Transcript
Pharmacological Management of Obesity: AnEndocrine Society Clinical Practice Guideline Caroline M. Apovian, Louis J. Aronne, Daniel H. Bessesen, Marie E. McDonnell,M. Hassan Murad, Uberto Pagotto, Donna H. Ryan,and Christopher D. Still Boston University School of Medicine and Boston Medical Center (C.M.A.), Boston, Massachusetts02118; Weill-Cornell Medical College (L.J.A.), New York, New York 10065; Denver Health MedicalCenter (D.H.B.), Denver, Colorado 80204; Brigham and Women’s Hospital (M.E.M.), Boston,Massachusetts 02115; Mayo Clinic, Division of Preventative Medicine (M.H.M.), Rochester, Minnesota55905; Alma Mater University of Bologna (U.P.), S. Orsola-Malpighi Hospital Endocrinology Unit, 40138Bologna, Italy; Pennington Biomedical Research Center (D.H.R.), Baton Rouge, Louisiana 70808; andGeisinger Health Care System (C.D.S.), Danville, Pennsylvania 17822 Objective: To formulate clinical practice guidelines for the pharmacological management ofobesity. Participants: An Endocrine Society-appointed Task Force of experts, a methodologist, and a med-ical writer. This guideline was co-sponsored by the European Society of Endocrinology and TheObesity Society. Evidence: This evidence-based guideline was developed using the Grading of Recommendations,Assessment,Development,andEvaluation(GRADE)systemtodescribethestrengthofrecommen-dations and the quality of evidence. ConsensusProcess: Onegroupmeeting,severalconferencecalls,ande-mailcommunicationsenabledconsensus.CommitteesandmembersoftheEndocrineSociety,theEuropeanSocietyofEndocrinology,and The Obesity Society reviewed and commented on preliminary drafts of these guidelines. Twosystematic reviews were conducted to summarize some of the supporting evidence. Conclusions: Weightlossisapathwaytohealthimprovementforpatientswithobesity-associatedriskfactors and comorbidities. Medications approved for chronic weight management can be useful ad- junctstolifestylechangeforpatientswhohavebeenunsuccessfulwithdietandexercisealone.Manymedications commonly prescribed for diabetes, depression, and other chronic diseases have weighteffects, either to promote weight gain or produce weight loss. Knowledgeable prescribing of medi-cations, choosing whenever possible those with favorable weight profiles, can aid in the preventionand management of obesity and thus improve health. ( J Clin Endocrinol Metab 100: 342–362, 2015) Summary of Recommendations 1.0 Care of the patient who is overweight orobese 1.1 We recommend that diet, exercise, and behavioralmodification be included in all obesity management ap-proachesforbodymassindex(BMI) 25kg/m 2 andthatother tools such as pharmacotherapy (BMI 27 kg/m 2 with comorbidity or BMI over 30 kg/m 2 ) and bariatricsurgery (BMI 35 kg/m 2 with comorbidity or BMI over40 kg/m 2 ) be used as adjuncts to behavioral modification ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2015 by the Endocrine SocietyReceived September 3, 2014. Accepted December 8, 2014.First Published Online January 15, 2015 For article see page 363 Abbreviations:ACE,angiotensin-convertingenzyme;AED,antiepilepticdrug;ARB,angioten-sin receptor blocker; BID, twice a day; BMI, body mass index; BP, blood pressure; CCK, cho-lecystokinin; CI, confidence interval; DPP-4, dipeptidyl peptidase IV; ER, extended release;GLP-1, glucagon-like peptide-1; H1, histamine; HbA1c, glycated hemoglobin; POMC, pro-opiomelanocortin; PYY, peptide YY; QD, every day; RCT, randomized controlled trial; SC,subcutaneous; SGLT, sodium-glucose-linked transporter; SNRI, serotonin-norepinephrine re-uptakeinhibitor;SSRI,selectiveserotoninreuptakeinhibitor;T2DM,type2diabetes;TID,threetimes a day. S P E C I A L F E A T U R EC l i n i c a l P r a c t i c e G u i d e l i n e 342 jcem.endojournals.org J Clin Endocrinol Metab, February 2015, 100(2):342–362 doi: 10.1210/jc.2014-3415 to reduce food intake and increase physical activity whenthisispossible.Drugsmayamplifyadherencetobehaviorchange and may improve physical functioning such thatincreased physical activity is easier in those who cannotexerciseinitially.Patientswhohaveahistoryofbeingun-able to successfully lose and maintain weight and whomeetlabelindicationsarecandidatesforweightlossmed-ications. (1| QQQQ )1.2Inordertopromotelong-termweightmaintenance,we suggest the use of approved 1 weight loss medication(over no pharmacological therapy) to ameliorate comor-biditiesandamplifyadherencetobehaviorchanges,whichmay improve physical functioning and allow for greaterphysicalactivityinindividualswithaBMI 30kg/m 2 orin individuals with a BMI of 27 kg/m 2 and at least oneassociated comorbid medical condition such as hyperten-sion,dyslipidemia,type2diabetes(T2DM),andobstruc-tive sleep apnea. (2| QQEE )1.3Inpatientswithuncontrolledhypertensionorahis-tory of heart disease, we recommend against using thesympathomimetic agents phentermine and diethylpro-pion. (1| QQQE )1.4 We suggest assessment of efficacy and safety atleast monthly for the first 3 months, then at least every3 months in all patients prescribed weight loss medica-tions. (2| QQEE )1.5 If a patient’s response to a weight loss medicationis deemed effective (weight loss 5% of body weight at3 mo) and safe, we recommend that the medication becontinued. If deemed ineffective (weight loss 5% at 3mo)oriftherearesafetyortolerabilityissuesatanytime,we recommend that the medication be discontinued andalternative medications or referral for alternative treat-ment approaches be considered. (1| QQQQ )1.6 If medication for chronic obesity management isprescribed as adjunctive therapy to comprehensive life-styleintervention,wesuggestinitiatingtherapywithdoseescalationbasedonefficacyandtolerabilitytotherecom-mended dose and not exceeding the upper approved doseboundaries. (2| QQEE )1.7 In patients with T2DM who are overweight orobese,wesuggesttheuseofantidiabeticmedicationsthathave additional actions to promote weight loss (such asglucagon-like peptide-1 [GLP-1] analogs or sodium-glu-cose-linked transporter-2 [SGLT-2] inhibitors), in addi-tion to the first-line agent for T2DM and obesity, met-formin. (2| QQQE )1.8 In patients with cardiovascular disease who seekpharmacologicaltreatmentforweightloss,wesuggestus-ing medications that are not sympathomimetics such aslorcaserin and/or orlistat. (2| QEEE ) 2.0 Drugs that cause weight gain and somealternatives 2.1 We recommend weight-losing and weight-neutralmedications as first- and second-line agents in the man-agement of a patient with T2DM who is overweight orobese.Cliniciansshoulddiscusspossibleweighteffectsof glucose-lowering medications with patients and considerthe use of antihyperglycemic medications that are weightneutral or promote weight loss. (1| QQQE )2.2 In obese patients with T2DM requiring insulintherapy,wesuggestaddingatleastoneofthefollowing:metformin, pramlintide, or GLP-1 agonists to mitigateassociated weight gain due to insulin. The first-line in-sulinforthistypeofpatientshouldbebasalinsulin.Thisispreferabletousingeitherinsulinaloneorinsulinwithsulfonylurea. We also suggest that the insulin therapystrategy be considered a preferential trial of basal in-sulin prior to premixed insulins or combination insulintherapy. (2| QQQE )2.3 We recommend angiotensin-converting enzyme(ACE) inhibitors, angiotensin receptor blockers (ARBs),and calcium channel blockers rather than -adrenergicblockers as first-line therapy for hypertension in patientswith T2DM who are obese. (1| QQQQ )2.4 When antidepressant therapy is indicated, we rec-ommend a shared decision-making process that providespatientswithquantitativeestimatesoftheexpectedweighteffect of the antidepressant to make an informed decisionaboutdrugchoice.Otherfactorsthatneedtobetakenintoconsideration include the expected length of treatment.(1| QQQE )2.5Werecommendusingweight-neutralantipsychoticalternatives when clinically indicated, rather than thosethat cause weight gain, and the use of a shared decision-making process that provides patients with quantitativeestimates of the expected weight effect of the alternativetreatments to make an informed decision about drugchoice. (1| QQQE )2.6 We recommend considering weight gain potentialin choosing an antiepileptic drug (AED) for any given pa-tient,andtheuseofashareddecision-makingprocessthatprovides patients with quantitative estimates of the ex-pected weight effect of the drugs to make an informeddecision about drug choice. (1| QQQE )2.7InwomenwithaBMI 27kg/m 2 withcomorbidi-tiesorBMI 30kg/m 2 seekingcontraception,wesuggestoral contraceptives over injectable medications due to 1 ApprovalintheUnitedStatesisbasedonFDAdetermination.ApprovalinEuropeisbasedon EMA determination. doi: 10.1210/jc.2014-3415 jcem.endojournals.org 343 weight gain with injectables, provided that women arewell-informed about the risks and benefits (ie, oral con-traceptives are not contraindicated). (2| QEEE )2.8 We suggest monitoring the weight and waist cir-cumference of patients on antiretroviral therapy due tounavoidable weight gain, weight redistribution, and as-sociated cardiovascular risk. (2| QQQE )2.9 We suggest the use of nonsteroidal anti-inflamma-tory drugs and disease-modifying antirheumatic drugswhen possible in patients with chronic inflammatory dis-ease like rheumatoid arthritis because corticosteroidscommonly produce weight gain. (2| QQQE )2.10 We suggest the use of antihistamines with lesscentral nervous system activity (less sedation) to limitweight gain. (2| QQEE ) 3.0 Off-label use of drugs approved for otherindications for chronic obesity management 3.1 We suggest against the off-label use of medica-tions approved for other disease states for the sole pur-pose of producing weight loss. A trial of such therapycan be attempted in the context of research and byhealthcare providers with expertise in weight manage-ment dealing with a well-informed patient. (UngradedBest Practice Recommendation) Method of Development of Evidence-Based Clinical Practice Guidelines T heClinicalGuidelinesSubcommittee(CGS)oftheEn-docrine Society deemed the pharmacological man-agement of obesity a priority area in need of practiceguidelines and appointed a Task Force to formulate evi-dence-based recommendations. The Task Force followedthe approach recommended by the Grading of Recom-mendations, Assessment, Development, and Evaluation(GRADE)group,aninternationalgroupwithexpertiseinthe development and implementation of evidence-basedguidelines (1). A detailed description of the gradingschemehasbeenpublishedelsewhere(2).TheTaskForceused the best available research evidence to develop therecommendations. The Task Force also used consistentlanguage and graphical descriptions of both the strengthofarecommendationandthequalityofevidence.Intermsofthestrengthoftherecommendation,strongrecommen-dations use the phrase “we recommend” and the number1, and weak recommendations use the phrase “we sug-gest” and the number 2. Cross-filled circles indicatethe quality of the evidence, such that QEEE denotes verylow quality evidence; QQEE , low quality; QQQE , mod-erate quality; and QQQQ , high quality. The Task Forcehasconfidencethatpersonswhoreceivecareaccordingtothestrongrecommendationswillderive,onaverage,moregood than harm. Weak recommendations require morecareful consideration of the person’s circumstances, val-ues,andpreferencestodeterminethebestcourseofaction.Linked to each recommendation is a description of the evidence and the values that panelists considered in mak-ing the recommendation; in some instances, there are re-marks, asectioninwhichpanelistsoffertechnicalsugges-tions for testing conditions, dosing, and monitoring.These technical comments reflect the best available evi-denceappliedtoatypicalpersonbeingtreated.Oftenthisevidencecomesfromtheunsystematicobservationsofthepanelistsandtheirvaluesandpreferences;therefore,theseremarks should be considered suggestions.The Endocrine Society maintains a rigorous conflict-of-interest review process for the development of clinicalpracticeguidelines.AllTaskForcemembersmustdeclareany potential conflicts of interest, which are reviewed be-fore they are approved to serve on the Task Force andperiodicallyduringthedevelopmentoftheguideline.Theconflict-of-interestformsarevettedbytheCGSbeforethemembers are approved by the Society’s Council to partic-ipate on the guideline Task Force. Participants in theguidelinedevelopmentmustincludeamajorityofindivid-ualswithoutconflictsofinterestinthematterunderstudy.Participants with conflicts of interest may participate inthe development of the guideline, but they must have dis-closed all conflicts. The CGS and the Task Force havereviewed all disclosures for this guideline and resolved ormanaged all identified conflicts of interest.Conflicts of interest are defined as remuneration in anyamountfromthecommercialinterest(s)intheformofgrants;researchsupport;consultingfees;salary;ownershipinterest(eg, stocks, stock options, or ownership interest excludingdiversified mutual funds); honoraria or other payments forparticipation in speakers’ bureaus, advisory boards, orboards of directors; or other financial benefits. Completedforms are available through the Endocrine Society office.Funding for this guideline was derived solely from theEndocrineSociety,andthustheTaskForcereceivednofund-ing or remuneration from commercial or other entities.A systematic review was commissioned by the Endo-crine Society to quantify weight gain and weight loss as-sociatedwithadiscretelistofdrugschosenaprioribythisguidelineTaskForce(3).Thesystematicreviewcompareda list of 54 commonly used drugs chosen a priori by theTask Force (drugs suspected of having weight implica-tions)thatwerecomparedtoplaceboinrandomizedcon-trolled trials. For trials to be included, the length of treat-menthadtobe 30days.Theoutcomeofinterestforthereview was weight change (expressed in absolute and rel- 344 Apovian et al Guidelines on Pharmacological Management of Obesity J Clin Endocrinol Metab, February 2015, 100(2):342–362 ative terms). The Task Force also used evidence derivedfrom existing systematic reviews, randomized trials, andobservational studies on the management of medicationsfor other conditions that may result in weight gain. Eco-nomic analyses and cost effectiveness studies were not re-viewedorconsideredasabasisfortherecommendations.Drugs associated with weight gain and suggested alterna-tives are presented in Supplemental Table 1.In several of the recommendations, we used evidencederivedfromrandomizedclinicaltrialsaboutthebenefitsofshareddecisionmakingintermsofimprovingpatients’knowledge, reducing decisional conflict and regret, andenhancing the likelihood of patients making decisionsconsistent with their own values (4). Although there isabundantevidenceforthevalueofshareddecisionmakingacrossseveralclinicalscenarios,specificevidenceforobe-sity management is scant. This highlights a limitation of the existing literature and poses a challenge for imple-menting a specific strategy for shared decision making inmanaging obesity. Medical management of the disease of obesity The Task Force agrees with the opinion of prominentmedical societies that current scientific evidence supportsthe view that obesity is a disease (5).Weightlossproducesmanybenefitsincludingriskfac-tor improvement, prevention of disease, and improve-ments in feeling and function. Greater weight loss pro-ducesgreaterbenefits,butmodest(5to10%)weightloss,suchasthatproducedbylifestylemodificationsandmed-ications, has been shown to produce significant improve-ments in many conditions (5, 6).Medications used for the management of conditionsotherthanobesitycancontributetoorexacerbateweightgain in susceptible individuals. Many of these conditionsarealsoassociatedwithobesity.Healthcareproviderscanhelp patients prevent or attenuate weight gain by appro-priately prescribing medications that would promoteweight loss or minimize weight gain when treating theseconditions. Healthcare providers can help selected pa-tients successfully lose weight by appropriately prescrib-ing weight loss medications or in some cases surgical in-tervention as an adjunct to lifestyle change.This guideline will target how providers can use med-ications as an adjunct to lifestyle change therapy to pro-mote weight loss and maintenance. It will also addresshow prescribers can prevent or attenuate weight gainwhen prescribing for diabetes, depression, and chronicdiseases often associated with obesity. The evidence re-viewaddressesmedicationswithaweightlossindication,as well as those medications that affect weight when pre-scribed for a nonobesity indication, ie, that have been as-sociated with significant weight gain and increase in riskof comorbidities or with weight loss. Clinical encounter with the patient who isoverweight or obese There are a number of steps a clinician should take inthe clinical encounter. ã Annual and symptom-based screening for majorchronic conditions associated with obesity in all adultpatientswithaBMIof30kg/m 2 orabove.TheseincludeT2DM,cardiovasculardisease,hypertension,hyperlip-idemia,obstructivesleepapnea,nonalcoholicfattyliverdisease, osteoarthritis, and major depression. ã Timely adherence to national cancer screening guide-lines with the understanding that individuals who areobese are at increased risk for many malignancies (7). ã Identification of contributing factors, including familyhistory,sleepdisorders,disorderedeating,genetics,andenvironmental or socioeconomic causes. ã Identificationofandappropriatescreeningforsecond-ary causes of obesity (Table 1). These need not be au-tomaticallyscreenedforunlessthehistoryand/orphys-ical examination suggests the diagnosis or suspicion of the diagnosis. ã Adherence to the AHA/ACC/TOS Guideline for theManagementofOverweightandObesityinAdults(8),which was updated in 2013 and includes recommen-dations for assessment and treatment with diet and ex-ercise, as well as bariatric surgery for appropriatecandidates. ã Identification of medications that contribute to weightgain. Prescribe drugs that are weight neutral or thatpromote weight loss when possible. ã Formulationofatreatmentplanbasedondiet,exercise,and behavior modifications as above. Rationale for pharmacological treatment ofobesity The challenge of weight reduction Ifpermanentweightlosscouldbeachievedexclusivelywithbehavioralreductionsinfoodintakeandincreasesinenergyexpenditure,medicationsforobesitywouldnotbeneeded. Weight loss is difficult for most patients, and thepatient’s desire to restrict food and energy intake is coun-teracted by adaptive biological responses to weight loss(9–12). The fall in energy expenditure (out of proportiontoreductioninbodymass)andincreaseinappetitethatareobserved after weight loss are associated with changes ina range of hormones (12–14). Some of these changes rep-resent adaptive responses to weight loss and result in al- doi: 10.1210/jc.2014-3415 jcem.endojournals.org 345
