Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis. — VialBase Research
In the largest obesity-drug network meta-analysis to date (262 trials, ~100,000 participants), retatrutide ranks among the emerging agents with the greatest projected one-year weight loss (13.1-14.6%), rivalling tirzepatide, though on very low to low certainty evidence.
- Network meta-analysis of 262 randomised trials (99,791 participants) evaluating 19 drugs, with follow-up from 12 to 172 weeks
- Emerging agents ecnoglutide, mazdutide, and retatrutide may produce weight loss of 13.1-14.6% at one year versus lifestyle modification, on very low to low certainty evidence
- For comparison, moderate-to-high certainty evidence showed weight loss of -14.9% with tirzepatide, -14.8% with cagrilintide-semaglutide (CagriSema), -10.9% with oral semaglutide, and -9.8% with subcutaneous semaglutide at one year
- Larger weight loss was generally accompanied by greater harms; subcutaneous semaglutide was the only drug linked to reduced all-cause mortality (RR 0.81, 95% CI 0.72-0.93) and myocardial infarction (0.72, 0.61-0.85)
- No drug convincingly reduced kidney failure or improved quality of life (43 trials, 45,663 participants) beyond minimally important differences
Summary
This systematic review and network meta-analysis pooled 262 randomised trials (99,791 participants) comparing 19 anti-obesity drugs against lifestyle modification, placebo, or one another, with follow-up from 12 to 172 weeks and evidence graded with GRADE. It quantified comparative weight loss and harms across the drug class to inform decision making. Retatrutide is included among the newer, still-emerging multi-receptor agents whose weight-loss estimates are promising but supported only by low-certainty evidence.
Key Findings
- Scope: 262 trials, 99,791 participants, 19 drugs; searches up to 12 November 2025; frequentist random-effects and bayesian dose-response models with GRADE and Cochrane RoB 2
- Emerging agents ecnoglutide, mazdutide, and retatrutide may produce similar or greater weight reductions of 13.1-14.6% at one year (very low to low certainty)
- Moderate-to-high certainty comparators at one year vs lifestyle modification: tirzepatide -14.9% (95% CI -16.0% to -13.9%), CagriSema -14.8%, oral semaglutide -10.9%, orforglipron -9.9%, subcutaneous semaglutide -9.8%, phentermine-topiramate -8.1%
- Tirzepatide reduced fat mass the most (25.7%) but also lean mass the most (8.3%); harms and discontinuations generally rose with larger weight loss
- Subcutaneous semaglutide was the only drug associated with reduced all-cause mortality (RR 0.81) and myocardial infarction (0.72); subcutaneous semaglutide (0.43) and tirzepatide (0.49) reduced heart failure risk; no drug meaningfully improved quality of life
Relevance to Retatrutide
This analysis places retatrutide in direct comparative context with the full anti-obesity drug class. Its projected one-year weight loss (13.1-14.6%) sits alongside Tirzepatide (-14.9%) and cagrilintide-semaglutide (-14.8%) at the top of the efficacy range, ahead of both oral and subcutaneous Semaglutide. Importantly, the authors grade retatrutide’s estimate as very low to low certainty because it is still an emerging agent without completed long-term phase 3 outcome data, so it does not yet carry the mortality, cardiovascular, or quality-of-life evidence established for subcutaneous semaglutide. The study frames retatrutide as a high-potential agent whose comparative standing will firm up as its phase 3 programme reports.
Citation
Nong K, Shi Q, Xie X, et al. Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis. BMJ (Clinical research ed.). 2026. doi:10.1136/bmj-2026-372161.
See Also
- Parent compound: Retatrutide
- Semaglutide
- Tirzepatide
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