Tirzepatide, CagriSema, and oral semaglutide achieve superior weight loss, up to -14.9%, in adults with overweight or obesity.

Obesity is a chronic, progressive disease affecting over 1 billion adults worldwide, significantly increasing risks for type 2 diabetes, hypertension, and cardiovascular disease. While lifestyle modifications are foundational, they often fall short in achieving and maintaining clinically meaningful weight loss for many individuals. This necessitates effective pharmacotherapy. GLP-1 receptor agonists (GLP-1RAs) and novel dual/triple agonists targeting GIP and glucagon receptors have emerged as powerful tools, but a comprehensive comparison of their efficacy and safety profiles has been needed to guide clinical decision-making.

This systematic review and network meta-analysis (NMA) synthesized data from 262 randomized controlled trials involving 99,791 participants to compare 19 different drugs for adults with overweight or obesity. Studies had a duration of 12 weeks or longer, with follow-up ranging from 12 to 172 weeks. Researchers used frequentist random effects models and Bayesian dose-response models, applying the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach and the Cochrane Risk of Bias 2 tool to assess evidence certainty. The primary endpoint was weight loss, with secondary endpoints including adverse events and discontinuation rates.

At one year, compared to lifestyle modification alone, moderate to high certainty evidence demonstrated substantial weight loss with several agents. Tirzepatide led with a mean difference of -14.9% (95% CI -16.0% to -13.9%), followed closely by cagrilintide-semaglutide (CagriSema) at -14.8% (95% CI -16.9% to -12.7%). Oral semaglutide achieved -10.9% (95% CI -12.7% to -9.1%), and orforglipron showed -9.9% (95% CI -12.4% to -7.5%). Subcutaneous semaglutide resulted in -9.8% (95% CI -10.6% to -9.1%), and phentermine-topiramate achieved -8.1% (95% CI -9.7% to -6.5%). Emerging agents like ecnoglutide, mazdutide, and retatrutide showed similar or greater reductions (13.1-14.6%), though with very low to low certainty. > Moderate to high certainty evidence indicated the highest discontinuation rates due to adverse events with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide, with risk ratios ranging 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 was particularly elevated with naltrexone-bupropion (risk ratio 8.9; absolute increase 331 per 1000 people over one year).