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.

BACKGROUND: 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.

PURPOSE: To conduct a living systematic review of pharmacologic treatments for weight management in overweight or obesity in adults.

DATA SOURCES: MEDLINE and Cochrane Central Register of Controlled Trials until October 2025.

STUDY SELECTION: 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.

DATA EXTRACTION: One reviewer extracted data and assessed risk of bias and certainty of the evidence; a second reviewer verified these data.

DATA SYNTHESIS: 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.

LIMITATION: Direct head-to-head comparisons of different treatments were limited.

CONCLUSION: 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.

PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42023491646).