BMJ Network Meta-Analysis of 262 Trials Shows Only Subcutaneous Semaglutide Reduces Mortality and MI Among Weight-Loss Agents

Researchers searched MEDLINE, EMBASE, and Cochrane Library through November 2025 and included trials of at least 12 weeks duration. They evaluated 24 outcomes spanning weight change, body composition, gastrointestinal adverse events, treatment discontinuation, and cardiovascular events. Tirzepatide, cagrilintide-semaglutide, and several GLP-1 agonists achieved 8-15 percent weight loss, but greater losses correlated with higher rates of nausea, diarrhea, fatigue, and 6-8 percent lean-mass reduction. The analysis reveals that weight reduction alone does not reliably translate into quality-of-life gains or broad cardiovascular protection. Subcutaneous semaglutide was the sole agent linked to lower mortality and infarction rates, while tirzepatide reduced heart-failure events but not hard endpoints. High discontinuation rates for orforglipron and naltrexone-bupropion underscore tolerability limits that offset efficacy in real-world use. These findings challenge assumptions embedded in current prescribing patterns and payer coverage. Long-term outcome trials with muscle-preserving co-interventions and standardized quality-of-life instruments are required before claims of comprehensive cardiometabolic benefit can be generalized beyond semaglutide.