Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis | Lifestyle Behaviors | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.170.64.36. Please contact the publisher to request reinstatement.
1.
Ng  M, Fleming  T, Robinson  M,  et al.  Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.  Lancet. 2014;384(9945):766-781.PubMedGoogle ScholarCrossref
2.
Yanovski  SZ, Yanovski  JA.  Long-term drug treatment for obesity: a systematic and clinical review.  JAMA. 2014;311(1):74-86.PubMedGoogle ScholarCrossref
3.
US Food and Drug Administration. FDA-approved drug products: Contrave. 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf. Accessed April 26, 2016.
4.
US Food and Drug Administration. FDA-approved drug products: Saxenda. 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206321s001lbl.pdf. Accessed April 26, 2016.
5.
Hutton  B, Salanti  G, Caldwell  DM,  et al.  The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.  Ann Intern Med. 2015;162(11):777-784.PubMedGoogle ScholarCrossref
6.
Khera  R, Singh  S, Chandar  A,  et al. Comparative effectiveness of weight loss medications: a systematic review and network meta-analysis. 2015. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015026114. Accessed October 10, 2015.
7.
Hoaglin  DC, Hawkins  N, Jansen  JP,  et al.  Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2.  Value Health. 2011;14(4):429-437.PubMedGoogle ScholarCrossref
8.
Puhan  MA, Schünemann  HJ, Murad  MH,  et al; GRADE Working Group.  A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis.  BMJ. 2014;349:g5630.PubMedGoogle ScholarCrossref
9.
Higgins  JP, Altman  DG, Gøtzsche  PC,  et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.  BMJ. 2011;343:d5928.PubMedGoogle ScholarCrossref
10.
Center for Drug Evaluation and Research. Guidance for Industry Developing Products for Weight Management. February 2007. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm071612.pdf. Accessed December 15, 2015.
11.
Jensen  MD, Ryan  DH, Apovian  CM,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society.  2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society.  Circulation. 2014;129(25)(suppl 2):S102-S138.PubMedGoogle ScholarCrossref
12.
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188.PubMedGoogle ScholarCrossref
13.
Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560.PubMedGoogle ScholarCrossref
14.
Hartung  J, Knapp  G.  A refined method for the meta-analysis of controlled clinical trials with binary outcome.  Stat Med. 2001;20(24):3875-3889.PubMedGoogle ScholarCrossref
15.
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634.PubMedGoogle ScholarCrossref
16.
Chaimani  A, Higgins  JP, Mavridis  D, Spyridonos  P, Salanti  G.  Graphical tools for network meta-analysis in STATA.  PLoS One. 2013;8(10):e76654.PubMedGoogle ScholarCrossref
17.
Lu  G, Ades  AE.  Combination of direct and indirect evidence in mixed treatment comparisons.  Stat Med. 2004;23(20):3105-3124.PubMedGoogle ScholarCrossref
18.
Dias  S, Sutton  AJ, Ades  AE, Welton  NJ.  Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials.  Med Decis Making. 2013;33(5):607-617.PubMedGoogle ScholarCrossref
19.
Salanti  G, Ades  AE, Ioannidis  JP.  Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial.  J Clin Epidemiol. 2011;64(2):163-171.PubMedGoogle ScholarCrossref
20.
Higgins  JPTGS. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. March 2011. http://handbook.cochrane.org/chapter_12/12_5_4_3_computing_absolute_risk_reduction_or_nnt_from_an_odds.htm. Accessed March 24, 2016.
21.
White  IR.  Multivariate random-effects meta-regression: updates to mvmeta.  Stata J. 2011;11(2):255.Google Scholar
22.
Bakris  G, Calhoun  D, Egan  B, Hellmann  C, Dolker  M, Kingma  I; Orlistat and Resistant Hypertension Investigators.  Orlistat improves blood pressure control in obese subjects with treated but inadequately controlled hypertension.  J Hypertens. 2002;20(11):2257-2267.PubMedGoogle ScholarCrossref
23.
Berne  C; Orlistat Swedish Type 2 diabetes Study Group.  A randomized study of orlistat in combination with a weight management programme in obese patients with type 2 diabetes treated with metformin.  Diabet Med. 2005;22(5):612-618.PubMedGoogle ScholarCrossref
24.
Broom  I, Wilding  J, Stott  P, Myers  N; UK Multimorbidity Study Group.  Randomised trial of the effect of orlistat on body weight and cardiovascular disease risk profile in obese patients: UK Multimorbidity Study.  Int J Clin Pract. 2002;56(7):494-499.PubMedGoogle Scholar
25.
Davidson  MH, Hauptman  J, DiGirolamo  M,  et al.  Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial.  JAMA. 1999;281(3):235-242.PubMedGoogle ScholarCrossref
26.
Finer  N, James  WP, Kopelman  PG, Lean  ME, Williams  G.  One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor.  Int J Obes Relat Metab Disord. 2000;24(3):306-313.PubMedGoogle ScholarCrossref
27.
Hanefeld  M, Sachse  G.  The effects of orlistat on body weight and glycaemic control in overweight patients with type 2 diabetes: a randomized, placebo-controlled trial.  Diabetes Obes Metab. 2002;4(6):415-423.PubMedGoogle ScholarCrossref
28.
Hauptman  J, Lucas  C, Boldrin  MN, Collins  H, Segal  KR.  Orlistat in the long-term treatment of obesity in primary care settings.  Arch Fam Med. 2000;9(2):160-167.PubMedGoogle ScholarCrossref
29.
Hollander  PA, Elbein  SC, Hirsch  IB,  et al.  Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study.  Diabetes Care. 1998;21(8):1288-1294.PubMedGoogle ScholarCrossref
30.
Kelley  DE, Bray  GA, Pi-Sunyer  FX,  et al.  Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: a 1-year randomized controlled trial.  Diabetes Care. 2002;25(6):1033-1041.PubMedGoogle ScholarCrossref
31.
Krempf  M, Louvet  JP, Allanic  H, Miloradovich  T, Joubert  JM, Attali  JR.  Weight reduction and long-term maintenance after 18 months treatment with orlistat for obesity.  Int J Obes Relat Metab Disord. 2003;27(5):591-597.PubMedGoogle ScholarCrossref
32.
Lindgärde  F.  The effect of orlistat on body weight and coronary heart disease risk profile in obese patients: the Swedish Multimorbidity Study.  J Intern Med. 2000;248(3):245-254.PubMedGoogle ScholarCrossref
33.
Miles  JM, Leiter  L, Hollander  P,  et al.  Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin.  Diabetes Care. 2002;25(7):1123-1128.PubMedGoogle ScholarCrossref
34.
Rössner  S, Sjöström  L, Noack  R, Meinders  AE, Noseda  G; European Orlistat Obesity Study Group.  Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity.  Obes Res. 2000;8(1):49-61.PubMedGoogle ScholarCrossref
35.
Sjöström  L, Rissanen  A, Andersen  T,  et al; European Multicentre Orlistat Study Group.  Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients.  Lancet. 1998;352(9123):167-172.PubMedGoogle ScholarCrossref
36.
Swinburn  BA, Carey  D, Hills  AP,  et al.  Effect of orlistat on cardiovascular disease risk in obese adults.  Diabetes Obes Metab. 2005;7(3):254-262.PubMedGoogle ScholarCrossref
37.
Torgerson  JS, Hauptman  J, Boldrin  MN, Sjöström  L.  Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.  Diabetes Care. 2004;27(1):155-161.PubMedGoogle ScholarCrossref
38.
Fidler  MC, Sanchez  M, Raether  B,  et al; BLOSSOM Clinical Trial Group.  A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial.  J Clin Endocrinol Metab. 2011;96(10):3067-3077.PubMedGoogle ScholarCrossref
39.
O’Neil  PM, Smith  SR, Weissman  NJ,  et al.  Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study.  Obesity (Silver Spring). 2012;20(7):1426-1436.PubMedGoogle ScholarCrossref
40.
Smith  SR, Weissman  NJ, Anderson  CM,  et al; Behavioral Modification and Lorcaserin for Overweight and Obesity Management Study Group.  Multicenter, placebo-controlled trial of lorcaserin for weight management.  N Engl J Med. 2010;363(3):245-256.PubMedGoogle ScholarCrossref
41.
Apovian  CM, Aronne  L, Rubino  D,  et al; COR-II Study Group.  A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II).  Obesity (Silver Spring). 2013;21(5):935-943.PubMedGoogle ScholarCrossref
42.
Greenway  FL, Fujioka  K, Plodkowski  RA,  et al; COR-I Study Group.  Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.  Lancet. 2010;376(9741):595-605.PubMedGoogle ScholarCrossref
43.
Hollander  P, Gupta  AK, Plodkowski  R,  et al; COR-Diabetes Study Group.  Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes.  Diabetes Care. 2013;36(12):4022-4029.PubMedGoogle ScholarCrossref
44.
Wadden  TA, Volger  S, Sarwer  DB,  et al.  A two-year randomized trial of obesity treatment in primary care practice.  N Engl J Med. 2011;365(21):1969-1979.PubMedGoogle ScholarCrossref
45.
Allison  DB, Gadde  KM, Garvey  WT,  et al.  Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP).  Obesity (Silver Spring). 2012;20(2):330-342.PubMedGoogle ScholarCrossref
46.
Gadde  KM, Allison  DB, Ryan  DH,  et al.  Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.  Lancet. 2011;377(9774):1341-1352.PubMedGoogle ScholarCrossref
47.
Davies  MJ, Bergenstal  R, Bode  B,  et al; NN8022-1922 Study Group.  Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial.  JAMA. 2015;314(7):687-699.PubMedGoogle ScholarCrossref
48.
Pi-Sunyer  X, Astrup  A, Fujioka  K,  et al; SCALE Obesity and Prediabetes NN8022-1839 Study Group.  A randomized, controlled trial of 3.0 mg of liraglutide in weight management.  N Engl J Med. 2015;373(1):11-22.PubMedGoogle ScholarCrossref
49.
Astrup  A, Carraro  R, Finer  N,  et al; NN8022-1807 Investigators.  Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.  Int J Obes (Lond). 2012;36(6):843-854.PubMedGoogle ScholarCrossref
50.
Gelman  A, Rubin  DB.  Inference from iterative simulation using multiple sequences.  Stat Sci. 1992;7(4):457-472.Google ScholarCrossref
51.
US Preventive Services Task Force.  Screening for obesity in adults: recommendations and rationale.  Ann Intern Med. 2003;139(11):930-932.PubMedGoogle ScholarCrossref
52.
Apovian  CM, Aronne  LJ, Bessesen  DH,  et al; Endocrine Society.  Pharmacological management of obesity: an endocrine Society clinical practice guideline.  J Clin Endocrinol Metab. 2015;100(2):342-362.PubMedGoogle ScholarCrossref
53.
Camilleri  M, Acosta  A.  Gastrointestinal traits: individualizing therapy for obesity with drugs and devices.  Gastrointest Endosc. 2016;83(1):48-56.PubMedGoogle ScholarCrossref
54.
Daubresse  M, Alexander  GC.  The uphill battle facing antiobesity drugs.  Int J Obes (Lond). 2015;39(3):377-378.PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    June 14, 2016

    Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City
    • 2Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
    • 3Division of Preventive Medicine, Mayo Clinic, Rochester, Minnesota
    • 4Division of Gastroenterology and Liver Diseases, Case Western Reserve University, Cleveland, Ohio
    • 5Division of Gastroenterology, University of California, San Diego, La Jolla
    • 6Department of Library Services, Mayo Clinic, Rochester, Minnesota
    • 7Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota
    • 8Division of Biomedical Informatics, University of California, San Diego, La Jolla
    JAMA. 2016;315(22):2424-2434. doi:10.1001/jama.2016.7602
    Abstract

    Importance  Five medications have been approved for the management of obesity, but data on comparative effectiveness are limited.

    Objective  To compare weight loss and adverse events among drug treatments for obesity using a systematic review and network meta-analysis.

    Data Sources  MEDLINE, EMBASE, Web of Science, Scopus, and Cochrane Central from inception to March 23, 2016; clinical trial registries.

    Study Selection  Randomized clinical trials conducted among overweight and obese adults treated with US Food and Drug Administration–approved long-term weight loss agents (orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, or liraglutide) for at least 1 year compared with another active agent or placebo.

    Data Extraction and Synthesis  Two investigators identified studies and independently abstracted data using a predefined protocol. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities. Quality of evidence was assessed using GRADE criteria.

    Main Outcomes and Measures  Proportions of patients with at least 5% weight loss and at least 10% weight loss, magnitude of decrease in weight, and discontinuation of therapy because of adverse events at 1 year.

    Results  Twenty-eight randomized clinical trials with 29 018 patients (median age, 46 years; 74% women; median baseline body weight, 100.5 kg; median baseline body mass index, 36.1) were included. A median 23% of placebo participants had at least 5% weight loss vs 75% of participants taking phentermine-topiramate (odds ratio [OR], 9.22; 95% credible interval [CrI], 6.63-12.85; SUCRA, 0.95), 63% of participants taking liraglutide (OR, 5.54; 95% CrI, 4.16-7.78; SUCRA, 0.83), 55% taking naltrexone-bupropion (OR, 3.96; 95% CrI, 3.03-5.11; SUCRA, 0.60), 49% taking lorcaserin (OR, 3.10; 95% CrI, 2.38-4.05; SUCRA, 0.39), and 44% taking orlistat (OR, 2.70; 95% CrI, 2.34-3.09; SUCRA, 0.22). All active agents were associated with significant excess weight loss compared with placebo at 1 year—phentermine-topiramate, 8.8 kg (95% CrI, −10.20 to −7.42 kg); liraglutide, 5.3 kg (95% CrI, −6.06 to −4.52 kg); naltrexone-bupropion, 5.0 kg (95% CrI, −5.94 to −3.96 kg); lorcaserin, 3.2 kg (95% CrI, −3.97 to −2.46 kg); and orlistat, 2.6 kg (95% CrI, −3.04 to −2.16 kg). Compared with placebo, liraglutide (OR, 2.95; 95% CrI, 2.11-4.23) and naltrexone-bupropion (OR, 2.64; 95% CrI, 2.10-3.35) were associated with the highest odds of adverse event–related treatment discontinuation. High attrition rates (30%-45% in all trials) were associated with lower confidence in estimates.

    Conclusions and Relevance  Among overweight or obese adults, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide, compared with placebo, were each associated with achieving at least 5% weight loss at 52 weeks. Phentermine-topiramate and liraglutide were associated with the highest odds of achieving at least 5% weight loss.

    ×