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

Summary

Across 262 RCTs, tirzepatide, CagriSema, and semaglutide produced the largest one-year weight loss but with higher GI adverse events and discontinuations. Subcutaneous semaglutide uniquely reduced all-cause mortality and myocardial infarction; both semaglutide and tirzepatide reduced heart failure risk, while most agents did not meaningfully improve quality of life.

Key Findings

• At one year, tirzepatide (~−14.9%), CagriSema (~−14.8%), and semaglutide (oral ~−10.9%; subcutaneous ~−9.8%) led weight loss versus lifestyle alone.
• GI adverse events and discontinuations were more frequent with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide.
• Subcutaneous semaglutide reduced all-cause mortality (RR 0.81) and myocardial infarction (RR 0.72); semaglutide and tirzepatide reduced heart failure risk.
• Quality-of-life improvements generally did not exceed minimally important differences.

Clinical Implications

Select agents based on individualized benefit–risk: prioritize semaglutide where cardiovascular benefit is desired; counsel about GI adverse events; set realistic expectations for quality-of-life change; integrate lifestyle and resistance exercise to preserve lean mass.

Limitations

• Substantial heterogeneity and reliance on indirect comparisons for several agents
• Quality-of-life outcomes showed limited improvements despite weight loss, and emerging agents had low-certainty evidence

Future Directions

Head-to-head RCTs for leading agents, standardized adverse event and QoL reporting, long-term cardiometabolic outcomes, and strategies to preserve lean mass during pharmacotherapy.