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.
Semaglutide and tirzepatide appear most effective for weight loss, but adverse events are a concern. Direct comparisons between treatments remain limited.
Where it sits
this study against the rest of the cagrilintide (am833) corpusSummary and findings
This living systematic review and network meta-analysis evaluated pharmacologic treatments for weight management in adults with overweight or obesity. The review included 69 studies with 112,511 participants, assessing interventions like semaglutide-cagrilintide. Nearly all interventions were more effective than placebo in reducing weight, but adverse event-related discontinuations were higher.
Abstract
<h4>Background</h4>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.<h4>Purpose</h4>To conduct a living systematic review of pharmacologic treatments for weight management in overweight or obesity in adults.<h4>Data sources</h4>MEDLINE and Cochrane Central Register of Controlled Trials until October 2025.<h4>Study selection</h4>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/m<sup>2</sup>) in adults for outcomes such as mortality, weight loss, and quality of life.<h4>Data extraction</h4>One reviewer extracted data and assessed risk of bias and certainty of the evidence; a second reviewer verified these data.<h4>Data synthesis</h4>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.<h4>Limitation</h4>Direct head-to-head comparisons of different treatments were limited.<h4>Conclusion</h4>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.<h4>Primary funding source</h4>American College of Physicians. (PROSPERO: CRD42023491646).
Background
Overweight and obesity are significant public health concerns linked to increased risks of type 2 diabetes, coronary heart disease, stroke, and mortality. Pharmacologic treatments are often used for weight management in these populations. This study aims to provide a comprehensive review of the effectiveness and safety of various pharmacologic interventions for weight management in adults with overweight or obesity.
Methods
This living systematic review and network meta-analysis included randomized controlled trials comparing pharmacologic treatments for weight management in adults with a BMI ≥25 kg/m². The data sources were MEDLINE and the Cochrane Central Register of Controlled Trials, with studies selected up to October 2025. A total of 69 studies with 112,511 participants were included, focusing on outcomes such as mortality, weight loss, and quality of life.
Results
The meta-analysis found that nearly all pharmacologic interventions were more effective than placebo and/or lifestyle intervention in reducing weight. Semaglutide and tirzepatide showed the most significant weight loss compared to placebo. However, there were more discontinuations due to adverse events in the pharmacologic treatment groups. Evidence for outcomes like mortality and major adverse cardiovascular events was limited.
Interpretation
The findings suggest that semaglutide and tirzepatide are among the most effective pharmacologic options for weight loss in adults with overweight or obesity. However, the clinical significance of these findings is tempered by the higher rate of adverse event-related discontinuations. The limited direct comparisons between treatments and the scarcity of data on mortality and cardiovascular outcomes restrict the ability to draw definitive conclusions about the best treatment option.
Key findings
- 69 studies, n=112,511.
- Semaglutide and tirzepatide led to the greatest weight loss.
- Nearly all interventions were more effective than placebo for weight reduction.
- More discontinuations due to adverse events with pharmacologic treatments.
- Evidence for mortality and MACE outcomes was limited.
Limitations
- Direct head-to-head comparisons limited.
- Evidence for mortality and MACE limited.
- Higher discontinuation rates due to adverse events.
- Potential bias in some included studies.
- Limited data on long-term outcomes.