Endo Doc Offlabel

We need to output a SKILL.md file with the specified format.

We have:

NAME: endo-doc-offlabel TITLE: Document off‑label use discussion and risks DESCRIPTION TARGET: Recommends that if a provider prescribes a non‑FDA‑approved medication for weight loss, they must advise the patient that the approach lacks safety/efficacy evaluation, discuss risks/benefits, and document this conversation and why an off‑label agent was chosen over approved options. Triggers include when a clinician asks, 'How should I document and discuss off‑label phentermine use for weight loss?' or 'What note should I write in the chart after prescribing off‑label metformin for obesity?'.

We need to produce:

name: description: <2 sentences. What + clinical trigger phrases. Under 1024 chars. Third person.>

STEP 1 — Gather Information

STEP 2 — Rule In / Rule Out

STEP 3 — Classify or Stratify

STEP 4 — Decide

Clinical Guardrails / Mimics / Pitfalls

<critical caveats; what to NOT do>

Concrete Clinical Example

Source: , , ,

We need to fill these sections based on the guideline text, focusing on Section 3.1 implementation remarks (pages 9-10). The relevant text is on page 9-10 (the PDF pages). Let's locate that.

From the provided text, page 9 starts at "--- PAGE 9 ---". Let's read page 9 and 10.

--- PAGE 9 --- 350 Apovianetal GuidelinesonPharmacologicalManagementofObesity JClinEndocrinolMetab,February2015,100(2):342–362 funding of additional long-term clinical trials in the Eu- 3monthsinallpatientsprescribedweightlossmedica- ropeanUnionandelsewheretostudythesafetyandeffi- tions. (2|QQEE) cacyofthesemedications,withthegoalofprovidingac- cess to medications for chronic obesity management to patientsinneedacrosstheworld. Diet,behaviormodification,and,ifappropriate,phar- macotherapyhavebeenshowntobesafeandeffectivein 1.3Inpatientswithuncontrolledhypertensionorahis- producingmodestbuteffectiveweightlossandameliora- tory of heart disease, we recommend against using sym- tion of comorbid medical problems. To promote maxi- pathomimetic agents phentermine and diethylpropion. mumeffectiveness,frequentassessmentsareindicatedto (1|QQQE)(Table4) assesseffectivenessofthetreatment,ensureaccountabil- ity, and monitor safety and efficacy of the weight loss Evidence medications.Themoreaccountablepatientsaretoweight The product labels for medications approved for lossprograms,thebettertheoutcomesthatareexpected. chronicweightmanagement(46–49)includecontraindi- Moreover,anyadversesideeffectsoftheweightlossmed- cations and cautions based on clinical data submission icationscanbedetectedearlyandrectified(8).TheAHA/ on (cid:3) 1500 individuals treated with each medication be- ACC/TOSGuidelinefortheManagementofOverweight foreapproval.ThesecontraindicationsaredetailedinTa- andObesityinAdultsreviewedrandomizedclinicaltrials ble 4. Prescribers should be familiar with these product onweightlossinterventionsanddeterminedthatthebest labels in order to avoid contraindications and to judi- weightlossoutcomesoccurwithfrequentface-to-facevis- ciouslychoosepatientsbasedonproductcautions. its(16visitsperyearonaverage)(8,38). Forthesympathomimeticagentsphentermineanddi- 1.5Ifapatient’sresponsetoaweightlossmedication ethylpropion, regulatory approval was given based on a isdeemedeffective(weightloss(cid:2)5%ofbodyweightat smallerclinicalprofileandwithoutacardiovascularout- 3 mo) and safe, we recommend that the medication be comesstudy.Thereisthusalackofevidenceonsafetyfor continued. If deemed ineffective (weight loss (cid:2) 5% at 3 these products across broad populations. In making a mo)oriftherearesafetyortolerabilityissuesatanytime, strongrecommendation,thepanelplacedahighvalueon werecommendthatthemedicationbediscontinuedand avoidingharmandalowervalueonpotentialshort-term alternative medications or referral for alternative treat- weightloss. mentapproachesbeconsidered.(1|QQQQ) Implementationremarks Evidence Because phentermine and diethylpropion are associ- Weightlossmedicationsdonotchangetheunderlying atedwithelevationsinmeanbloodpressure(BP)andpulse physiology of weight regulation in any permanent way. rateintreatedpopulations,wedonotadvocatetheirpre- Trialsofweightlossmedicationthathaveusedacrossover scriptioninpatientswithahistoryofcardiovasculardis- design have demonstrated that the weight loss effects of ease, and we suggest caution and careful monitoring in these medications are only sustained as long as they are patients with hypertension history. Thus, caution is ad- taken and these same benefits occur on introducing the vised in prescribing these agents in patients with hyper- medication in patients previously treated with lifestyle tension,historyofcardiacarrhythmia,orseizures.Ase- alone. Historically, patients and providers thought that rotonin receptor agonist such as lorcaserin would be a weightlossmedicationscouldbeusedtoproduceaninitial betterchoiceinapatientwiththeseconditions. weight loss that could subsequently be sustained by be- Another example is the patient with obesity and de- havioralmeans.Theavailableevidencedoesnotsupport pressiononaselectiveserotoninreuptakeinhibitor(SSRI) thisview.MuchasantihypertensivemedicationslowerBP or serotonin-norepinephrine reuptake inhibitor (SNRI). toanewsteadystatewithBPrisingtobaselinelevelsupon Inthesepatients,lorcaserinwouldnotbethebestchoice discontinuing medication, weight loss medications pro- due to the potential for serotonin syndrome. A better moteweightlosstoanewsteadystatewithgradualweight choicewouldbephentermine/topiramateorphentermine gain typically occurring when medications are stopped alone.Orlistatislikelytobesafeinallinstancesduetoits (50,51). mechanismofaction.Othercautionaryinstancesareout- 1.6Ifmedicationforobesitymanagementisprescribed linedinTable4. asadjunctivetherapytocomprehensivelifestyleinterven- 1.4 We suggest assessment of efficacy and safety at tion, we suggest initiating therapy with dose escalation leastmonthlyforthefirst3months,thenatleastevery based on efficacy and tolerability to the recommended Downloaded from https://academic.oup.com/jcem/article/100/2/342/2813109 by guest on 14 June 2026

--- PAGE 10 --- doi:10.1210/jc.2014-3415 jcem.endojournals.org 351 Table 4. PharmacotherapyforObesityintheUnitedStates(December2014) WeightLossAboveDiet andLifestyleAlone,Mean WeightLoss,%orkga; DurationofClinical Drug(Generic) Dosage MechanismofAction Studies Status CommonSideEffects Contraindications Phentermineresin AdipexP Norepinephrine-releasing 3.6kg(7.9lb);2–24wk Approvedin1960sfor Headache,elevatedBP,elevatedHR, Anxietydisorders (37.5mg), agent short-termuse insomnia,drymouth,constipation, (agitatedstates), 37.5mg/d (3mo) anxiety historyofheart Ionamin(30mg), Cardiovascular:palpitation, disease,uncontrolled 30–37.5 tachycardia,elevatedBP,ischemic hypertension, mg/d events seizure,MAO Centralnervoussystem: inhibitors,pregnancy overstimulation,restlessness, andbreastfeeding, dizziness,insomnia,euphoria, hyperthyroidism, dysphoria,tremor,headache, glaucoma,historyof psychosis drugabuse, Gastrointestinal:drynessofthemouth, sympathomimetic unpleasanttaste,diarrhea, amines constipation,othergastrointestinal disturbances Allergic:urticaria Endocrine:impotence,changesin libido Diethylpropion Tenuate(75mg), Norepinephrine-releasing 3.0kg(6.6lb);6–52wk FDAapprovedin Seephentermineresin Seephentermineresin 75mg/d agents 1960sforshort- termuse(3mo) Orlistat, 120mgTID Pancreaticandgastric 2.9–3.4kg(6.5–7.5lb), FDAapprovedin1999 Decreasedabsorptionoffat-soluble Cyclosporine(taken2h prescription lipaseinhibitor 2.9–3.4%;1y forchronicweight vitamins,steatorrhrea,oilyspotting, beforeorafter (120mg) management flatulencewithdischarge,fecal orlistatdose),chronic urgency,oilyevacuation,increased malabsorption defecation,fecalincontinence syndrome, pregnancyand breastfeeding, cholestasis, levothyroxine, warfarin, antiepilepticdrugs Orlistat,over-the- 60–120mgTID Pancreaticandgastric 2.9–3.4kg(6.5–7.5lb), FDAapprovedin1999 SeeOrlistat,prescription SeeOrlistat,prescription counter(60mg) lipaseinhibitor 2.9–3.4%;1y forchronicweight management Lorcaserin(10mg) 10mgBID 5HT2creceptoragonist 3.6kg(7.9lb),3.6%;1y FDAapprovedin2012 Headache,nausea,drymouth, Pregnancyand forchronicweight dizziness,fatigue,constipation breastfeeding management Usewithcaution: SSRI,SNRI/MAOI,St John’swort,triptans, buproprion, dextromethorphan Phentermine(P)/ 3.75mgP/23 GABAreceptor 6.6kg(14.5lb) FDAapprovedin2012 Insomnia,drymouth,constipation, Pregnancyand topiramate(T) mgTERQD modulation(T)plus (recommendeddose), forchronicweight paraesthesia,dizziness,dysgeusia breastfeeding, (startingdose) norepinephrine- 6.6% management hyperthyroidism, 7.5mgP/46mg releasingagent(P) 8.6kg(18.9lb)(highdose), glaucoma,MAO TERdaily 8.6%;1y inhibitor, (recommended sympathomimetic dose) amines 15mgP/92mg P/TERdaily (highdose) Naltrexone/ 32mg/360mg Reuptakeinhibitorof 4.8%;1y(Ref.79) FDAapprovedin2014 Nausea,constipation,headache, Uncontrolled bupropion 2tabletsQID dopamineand forchronicweight vomiting,dizziness hypertension,seizure (highdose) norepinephrine management disorders,anorexia (bupropion)and nervosaorbulimia, opioidantagonist drugoralcohol (naltrexone) withdrawal,MAO inhibitors Liraglutide 3.0mginjectable GLP-1agonist 5.8kg;1y(Ref.30,31) FDAapprovedin2014 Nausea,vomiting,pancreatitis Medullarythyroid forchronicweight cancerhistory, management multipleendocrine neoplasiatype2 history Abbreviations:GABA,(cid:6)-aminobutyricacid;HR,heartrate;MAO,monoamineoxidase(Ref.46–49). aMeanweightlossinexcessofplaceboaspercentageofinitialbodyweightormeankilogramweightlossoverplacebo. Downloaded from https://academic.oup.com/jcem/article/100/2/342/2813109 by guest on 14 June 2026

But the Implementation remarks section we need is on page 9? Actually the Implementation remarks heading appears on page 9 after the evidence for 1.5? Let's scroll: On page 9 we see:

Implementationremarks Evidence Because phentermine and diethylpropion are associ- Weightlossmedicationsdonotchangetheunderlying atedwithelevationsinmeanbloodpressure(BP)andpulse physiology of weight regulation in any permanent way. ...

But the specific section 3.1 is earlier in the document. Let's find "3.0 Off-label use of drugs approved for other indications for chronic obesity management" and "3.1 We suggest against the off-label use of medications...". That appears later in the document, likely after page 12? Let's search.

Scrolling further: after page 12 we see page 13 etc. Eventually we see:

--- PAGE 16 --- ... (some text) --- PAGE 17 --- ... --- PAGE 18 --- ... --- PAGE 19 --- ... --- PAGE 20 --- ... --- PAGE 21 ---

But we need to locate the section 3.0 and 3.1. Let's search in the provided text for "3.0 Off-label". I see near the end:

--- PAGE 16 --- ... Actually after page 15 we see:

--- PAGE 16 --- ... (some text) --- PAGE 17 --- ... --- PAGE 18 --- ... --- PAGE 19 --- ... --- PAGE 20 --- ... --- PAGE 21 ---

But I recall seeing "3.0 Off-label use of drugs approved for other indications for chronic obesity management" somewhere near the end. Let's search manually: I see at page 15 maybe? Let's look at page 14-15.

--- PAGE 14 --- ... (some text) --- PAGE 15 --- ... --- PAGE 16 --- ... --- PAGE 17 --- ... --- PAGE 18 --- ... --- PAGE 19 --- ... --- PAGE 20 --- ... --- PAGE 21 ---

Actually the text after page 15 includes:

--- PAGE 15 --- 356 Apovianetal GuidelinesonPharmacologicalManagementofObesity JClinEndocrinolMetab,February2015,100(2):342–362 ... 2.6Werecommendconsideringweightgainpotential inchoosinganAEDforanygivenpatient,andtheuseof a shared decision-making process that provides patients withquantitativeestimatesoftheexpectedweighteffectof thedrugstomakeaninformeddecisionaboutdrugchoice. (1|QQQE) ...

Then page 16 continues with more sections.

Eventually we see:

--- PAGE 16 --- ... (some text) --- PAGE 17 --- ... --- PAGE 18 --- ... --- PAGE 19 --- ... --- PAGE 20 --- ... --- PAGE 21 ---

But I need to locate the exact 3.0 section. Let's search for "3.0 Off-label". I see near the bottom of the provided text maybe after page 21? Actually the provided text ends at page 21. Let's scroll to the very end of the provided text:

--- PAGE 21 --- 362 Apovianetal GuidelinesonPharmacologicalManagementofObesity JClinEndocrinolMetab,February2015,100(2):342–362 129. RatliffJC,BarberJA,PalmeseLB,ReutenauerEL,TekC.Asso- tionalcounselingresultsinhistologicalimprovementinpatients ciationofprescriptionH1antistamineusewithobesity:results withnon-alcoholicsteatohepatitis:apilotstudy.AmJGastroen- from the National Health and Nutrition Examination Survey. terol.2005;100:1072–1081. Obesity(SilverSpring).2010;18:2398–2400. 142. PalmerM,SchaffnerF.Effectofweightreductiononhepaticab- 1408–1413. ... ... (references)

Thus the 3.0 section might be missing from the provided excerpt? But the user said: "GUIDELINE SECTION TO USE: Section 3.1 implementation remarks, pages 9-10". However the text we have for pages 9-10 does not contain a section labeled "3.1". It contains "Implementationremarks" under 1.5? Actually the text we saw on page 9 includes "Implementationremarks" after the evidence for 1.5. That might be the implementation remarks for recommendation 1.5? But the user says Section 3.1 implementation remarks, pages 9-10. Possibly the numbering is off because the document may have sections: 1.0, 2.0, 3.0 etc. The section 3.0 is about off-label use. The implementation remarks for 3.1 might be on pages 9-10? Let's search for "3.1" in the provided text.

I can search mentally: I see "3.1" appears in the text on page 9? Let's look: On page 9 we saw "1.3Inpatientswithuncontrolledhypertensionorahis-". Not 3.1.

Maybe the section 3.0 starts later but the implementation remarks for 3.1 are on pages 9-10 of the guideline (maybe the PDF page numbers differ from the text we have). However we have the text for pages 9-10 as shown. It does not contain any mention of off-label use. So perhaps the user mis-specified but we must use the section heading "GUIDELINE SECTION TO USE" as focus, but we may pull adjacent context from anywhere in the document if needed for clinical accuracy.

Thus we need to find the off-label section somewhere else in the document. Let's search for "Off-label" in the provided text.

I see at page 12 maybe? Let's search: I recall seeing "Off-label" near the end of the document. Let's look at page 12-13 etc.

--- PAGE 12 --- ... (some text) --- PAGE 13 --- ... --- PAGE 14 --- ... --- PAGE 15 --- ... --- PAGE 16 --- ... --- PAGE 17 --- ... --- PAGE 18 --- ... --- PAGE 19 --- ... --- PAGE 20 --- ... --- PAGE 21 ---

I need to actually scan the text for the word "Off-label". Let's do a quick mental scan: I see at page 15 maybe? Not sure.

Better approach: Let's search for "Off-label" in the provided text string. Since I cannot run code, I'll approximate by looking at the text we have.

I see at the very end of the provided text (page 21) there is a reference list. No.

Maybe the off-label section is earlier but we missed because the text is fragmented. Let's look at page 10 again: after the table, there is no more text on page 10. Page 11 starts at "--- PAGE 11 ---". Let's read page 11.

--- PAGE 11 --- 352 Apovianetal GuidelinesonPharmacologicalManagementofObesity JClinEndocrinolMetab,February2015,100(2):342–362 doseandnotexceedingtheupperapproveddosebound- nausea develop during dose escalation, the dose should aries.(2|QQEE) notbeincreasedfurtheruntiltolerated(31). There are no comparative data of different doses of Evidence phentermineandothersympathomimeticsusedasasingle Forthemedicationsapprovedforlong-termtreatment agent.Therefore,theonce-dailydosesof30mgphenter- for obesity, the recommended doses are as follows: orl- mine (37.5 mg as resin) or 75 mg tenuate should not be istat,120mgthreetimesaday(TID);phentermine/topi- exceeded. ramate,7.5mg/46mgeveryday(QD);lorcaserin,10mg 1.7 In patients with T2DM who are overweight or twiceaday(BID);naltrexone/bupropion,8mg/90mg,2 obese,wesuggesttheuseofantidiabeticmedicationsthat tabletsBID;andforliraglutide,3.0mgSCQD(46–49). have additional actions to promote weight loss (such as Fororlistat,thedrugisavailableoverthecounterata dosage of 60 mg TID. This dosage has been shown to GLP-1 analogs or SGLT-2 inhibitors) in addition to the produce greater weight loss than placebo (52). The rec- first-line agent for T2DM and obesity, metformin (63). ommendedprescriptiondosageis120mgTID.Giventhe (2|QQQE) favorablesafetyprofileandweightlossefficacyoforlistat Evidence at 120 mg TID, it is the preferred dose for prescription (47).Thereisnoevidencefromclinicaltrialsusingdosages IndividualswithobesityandT2DMmayhavethedual higherthan120mgTIDthatefficacyisgreaterathigher benefit of weight loss and glycemic control while pre- dosages,andprescribersshouldnotexceed120mgTID. scribedaregimenincludingoneormoreofthreecurrently Orlistat,120mgTID,hasbeenstudiedandapprovedfor availabledrugclasses:metformin,theGLP-1agonists(ex- treatmentofadolescentswithobesity(58–60). enatide,liraglutide),andthenewclassofSGLT-2inhib- Forphentermine/topiramateextendedrelease(ER),itis itors.Forthegoalofclinicallysignificantweightloss,trials necessary to escalate the dose when starting the medica- comparing GLP-1 agonists and other antihyperglycemic tion.Theclinicaltrialdatasupportstartingatadosageof agentshaveshownweightlossinsomesubjectsinhigher 3.75 mg/23 mg QD and maintaining this for at least 2 rangesbetween5.5and8kg(62).Althoughotheragents weeks.Ifthepatienttoleratesthemedication,anincrease including metformin and SGLT-2 inhibitors produce to7.5mg/46mgisinorder.Becauseofthemorefavorable moremodestweightloss,ie,inthe1-to3-kgrangeinmost tolerabilityprofileinclinicalstudiesofthe7.5mg/46mg studies,theseagentshavenotbeenstudiedinthesettingof dose,furtherescalationisonlyrecommendedforpatients concomitantbehavioraltherapy,andthefullweightloss whohavenotlost3%oftheirbodyweightat12weeks.In potentialisthereforenotyetknown.Insummary,because that case, the dose can be increased to 11.25 mg/69 mg, asubsetofdiabetespatientsmayhavesubstantialweight andthento15mg/92mg.Theproductlabelrecommends lossoncertaindiabetesagentsthatalsolowerbloodglu- agradualreductionofdoseover3–5daysbecauseofthe cose,mostpatientswithdiabetesshouldtryoneormore observation of seizures occurring when topiramate was of these before being considered for additional medica- stoppedabruptlyinpatientswithepilepsy(41,43,61). tionsdesignedforthespecificgoalofweightloss.Themost Forlorcaserin,therecommendeddosageis10mgBID. substantialevidencesupportsatrialofGLP-1agonists(see Inclinicaltrials,lorcaserin10mgQDproducednearlyas recommendation2.1). muchweightlossas10mgBID(42,44,45). Naltrexone/bupropionisavailablein8mg/90mgcom- 1.8 In patients with cardiovascular disease who seek binationtablets.Onetabletshouldbestartedinthemorn- pharmacologicaltreatmentforweightloss,wesuggestus- ingandin1week1tabletaddedbeforedinner.Astoler- ing medications that are not sympathomimetics, such as ated, the dose should be increased to 2 tablets in the lorcarserinand/ororlistat.(2|QEEE) morning the 3rd week, and 2 tablets before the evening mealthe4thweektothemaximumof2tabletstwicedaily. Evidence Ifsideeffectssuchasnauseadevelopduringdoseescala- Becausepatientswithapriorhistoryofcardiovascular tion,thedoseshouldnotbeincreasedfurtheruntiltoler- disease may be susceptible to sympathetic stimulation, ated.Ifapatienthasnotlostmorethan5%ofbodyweight agents without cardiovascular signals (increased BP and at 12 weeks, naltrexone/bupropion should be discontin- pulse)shouldbeusedpreferentially.Forpatientswithes- ued(79,93). tablishedcardiovasculardiseasewhorequiremedication Liraglutideshouldbeinitiatedatadoseof0.6mgdaily for weight loss, orlistat and lorcaserin should be used. bySCinjection.Thedosecanbeincreasedby0.6mgper ThesedrugshavealowerriskofincreasedBPthanphen- weekuptoamaximumof3.0mg.Ifsideeffectssuchas termineandtopiramateER.Lorcaserinshowedareduc- Downloaded from https://academic.oup.com/jcem/article/100/2/342/2813109 by guest on 14 June 2026

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--- PAGE 12 --- doi:10.1210/jc.2014-3415 jcem.endojournals.org 353 tioninpulseandBPgreaterthanplaceboinrandomized withaweightlossof0.1kgintheplacebogroup(69).A placebo-controlledtrials(44). recent study comparing sitagliptin plus metformin with pioglitazone in drug-naive patients with T2DM showed 2.0 Drugs that cause weight gain and some that the sitagliptin-metformin combination resulted in alternatives weightloss((cid:5)1.4kg)whereaspioglitazoneledtoweight Avarietyofprescriptionmedicationshavebeenasso- gain (3.0 kg) (70). A retrospective analysis of exenatide ciated with weight gain. Drug-induced weight gain is a (n (cid:4) 6280), sitagliptin (n (cid:4) 5861), and insulin (n (cid:4) preventablecauseofobesity.Forallpatients,andpartic- 32398) indicated that exenatide-treated subjects lost an ularlyforpatientswhohaveaBMI(cid:3)27kg/m2withco- averageof3.0kg,sitagliptin-treatedsubjectslost1.1kg, morbiditiesorBMI(cid:3)30kg/m2,thedesiredlevelofclinical andinsulin-treatedsubjectsgained0.6kg(71). efficacyforachosentherapyshouldbebalancedagainst Ina1-yeartrialcomparingtwodosesofliraglutide(1.2 side effects, including the likelihood of weight gain. In and1.8mg)withglimepiride8mg,subjectslost2.05and cases where there are no acceptable therapeutic alterna- 2.45kginthe1.2-and1.8-mggroups,respectively,com- tives, the minimal dose required to produce clinical effi- paredwitha1.12-kgweightgainintheglimepiridegroup. cacymaypreventdrug-inducedweightgain.Patients’ini- Glycatedhemoglobin(HbA1c)significantly(P(cid:4).0014) tial weight status, the presence of risk factors for decreasedby0.84%withliraglutide1.2mgandby1.14% cardiovasculardisease,diabetes,andotherobesity-related withliraglutide1.8mg(P(cid:2).0001)comparedto0.51% health complications, as well as the benefits of pharma- withglimepiride(72).Ananalysisof17randomizedpla- cological therapies warrant careful consideration when cebo-controlledtrialsshowedthatallGLP-1agonistsre- prescribingafirst-linetherapyorchangeinmedication. ducedHbA1clevelsbyabout1%(62).TheDPP-4inhib- itorssitagliptinandvildagliptinhavealsobeenshownin 2.1 We recommend weight-losing and weight-neutral ameta-analysisof25studiestolowerHbA1cbyapprox- medications as first- and second-line agents in the man- imately 0.7 and 0.6%, respectively, in comparison with agement of a patient with T2DM who is overweight or obese.(1|QQQE) placebo(73). Arecentreviewofdirectcomparisonswithactiveglu- Evidence cose-loweringagentsindrug-naivepatientsdemonstrated Theeffectofmetforminforpromotingmildweightloss thatDPP-4inhibitorsreduceHbA1cslightlylessthanmet- is likely due to multiple mechanisms (63). However, in formin (by approximately 0.28) and provide similar animal models, metformin mediates a phenotypic shift glucose-loweringeffectsasathiazolidinedione.DPP-4in- awayfromlipidaccretionthroughAMP-activatedProtein hibitorshavebettergastrointestinaltolerabilitythanmet- Kinase-Nicotinamidephosphoribosyltransferase-Sirtuin forminyetareweightneutral(74,75).Anothermeta-anal- 1-mediatedchangesinmetabolismsupportingtreatment ysisfoundthatanincreaseinbodyweight(1.8to3.0kg) for obesity (64). GLP-1 agonists such as exenatide and wasobservedwithmostsecond-linetherapies,theexcep- liraglutidehavealsobeenshowntopromotemildweight tions being DPP-4 inhibitors, (cid:4)-glucosidase inhibitors, loss.Pramlintideisanamylinanalogthatpromotesweight andGLP-1analogs((cid:6)0.6to(cid:5)1.8kg)(76).Pramlintide, lossbyincreasingsatietyanddecreasingfoodintake(65, indicatedasanadjuncttoinsulin,mayalsoaidwithweight 66).DipeptidylpeptidaseIV(DPP-4)inhibitorsappearto loss.Ameta-analysisdemonstratedaweightlossof(cid:5)2.57 beweightneutralormayleadtominimalweightchange. kgforthosetakingpramlintidevsthecontrolgroups(77). (cid:4)-Glucosidase inhibitors such as acarbose and miglitol TheSGLT-2inhibitorsdapagliflozinandcanagliflozin maybeweightneutralorleadtoasmallchangeinweight are a new class of antidiabetic drugs that reduce renal (152,153). glucosereabsorptionintheproximalconvolutedtubule, Cliniciansshoulddiscusspossibleweighteffectsofglu- leadingtoincreasedurinaryglucoseexcretion(78).Are- cose-loweringmedicationswithpatientsandconsiderthe centsystematicreviewandmeta-analysis(79)looksatnot useofantihyperglycemicmedicationsthatareweightneu- onlytheeffectofthesemedicationsonglycemicindicesbut tralorpromoteweightloss. alsotheireffectsonbodyweight.Comparedwithplacebo, Weight gain is often associated with many diabetes themeanpercentagechangeinbodyweightfrombaseline therapies.Patientscangainasmuchas10kginarelatively in eight studies of (cid:3) 12 weeks comparing the SGLT-2 short period (3 to 6 mo) after initiating treatment with inhibitortoplacebowas(cid:5)2.37%(95%confidenceinter- insulin,sulfonylureas,andotherinsulinsecretagogueslike val[CI],(cid:5)2.73to(cid:5)2.02).Canagliflozinappearstopro- glitinidesandthiazolidinediones.ParticipantsintheDia- duce slightly more weight loss on average because three betesPreventionProgramwithimpairedglucosetolerance studies with dapagliflozin vs placebo showed mean loss whotookmetformin(850mgBID)lost2.1kgcompared of (cid:5)2.06% of initial body weight (95% CI, (cid:5)2.38 to Downloaded from https://academic.oup.com/jcem/article/100/2/342/2813109 by guest on 14 June 2026

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--- PAGE 13 --- 354 Apovianetal GuidelinesonPharmacologicalManagementofObesity JClinEndocrinolMetab,February2015,100(2):342–362 (cid:5)1.74), and five studies of canagliflozin vs placebo neutralDPP-4inhibitorsitagliptin(91)andweight-reduc- showed (cid:5)2.61% loss (95% CI, (cid:5)3.09 to (cid:5)2.13); how- ingcombinationtherapywithliraglutideandmetformin. ever, this was not statistically significant. This analysis Buse et al (92) investigated the addition of exenatide or may underestimate the weight loss effects of these drugs placebotoregimensofinsulinglarginealone,orincom- because studies of 12 weeks were included. In 52-week binationwithmetforminorpioglitazoneorboth,inadult observations,thereisnoweightregainaftermaximalloss T2DM patients with HbA1c of 7.1 to 10.5%. Despite at24weeks. superiorHbA1creduction,weightalsodecreasedby1.8 In addition, because weight-sparing medications are kg in the exenatide group compared with an increase of uniqueinthattheydonotindependentlycausehypogly- 1.0 kg in the placebo group (between-group difference, cemia,theyhavealowerpotentialforhinderinganexer- (cid:5)2.7kg;95%CI,(cid:5)3.7to(cid:5)1.7). cise program. Exercise adjustment is generally necessary Finally,someweightbenefitshavebeenseenwiththe onlywithinsulinandwithmedicationsthatcanpromote basalinsulinanalogsrelativetobiphasicandprandialin- endogenous insulin secretion despite decreasing glucose sulinanalogregimens.TheTreatingToTargetinType2 levels, such as the sulfonylurea and glinide classes of Diabetes trial in patients receiving metformin/ sulfonyl- agents(80).Hence,prioritizingmetformin,incretin-based urea compared the initiation of basal insulin detemir medications, and SGLT-2s as therapeutic strategies can (twicedaily,ifrequired)tothatofbiphasicinsulinaspart reduceexercise-relatedhypoglycemiaandpotentiallyin- BIDorprandialinsulinaspartTID.Basalinsulinusewas creasethesafetyandefficacyofexerciseinpatientswith associated with the least weight gain at 1 year ((cid:6)1.9 vs diabetes,thussupportingthisimportantweight-reduction (cid:6)4.7vs(cid:6)5.7kg,detemirvsbiphasicvsprandial,respec- strategy(67,68). tively)(93),andtheweightadvantagepersistedduringthe 2.2 In obese patients with T2DM requiring insulin 3-yeartrial(94). therapy,wesuggestaddingatleastoneofthefollowing: 2.3WerecommendACEinhibitors,ARBs,andcalcium metformin,pramlintide,orGLP-1agoniststomitigateas- channel blockers rather than (cid:3)-adrenergic blockers as sociatedweightgainduetoinsulin.Thefirst-lineinsulin first-linetherapyforhypertensioninpatientswithT2DM for this type of patient should be basal insulin. This is whoareobese.(1|QQQQ) preferable to using either insulin alone or insulin with a sulfonylurea. We also suggest that the insulin therapy Evidence strategybeconsideredapreferentialtrialofbasalinsulin Angiotensin is overexpressed in obesity, directly con- priortopremixedinsulinsorcombinationinsulintherapy. tributingtoobesity-relatedhypertension,providingsup- (2|QQQE) portfortheuseofanACEinhibitorasafirst-lineagent. Calcium channel blockers are also effective in the treat- Evidence ment of obesity-related hypertension and have not been Insulinremainsthemosteffectiveagenttocontrolse- associatedwithweightgainoradversechangesinlipids. rum glucose (81). However, multiple large studies typi- ACEinhibitorsandARBshavenotbeenassociatedwith callyshowweightgainassociatedwithinsulinuse,either weight gain or insulin resistance and provide renal pro- asmonotherapyorincombinationwithoralantidiabetic tectionindiabetes(95). agents(82–85).Treatmentwithbothmetforminandin- If required, selective or nonselective (cid:3)-blockers sulin,orwhenmetforminisprescribedinadditiontoan with a vasodilating component such as carvedilol and insulinprogram,yieldssimilarglycemicbenefittoinsulin nebivolol are recommended because these agents ap- alonewithoutexcessiveadditionalweightgain,asshown pear to have less weight gain potential and less of an bymeta-analysesandrandomizedtrials(86–88). impactonglucoseandlipidmetabolismthanothernon- Amylin analogs are FDA approved for use in combi- selective (cid:3)-blockers (96, 97). nation with existing insulin treatment. A dose-finding A study in patients taking metoprolol tartrate com- studywithpramlintideaddedtoavarietyofinsulinregimens pared with those taking carvedilol for hypertension showedweightloss((cid:5)1.4kg)intreatmentgroups(89),with showed a mean weight gain of 1.19 kg, suggesting that HbA1c reductions of 0.62 to 0.68% in the 120-(cid:5)g dose weightgainisnotaclasseffectofthe(cid:3)-adrenergicblock- group.Additionally,weightgainwaspreventedwhenpram- ers(98).Ameta-analysisofbodyweightchangesinaseries lintidewasaddedtothebasalinsulinsglargineordetemir. of randomized controlled hypertension trials of at least Other studies have found more substantial weight loss of 6-monthdurationshowedthatbodyweightwashigherin over3kgwiththeuseofpramlintide(90). the (cid:3)-blocker group, with a median difference of 1.2 kg Otherweight-sparingregimenshavebeenstudied,in- betweenthe(cid:3)-blockergroupandthecontrolgroup(97). cludingthecombinationofbasalinsulinwiththeweight- TheSecondAustralianNationalBloodPressureTrialre- ported slightly better cardiovascular outcomes in hyper- tensive men treated with a regimen that began with an Downloaded from https://academic.oup.com/jcem/article/100/2/342/2813109 by guest on 14 June 2026

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--- PAGE 14 --- doi:10.1210/jc.2014-3415 jcem.endojournals.org 355 making process that provides patients with quantitative tensive men treated with a regimen that began with an estimatesoftheexpectedweighteffectofthealternative ACE inhibitor compared with a regimen starting with a treatments to make an informed decision about drug diuretic(95). choice.(1|QQQE) 2.4Whenantidepressanttherapyisindicated,werec- Evidence ommendashareddecision-makingprocessthatprovides Although better tolerated than the older antipsychot- patientswithquantitativeestimatesoftheexpectedweight ics, many of the new atypical antipsychotic agents have effectoftheantidepressanttomakeaninformeddecision weight gain as a side effect (104). This weight gain is of aboutdrugchoice.Otherfactorsthatneedtobetakeninto clinical concern because it impedes patient compliance consideration include the expected length of treatment. (1|QQQE) andhasdeleterioushealthconsequences(104,105)inpa- tients who are often overweight or obese to begin with. Evidence Thedifferentialeffectofatypicalantipsychoticsonhista- Theantidepressantsvaryconsiderablywithrespectto mine(H1)receptors,anticholinergiceffects,andserotonin their long-term weight gain potential. Serretti and Man- type 2C antagonistic effects may explain differences in delli(99)evaluatedtherelativeriskofweightgainasso- weightgainamongthedrugs.Hendersonetal(106)dem- ciatedwithdrugswithinthemajorclassesofantidepres- onstratedthatweightgainassociatedwithclozapinetreat- santmedicationsinarecentmeta-analysis.Paroxetineis mentcontinuedforaslongas46monthsandwasaccom- considered to be the SSRI associated with the greatest paniedbyasignificantincreaseintriglyceridelevelsanda long-termincreaseinbodyweight(100),amitriptylineis 37% increase in the incidence of T2DM over the 5-year themostpotentinducerofweightgainamongthetricyclic period of observation. A randomized trial investigating antidepressants (99), and mirtazapine (a noradrenergic theeffectivenessoffiveantipsychoticmedicationsfound andspecificserotoninergicantidepressant)isalsoassoci- thataweightgainof(cid:3)7%frombaselineoccurredin30% atedwithweightgaininthelongterm(101).Otherspecific ofthosetakingolanzapine,16%forquetiapine,14%for tricyclics that have been associated with weight gain in- risperidone,12%forperphenazine,and7%ofthosetak- cludenortriptyline(102),whereastheeffectofimipramine ingziprasidone(107).AllisonandCasey(104)notedthat seems to be neutral (99). SSRIs such as fluoxetine and patients lost weight when switched from olanzapine to sertraline have been associated with weight loss during ziprasidone,andthisweightlosswasassociatedwithim- acutetreatment(4–12wk)andwithweightneutralityin provementsintheirserumlipidprofileandglucosetoler- themaintenance((cid:3)4mo)phase(99).Nosignificanteffect ance. In a 6-week, double-blind trial, patients were ran- couldbeobservedforcitalopramorescitalopramonbody domly assigned to receive ziprasidone (n (cid:4) 136) or weight(99).Amongtheserotoninandnorepinephrinere- olanzapine(n(cid:4)133).Bodyweightincreasedsignificantly uptake inhibitors, venlafaxine and duloxetine have been inthosetakingolanzapine(3.6kg)comparedwiththose reportedtoslightlyincreasebodyweightoverlong-term taking ziprasidone (1.0 kg) (108). A review of nine ran- treatment, although long-term data for venlafaxine are domized controlled trials comparing ziprasidone with scarce(99).Bupropionselectivelyinhibitsreuptakeofdo- amisulpride, clozapine, olanzapine, quetiapine, and ris- pamine and, to a lesser extent, norepinephrine. It is the peridone showed that ziprasidone produced less weight only antidepressant that consistently causes weight loss gainthanolanzapine(fiveRCTs;n(cid:4)1659;meandiffer- (103).Itwasoriginallyapprovedbothfortreatingdepres- ence,(cid:5)3.82;95%CI,(cid:5)4.69to(cid:5)2.96),quetiapine(two sionandforinducingsmokingcessation.Duringclinical randomized controlled trials [RCTs]; n (cid:4) 754; relative trials,itsuppressedappetiteandfoodcravingsandsignif- risk, 0.45; 95% CI, 0.28 to 0.74), or risperidone (three icantly decreased body weight (103). The commissioned RCTs; n (cid:4) 1063; relative risk, 0.49; 95% CI, 0.33 to systematic review accompanying this guideline (3) was 0.74). Ziprasidone was also associated with less choles- only able to demonstrate weight gain with amitriptyline terol increase than olanzapine, quetiapine, and risperi- (1.8 kg) and mirtazapine (1.5 kg) and weight loss with done(109).Finally,areviewof34trialsofantipsychotics bupropion ((cid:5)1.3 kg) and fluoxetine ((cid:5)1.3 kg). The evi- inyouthwithpsychoticandbipolardisordersfoundthat denceforweightchangeswithotherantidepressantswas weightgainrangedfrom3.8to16.2kgwitholanzapine, oflowerquality. 0.9 to 9.5 kg with clozapine, 1.9 to 7.2 kg with risperi- 2.5Werecommendusingweight-neutralantipsychotic done,2.3to6.1kgwithquetiapine,and0to4.4kgwith alternatives when clinically indicated, rather than those aripiprazole(110).Despitethevariableeffectsonweight thatcauseweightgain,andtheuseofashareddecision- gain among the antipsychotic agents, the prediabetes ef- Downloaded from https://academic.oup.com/jcem/article/100/2/342/2813109 by guest on 14 June 2026

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--- PAGE 15 --- 356 Apovianetal GuidelinesonPharmacologicalManagementofObesity JClinEndocrinolMetab,February2015,100(2):342–362 fect may be similar via weight-independent mechanisms conducted so far are difficult to compare because of the (111). differentformulationsofcontraceptivescontainingvari- able doses of estrogens, and with the progestins having 2.6Werecommendconsideringweightgainpotential different androgenic/antiandrogenic profiles. Moreover, inchoosinganAEDforanygivenpatient,andtheuseof randomized controlled trials comparing hormonal con- a shared decision-making process that provides patients traceptive methods with a placebo usually raise ethical withquantitativeestimatesoftheexpectedweighteffectof thedrugstomakeaninformeddecisionaboutdrugchoice. issues.AsrecentlydocumentedbyGalloetal(118),only (1|QQQE) four trials included a placebo group or no intervention group, and no evidence has been found to support the Evidence associationbetweencombination(estrogenplusaproges- AEDsassociatedwithweightlossarefelbamate,topi- tin) hormonal contraception and weight change. In ramate, and zonisamide. AEDs associated with weight addition,thesameauthors,byexamining79trialsofcom- gainaregabapentin,pregabalin,valproicacid,vigabatrin, bination contraceptives, concluded that no substantial and carbamazepine. Weight-neutral AEDs are lam- differenceinweightcouldbefound.Moreover,discon- otrigine,levetiracetam,andphenytoin.Inclinicalpractice, tinuation of combination contraceptives because of itiscriticaltoweighpatientsregularly,andAEDselection weightchangedidnotdifferbetweengroupswherethis should be based on each patient’s profile without sacri- was studied (118). ficingtherapeuticefficacy(112). There is limited evidence of weight gain when using Valproic acid hasbeenshowntocauseweightgainin progestin-onlycontraceptives.Meangainwaslessthan2 both adults and children (113). A retrospective study of kg for most studies up to 12 months (119). However, it long-term weight gain in adult epileptic patients on val- shouldbenotedthatmostofthetrialswereconductedin proic acid mono- or polytherapy showed that mild-to- normal-weightwomenandexcludedobesesubjects. moderateweightgain(5to10%ofbaselineweight)was shown in 24% of patients, whereas marked weight gain Remarks ((cid:3)10% gain of baseline weight) was shown in 47% of Selected studies have reported an increase in contra- patients(114).Astudyofpatientstakinggabapentinfor ceptivefailureinwomenwithaBMI(cid:3)27kg/m2.Dataon 12 months or more showed that of 44 patients, 57% thisissueareconflictingbutshouldbediscussedwiththe gained more than 5% of their baseline body weight; of appropriatepatientsonanindividualbasis. these,10patients(23%)gainedmorethan10%oftheir baseline weight (115). Our commissioned systematic re- 2.8 We suggest monitoring the weight and waist cir- view (3) suggested weight gain with gabapentin (2.2 kg cumference of patients on antiretroviral therapy due to after1.5moofuse)anddivalproex(relativeriskforweight unavoidable weight gain, weight redistribution, and as- gain,2.8;95%CI,1.30,6.02).Carbamazepineisanolder sociatedcardiovascularrisk.(2|QQQE) AED and has also been associated with weight gain, al- though not as significant as valproic acid or gabapentin Evidence (116). A study of 66 patients taking AEDs showed that Treatments for human immunodeficiency disease in- 66.7%ofthoseoncarbamazepinehadgainedanaverage include administration of antiretroviral therapy and pro- of1.5kgata6-to8-monthfollow-upvisit(117). tease inhibitors. Although effective for suppressing HIV 2.7InwomenwithaBMI(cid:3)27kg/m2withcomorbidi- viralactivity,whichshouldbeassociatedwithappropriate tiesorBMI(cid:3)30kg/m2seekingcontraception,wesuggest weightg

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