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. 2016 Jun 14;315(22):2424-34.
doi: 10.1001/jama.2016.7602.

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

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

Rohan Khera et al. JAMA. .
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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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Loomba reports research funded by the National Institutes of Health, National Science Foundation, and AGA-RSA; funding from Gilead, Merck, Promedior, Kinemed, Adheron, Tobira, Immuron, Siemens, GE, NGM Bio, Bristol-Myers Squibb, Arisaph, and Daiichi-Sankyo; participation in advisory committees for Galmed, Nimbus, Gilead, Bristol-Myers Squibb, Arrowhead Research, Conatus, and Tobira; consulting for Gilead, Bristol-Myers Squibb, Merck, Pfizer, Fibrogen, NGM Bio, Alnylam, DeuteRx, Zafgen, RuiYi, Shire, Scholar Rock, Metacrine, Viking, Receptos, Isis, Enanta, Celgene, Zafgen, Boehringer Ingelheim, Eli Lilly, Conatus, and Janssen; and is a cofounder of Liponexus Inc. Dr Camilleri reports conducting research on liraglutide, supported in part by NIH grant 2R56DK067071-11 and by NovoNordisk; VIVUS and NovoNordisk provided medication for research studies conducted in Dr Camilleri’s laboratory at Mayo Clinic. No other disclosures are reported.


Figure 1
Figure 1
Study Identification and Selection
Figure 2
Figure 2. Network of Included Studies With Available Direct Comparisons for Primary Efficacy Outcome (≥5%Weight Loss)
The size of the nodes and the thickness of the edges are weighted according to the number of studies evaluating each treatment and direct comparison, respectively. The study by Swinburn et al reported only continuous weight loss outcomes and is not included in this network. Network of included studies for all other outcomes is shown in eFigure 1 in the Supplement.
Figure 3
Figure 3. Comparison of Weight Loss and Adverse Events With Pharmacological Weight Loss Agents in Network Meta-analysis
Summary estimate represents odds ratio of achieving at least 5%weight loss (light gray background) and discontinuation due to adverse events (light blue background). Agents are ordered by rankings for the 5%weight loss outcome. Odds ratio for comparisons are in the cell in common between the column-defining and row-defining treatment. For weight loss outcome, row treatment is compared with column treatment (ie, column treatment is reference). For adverse event outcome, column treatment is compared with row treatment (ie, row treatment is reference). Numbers in parentheses indicate 95%credible intervals (95%CrIs). Numbers in bold represent statistically significant results.
Figure 4
Figure 4. SUCRAs for Weight Loss and Adverse Event Outcomes
Surface under the cumulative rankings (SUCRAs) between 0 and 1 represent the probability of being ranked highest. For the weight loss outcomes, higher score corresponds to higher proportion achieving at least 5%weight loss with a particular therapy. For the adverse event outcome, higher scores reflect lower probability of discontinuation due to adverse events. The median ranks on both weight loss and adverse event rates (rank 1 through 6 on each scale) are tabulated along with their corresponding 95%credible intervals (95%CrIs).

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