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Background: Pharmacotherapy provides an option for overweight and obese adults to reduce their body weight if lifestyle modification fails. This systematic review summarises latest and likely practice-changing evidence for the benefits and harms of weight-lowering drugs.

Methods: The network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) for randomised controlled trials of weight-lowering drugs in overweight and obese adults. We performed a frequentist random-effect network meta-analysis to summarise the evidence and applied GRADE frameworks to rate the certainty of the evidence, calculate the absolute effects, categorise interventions and present the findings.

Findings: The 143 eligible trials enrolled 49 810 participants. Except for levocarnitine, all drugs lowered body weight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification alone. High to moderate certainty evidence established phentermine/topiramate (odds ratio [OR] of≥ 5% weight reduction: 8· 00, 95% confidence interval [CI]: 5· 19 to 12· 34; mean difference [MD] of percent body weight change:− 7· 97%, 95% CI:− 9· 28 to− 6· 66%) and glucagon-like peptide-1 (GLP-1) receptor agonists (OR: 6· 20, 95% CI: 4· 88 to 7· 89; MD:− 5· 75%, 95% CI:− 6· 30 to− 5· 20%) were among the most effective in lowering weight. Naltrexone/bupropion (OR: 2· 68, 95% CI: 2· 06 to 3· 49), phentermine/topiramate (OR, 2· 36, 95% CI: 1· 60 to 3· 46), GLP-1 receptor agonists (OR: 2· 16, 95% CI: 1· 68 to 2· 78), and orlistat (OR: 1· 68, 95% CI: 1· 38 to 2· 05) increase any adverse event leading to drug …