Pharmacotherapy for Overweight and Obese Adults: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials

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 discontinuation.  In a post hoc analysis, semaglutide, one of the GLP-1 receptor agonists, demonstrated for both likelihood of ≥5% weight loss (OR: 9·81, 95% CI: 7·06 to 13·63) and percent body weight change (MD: −11.41%, 95%CI: −12.54 to −10.27%) and substantially larger than any other drugs with an increased risk of adverse events leading to discontinuation (OR: 1·98; 95% CI: 1·33 to 2·96). Interpretation: In overweight and obese adults, phentermine/topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide may be the most effective. Funding: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (grant numbers ZYGD18022 and 2020HXF011). Declaration of Interest: We declare no competing interests.