FL, Whitehouse MJ, Guttadauria M, et al. Rational Design of aCombinationMedication for the Treatment of Obesity. Obes (Silver Spring).2009;17(1):30-39.doi:10.1038/oby.2008.461
30. Takeda Pharmaceuticals America I. Highlights of Prescribing Informa-tion. Retrieved from https//www.accessdata.fda.gov/drugsatfda_docs/la-bel/2014/200063s000lbl.pdf.2014.
39. WaddenTA,ForeytJP,FosterGD,etal.WeightLossWithNaltrexoneSR/Bu-propion SR Combination Therapy as an Adjunct to Behavior Modification:TheCOR-BMODTrial.Obes (SilverSpring.2011;19(1):110-120.doi:10.1038/oby.2010.147
40. NissenSE,WolskiKE,PrcelaL,etal.EffectofNaltrexone-BupropiononMajorAdverseCardiovascularEventsinOverweightandObesePatientsWithCardio-vascular Risk Factors A RandomizedClinical Trial. JAMA. 2016;315(10):990-1004.doi:10.1001/jama.2016.1558
41. Harrison SA, Fecht W, Brunt EM, Neuschwander-tetri BA. Orlistat for over-weightsubjectswithnonalcoholicsteatohepatitis:Arandomized,prospectivetrial.Hepatology.2009;49(01):80-86.doi:10.1002/hep.22575
42. Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trialofmetformin versus vitamin E or prescriptive diet in nonalcoholic fatty liverdisease. Am J Gastroenterol. 2005;100(5):1082-1090. doi:10.1111/j.1572-0241.2005.41583.x
43. YgunAU,AdayifciAK, IsikAT,etal.Metformin in thetreatmentofpatientswithnon-alcoholic steatohepatitis.Aliment Pharmacol Ther. 2004;19(5):537-544.doi:10.1111/j.1365-2036.2004.01888.x
46. WangF,WuY,ZhuY,etal.Pharmacologic therapy to induceweight loss inwomenwhohaveobesity/overweightwithpolycysticovarysyndrome:asys-tematicreviewandnetworkmeta-analysis.ObesRev.2018;19(10):1424-1445.doi:10.1111/obr.12720
47. Elkind-hirschK,MarrioneauxO,BhushanM,VernorD,BhushanR.Comparisonof Single andCombinedTreatmentwith Exenatide andMetforminonMen-strualCyclicity inOverweightWomenwithPolycysticOvarySyndrome.JClinEndocrinolMetab.2008;93(7):2670-2678.doi:10.1210/jc.2008-0115
48. Kolotkin R, SmolarzG,MeinckeH, FujiokaK. Improvements in health-relat-ed quality of life over 3 yearswith liraglutide 3. 0mg comparedwith pla-cebo in participants with overweight or obesity. Clin Obes. 2018;8(1):1-10.doi:10.1111/cob.12226
52. Toplak H, Hamann A, Moore R, et al. Efficacy and safety of topiramate incombinationwithmetformin in the treatmentofobesesubjectswith type2diabetes: a randomized, double-blind, placebo-controlled study. Int J Obes.2007;31(1):138-146.doi:10.1038/sj.ijo.0803382
54. Wharton S, Raiber L, Serodio KJ, Lee J, Christensen RAG.Medications thatcauseweight gain and alternatives in Canada: a narrative review. DiabetesMetabSyndrObes.2018;21:427-438.
58. GoldenbergRM,SteenO.Semaglutide:ReviewandPlaceinTherapyforAdultsWith Type 2 Diabetes. Can J Diabetes. 2019;43(2):136-145. doi:10.1016/j.jcjd.2018.05.008
59. MarsoS,BainS,ConsoliA,etal.SemaglutideandCardiovascularOutcomesin Patients with Type 2 Diabetes. Engl J Med. 2016;375(19):1834-1844.doi:10.1056/NEJMoa1607141
60. O’NeilPM,BirkenfeldAL,McGowanB,etal.Efficacyandsafetyofsemaglu-tide comparedwith liraglutide and placebo forweight loss in patientswithobesity:arandomised,double-blind,placeboandactivecontrolled,dose-rang-ing, phase 2 trial. Lancet. 2018;392(10148):637-649. doi:10.1016/S0140-6736(18)31773-2
61. Domecq JP, Prutsky G, Leppin A, et al. Drugs Commonly Associated WithWeightChange:ASystematicReviewandMeta-analysis.JClinEndocrinolMe-tab.2015;100(2):363-370.doi:10.1210/jc.2014-3421