Benefits and Harms of Pharmacologic Treatments in Adults With Overweight or Obesity: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.
This living systematic review and network meta-analysis, commissioned by the American College of Physicians, synthesized evidence from 69 randomized controlled trials involving 112,511 adults with overweight or obesity (BMI ≥25 kg/m²) to compare pharmacologic weight-management treatments. Drugs examined included GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide), dual agonists (tirzepatide, retatrutide, semaglutide-cagrilintide), and other agents (naltrexone-bupropion, phentermine, phentermine-topiramate, orforglipron), with or without lifestyle intervention. The review found that nearly all studied interventions produced greater weight loss than placebo and/or lifestyle intervention alone. Semaglutide was found to probably reduce mortality and major adverse cardiovascular events (MACE). Semaglutide and tirzepatide demonstrated the greatest weight loss in both pairwise and network meta-analyses. However, nearly all active treatments were also associated with more treatment discontinuations due to adverse events compared with placebo. The authors noted that evidence for critical outcomes such as mortality, MACE, and serious adverse events remained limited, and direct head-to-head comparisons between treatments were scarce. Thirty-seven of the 69 included studies were rated at low risk of bias. The living review design allows for ongoing evidence updates as new trials emerge.
Why this grade: This is a large, pre-registered living systematic review and network meta-analysis of 69 RCTs with over 112,000 adult participants, providing the highest tier of synthesized human evidence, though the authors themselves note limitations in direct comparisons and evidence for some critical outcomes.
Overweight and obesity are closely linked to diseases such as type 2 diabetes, coronary heart disease, and stroke and have been shown to increase mortality risk. To conduct a living systematic review of pharmacologic treatments for weight management in overweight or obesity in adults. MEDLINE and Cochrane Central Register of Controlled Trials until October 2025. Randomized controlled trials that compared pharmacologic treatments for weight management (dulaglutide, exenatide, liraglutide, lixisenatide, naltrexone-bupropion, orforglipron, phentermine, phentermine-topiramate, retatrutide, semaglutide, semaglutide-cagrilintide, tirzepatide, or any combination with or without lifestyle intervention [LI]) for overweight or obesity (body mass index ≥25 kg/m2) in adults for outcomes such as mortality, weight loss, and quality of life. One reviewer extracted data and assessed risk of bias and certainty of the evidence; a second reviewer verified these data. The review included 69 studies with a total of 112 511 participants. Thirty-seven studies were at low risk of bias. In meta-analyses, nearly all studied interventions were more effective than placebo and/or LI in reducing weight, but more discontinuations due to adverse events were observed. Semaglutide probably reduced mortality and major adverse cardiovascular events (MACE), and both semaglutide and tirzepatide led to the greatest weight loss compared with placebo and/or LI in pairwise and network meta-analyses. Evidence for outcomes such as mortality, MACE, and serious adverse events was limited. Direct head-to-head comparisons of different treatments were limited. Nearly all studied interventions were more effective than placebo and/or LI in reducing weight. Semaglutide and tirzepatide showed the most favorable results across outcomes. American College of Physicians. (PROSPERO: CRD42023491646).
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