Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis.
This meta-analysis indicates that obesity drugs can lead to significant weight loss, but often at the cost of increased adverse events, and many do not meaningfully improve quality of life.
Where it sits
this study against the rest of the mazdutide (ibi362) corpusSummary and findings
This systematic review and network meta-analysis evaluated the comparative effects of various drugs for adults with overweight or obesity across 262 trials involving 99,791 participants. The study reported weight loss percentages for several drugs compared to lifestyle modification, with findings indicating substantial weight loss for agents like tirzepatide and cagrilintide-semaglutide. Adverse events were also noted, with certain drugs associated with higher discontinuation rates due to side effects.
Abstract
<h4>Objective</h4>To provide an up-to-date evidence summary about the comparative benefits and harms of drugs for adults with overweight or obesity to inform decision making for policymakers, payers, clinicians, and patients.<h4>Design</h4>Systematic review and network meta-analysis of 24 outcomes using frequentist random effects models and bayesian dose-response models, the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach, and the Cochrane Risk of Bias 2 tool.<h4>Data sources</h4>Medline, Embase, and Cochrane Library, searched up to 12 November 2025.<h4>Study selection</h4>Randomised controlled trials of 12 weeks' duration or longer comparing one or more drugs with lifestyle modification, placebo, or another drug.<h4>Results</h4>This network meta-analysis comprised 262 trials (99 791 participants) evaluating 19 drugs with follow-up from 12 to 172 weeks. Compared with lifestyle modification alone, at one year, moderate to high certainty evidence shows substantial weight loss with tirzepatide (mean difference -14.9%, 95% confidence interval -16.0% to -13.9%), cagrilintide-semaglutide (CagriSema, -14.8%, -16.9% to -12.7%), oral semaglutide (-10.9%, -12.7% to -9.1%), orforglipron (-9.9%, -12.4% to -7.5%), subcutaneous semaglutide (-9.8%, -10.6% to -9.1%), and phentermine-topiramate (-8.1%, -9.7% to -6.5%). Emerging agents (ecnoglutide, mazdutide, retatrutide) may produce similar or greater reductions (13.1-14.6%; very low to low certainty). Moderate to high certainty evidence supports discontinuation because of adverse events to be highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide (risk ratios from 1.9 to 4.2); gastrointestinal events were most increased with naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide (risk ratios from 3.1 to 4.2). Fatigue risk increased, particularly with naltrexone-bupropion (risk ratio 8.9; absolute increase 331 per 1000 people over one year), orforglipron (3.4; 100 more per 1000), and CagriSema (3.2; 92 more per 1000). Tirzepatide reduced fat mass the most (by 25.7%) but also lean mass the most (by 8.3%). Subcutaneous semaglutide was the only drug associated with reduced all cause mortality (risk ratio 0.81, 95% confidence interval 0.72 to 0.93) and myocardial infarction (0.72, 0.61 to 0.85), with these estimates largely informed by cardiovascular outcome trials in high risk populations. Subcutaneous semaglutide (0.43, 0.21 to 0.84) and tirzepatide (0.49, 0.27 to 0.88) reduced heart failure risk. No drugs convincingly reduced kidney failure or improved quality of life (43 trials with 45 663 participants) beyond established minimally important differences (all mean differences <5 points; minimally important difference 10). Except for larger weight reductions in trials with longer duration (shown for subcutaneous semaglutide), subgroup analyses for drug dosages and key patient characteristics did not identify credible differences in relative effects of treatment.<h4>Conclusions</h4>Obesity drugs produce variable weight loss at one year, with larger benefits generally accompanied by greater harms and discontinuation. Most agents do not improve quality of life meaningfully and few show cardiovascular benefits. Decisions in clinical practice should consider trade-offs between benefits and harms within the context of shared decision making.<h4>Systematic review registration</h4>PROSPERO CRD42024507993.
Background
The paper addresses the clinical question of how different pharmacological treatments compare in efficacy for weight loss in adults with overweight or obesity. Previous studies have shown varying degrees of effectiveness among these treatments, but a comprehensive comparison has been lacking. This study is significant as it aims to provide a clearer understanding of the relative benefits of these drugs.
Methods
The study utilized a systematic review and network meta-analysis design, synthesizing data from multiple randomized controlled trials (RCTs). The specific population included adults with overweight or obesity, but the exact sample size (n) and duration of treatment were not reported in the abstract. The primary outcome measure focused on weight loss, while secondary outcomes were not specified.
Results
Not reported in abstract.
Interpretation
The findings of this study could potentially align with previous literature suggesting varying efficacy among obesity treatments; however, without specific numeric results, it is difficult to assess the clinical significance of the findings. Limitations such as potential publication bias and the quality of included studies may confound the conclusions drawn. Therefore, practitioners should approach the results with caution until more detailed data is available.
Key findings
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Limitations
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