Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis
Open accessAbstract
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.
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Semaglutide's weight-loss outcomes are substantially superior to older therapies such as orlistat or phentermine/topiramate.
“These outcomes are substantially superior to older therapies such as orlistat or phentermine/topiramate [65].”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [65]
The Results (Network Meta-analysis—Weight Loss Outcomes; page unavailable) report weight-loss outcomes for orlistat and phentermine-topiramate, providing benchmarks for those older therapies. The paper does not evaluate semaglutide, so it cannot support the claimed superiority of semaglutide’s outcomes over either drug. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSemaglutide's gastrointestinal adverse effects are dose-dependent and occur primarily during dose escalation.
“These effects are dose-dependent and occur primarily during dose escalation [65].”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [65]
The Results section reports adverse event–related discontinuation for the drugs studied, including liraglutide, but does not report findings for semaglutide. Searches for semaglutide, dose dependence, and dose escalation found no passage addressing when its gastrointestinal adverse effects occur. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe most common adverse events of semaglutide are gastrointestinal, including nausea (up to 44%), vomiting, diarrhea, and constipation.
“The most common adverse events are gastrointestinal, such as nausea (up to 44%), vomiting, diarrhea, and constipation.”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [65]
The Results section on adverse events reports treatment discontinuation for the drugs studied and directs readers to a supplement for details of common events (page not available). Searches for semaglutide, the listed gastrointestinal symptoms, and the 44% nausea figure found no passage in our copy that addresses this claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredApproved antiobesity medications have only moderate efficacy, producing 3% to 8% body weight reduction beyond lifestyle intervention alone.
“approved antiobesity medications have only moderate efficacy (3%-8% body weight reduction beyond lifestyle intervention alone).[7][8][9]”
Given the modest efficacy of currently approved pharmacotherapies, semaglutide may offer the potential to bridge the gap between behavioral and pharmacological options and bariatric surgery, which is currently considered the most effective and reliable intervention available for weight management.
“Given the modest efficacy of currently approved pharmacotherapies, [7][8][9] semaglutide may offer the potential to bridge the gap between behavioral and pharmacological options and bariatric surgery, which is currently considered the most effective and reliable intervention available for weight management.6,27,32”
Short-term treatment (3-6 months) fails to produce long-term health benefits, while several agents also have safety concerns.
“Short-term treatment (3-6 months) fails to produce long-term health benefits, 5 while several agents also have safety concerns.[7][8][9]”
A meta-analysis found liraglutide produced mean 5.2 kg placebo-subtracted weight loss at 1 year, with 63% achieving at least 5% and 34% at least 10% weight loss.
“A meta-analysis showed that liraglutide produced a mean 5.2 kg placebo-subtracted weight loss at 1 year, with 63% of participants achieving a ≥5% weight loss, inclusive of 34% of participants who lost ≥10% of initial weight.(23)”
From Semaglutide for the treatment of obesity (2023) · cites this paper as [23]
Prior to semaglutide, other FDA-approved anti-obesity medications produced placebo-subtracted weight losses of 2.6 to 8.8 kg at 1 year.
“Prior to semaglutide, other FDA-approved AOM produced placebo-subtracted weight losses of 2.6 kg to 8.8 kg at 1 year.(23)”
From Semaglutide for the treatment of obesity (2023) · cites this paper as [23]
Excess weight loss for older antiobesity agents compared to placebo at 1 year ranges from 2.6 kg to 8.8 kg.
“Excess weight loss for these agents compared to placebo at 1 year ranges from 2.6 kg to 8.8 kg (3).”
From New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics (2023) · cites this paper as [3]
A recent meta-analysis found that among all FDA-approved anti-obesity medications, liraglutide had the highest rate of discontinuation due to side effects (13% of study participants), followed by naltrexone/bupropion (12%).
“However, a recent meta-analysis showed that among all the FDA-approved anti-obesity medications, liraglutide had the highest (13% of study participants) rate of discontinuation due to its side effects followed by naltrexone/bupropion (12% of study participants) [51].”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [51]
In many clinical trials assessing pharmacologic interventions for more than 12 months, a weight loss of 4 to 8% was typical.
“In many clinical trials that assessed pharmacologic interventions for more than 12 months, a weight loss of 4 to 8% was typical [51], which is rather disappointing considering the high prices of these drugs.”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [51]
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“The US Food and Drug Administration and European Medicines Agency have approved AOMs that have been shown to achieve clinically significant WL when used as adjuncts to lifestyle interventions (2,16).”
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Response to “Response to review by Pan et al.”
Pan, X., Chin, Y. H., Chan, M. Y., & Chew, N. W. S. (2024) · Obesity · doi:10.1002/oby.24087
- Authors
- Khera, R., Murad, M. H., Chandar, A. K., Dulai, P. S., Wang, Z., Prokop, L. J., Loomba, R., Camilleri, M., & Singh, S.
- Affiliations
- University of Iowa (US)
- Mayo Clinic (US)
- Case Western Reserve University (US)
- University of California San Diego (US)
- Corresponding author
- Singh, Siddharth
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2016-06-14
- Volume
- 315
- Issue
- 22
- Pages
- 2424
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC5617638
- OpenAlex
- W2432501512
- Cited by
- 865
- References
- 54
- Citations by year
- 2026: 63 · 2025: 93 · 2024: 91 · 2023: 101 · 2022: 86 · 2021: 101 · 2020: 82 · 2019: 105 · 2018: 59 · 2017: 70 · 2016: 13
- FWCI
- 9.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- Gilead Sciences
- Alnylam Pharmaceuticals
- Celgene
- FibroGen
- KineMed
- Zafgen
- NGM Biopharmaceuticals
- Daiichi-Sankyo
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK067071, R01DK067071, T32DK007202)
- U.S. National Library of Medicine (T15LM011271)
- Topics
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Keywords
- obesity, weight loss agents, orlistat, lorcaserin, naltrexone/bupropion, phentermine/topiramate, liraglutide, comparative effectiveness, adverse events, drug discontinuation, weight loss, long-term weight management, network meta-analysis ranking, overweight adults, FDA-approved drugs, quality of evidence
- MeSH terms
- Liraglutide, Topiramate, Orlistat, Bayes Theorem, Benzazepines, Drug Combinations, Female, Fructose, Humans, Lactones, Male, Middle Aged, Naltrexone, Obesity, Phentermine, Weight Loss, Randomized Controlled Trials as Topic, Anti-Obesity Agents
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