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Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials
Abstract
Background Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. Methods This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. Findings 14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29). Interpretation In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. Funding 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.
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“Among these, incretin hormone‐based drugs, first and foremost glucagon‐like peptide 1 receptor agonists (GLP‐1RA), 11 have emerged as a pivotal treatment option for managing both obesity and T2D. 12 , 13 , 14 , 15”
From Real‐world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer GLP ‐ 1RA ‐based weight‐loss therapies (2025) · cites this paper as [15]
In the citing paper
“The three GLP‐1RA‐based agents currently approved for weight loss have all shown clear efficacy in promoting weight loss in randomized controlled trials (RCTs), 17 , 18 , 19 that is, in settings with good medication adherence among participants and a follow‐up of typically one to two years. 15”
From Real‐world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer GLP ‐ 1RA ‐based weight‐loss therapies (2025) · cites this paper as [15]
In the citing paper
“In a 2024 network meta-analysis of 61 randomized controlled trials (RCTs) comparing active treatments to lifestyle modification in adults with overweight or obesity, both phentermine-topiramate (odds ratio [OR]: 2.40, 95% CI 1.68, 3.44) and naltrexone-bupropion (OR: 2.69, 95% CI 2.10, 3.44) ranked among the highest for treatment discontinuation due to adverse events.14”
From The expanding role of GLP-1 receptor agonists: a narrative review of current evidence and future directions (2025) · cites this paper as [14]
In the citing paper
“In contrast, GLP-1 RAs have primarily been associated with gastrointestinal side effects and have demonstrated more favorable psychiatric and cardiovascular safety profiles.13,14”
From The expanding role of GLP-1 receptor agonists: a narrative review of current evidence and future directions (2025) · cites this paper as [14]
In the citing paper
“Several NMAs20–23 and a traditional meta-analysis24 on different therapeutic options for overweight and obesity were published in the last few years, but they did not include more recently available OMMs, such as tirzepatide20–22, or they included medications not approved for the treatment of overweight/obesity (for example, metformin, SGLT2 inhibitors or GLP-1 agonists, such as dulaglutide)22, or”
From A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults (2025) · cites this paper as [22]
In the citing paper
“These results are in line with those reported in previous NMA and meta-analysis20–22,24”
From A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults (2025) · cites this paper as [22]
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Metadata
- Authors
- Shi, Q., Wang, Y., Hao, Q., Vandvik, P. O., Guyatt, G., Li, J., Chen, Z., Xu, S., Shen, Y., Ge, L., Sun, F., Li, L., Yu, J., Nong, K., Zou, X., Zhu, S., Wang, C., Zhang, S., Qiao, Z., Jian, Z., Li, Y., Zhang, X., Chen, K., Qu, F., Wu, Y., He, Y., Tian, H., & Li, S.
- Affiliations
- Sichuan University (CN)
- Lovisenberg Diakonale Sykehus (NO)
- McMaster University (CA)
- Tianjin University of Traditional Chinese Medicine (CN)
- Lanzhou University (CN)
- Peking University (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Corresponding author
- Li, Sheyu
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2024-04
- Volume
- 403
- Issue
- 10434
- Pages
- e21-e31
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W4393952591
- Cited by
- 155
- References
- 43
- Citations by year
- 2026: 60 · 2025: 67 · 2024: 27
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Update notices
- erratum (2024-04-06)
- Open access
- closed
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Funders
- West China Hospital, Sichuan University (ZYGD18022, 2020HXF011)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
- Keywords
- pharmacotherapy, obesity, overweight, phentermine/topiramate, GLP-1 receptor agonists, semaglutide, naltrexone/bupropion, orlistat, lifestyle modification, weight loss, adverse events, drug discontinuation, adults, GRADE certainty of evidence
- MeSH terms
- Network Meta-Analysis, Topiramate, Adult, Humans, Obesity, Phentermine, Weight Loss, Randomized Controlled Trials as Topic, Overweight
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