Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis

OBJECTIVE: 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. DESIGN: 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. DATA SOURCES: Medline, Embase, and Cochrane Library, searched up to 12 November 2025. STUDY SELECTION: Randomised controlled trials of 12 weeks' duration or longer comparing one or more drugs with lifestyle modification, placebo, or another drug. RESULTS: 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. CONCLUSIONS: 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. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42024507993.