Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis
Authors' conclusion
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.
Study context
- Population
- Adults with overweight or obesity; RCTs of ≥12 weeks, 19 drugs, follow-up 12 to 172 weeks
- Participants
- 99,791 adults262 trials
- Comparison
- Drugs for overweight or obesity vs lifestyle modification, placebo or another drug
- Outcome
- Weight loss
- Follow-up
- One year
Methodological detailsfrequentist random effects models, bayesian dose-response models, GRADE approach, Cochrane Risk of Bias 2 tool
- Frequentist random effects models
- Bayesian dose-response models
- GRADE approach
- Cochrane Risk of Bias 2 tool
Pooled result
As reported in the abstract
Each group vs lifestyle modificationMD, % (95% CI)
Tirzepatide
−14.9(−16.0% to −13.9%)
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%)
Phentermine-topiramate
−8.1(−9.7% to −6.5%)
Further pooled results
| Outcome | RR | |
|---|---|---|
| All cause mortalitySubcutaneous semaglutidevs Lifestyle modification | 0.81 (95% CI 0.72–0.93) | |
| MISubcutaneous semaglutidevs Lifestyle modification | 0.72 (CI 0.61–0.85) | |
| 0.512Relative risk (log scale) |
| Outcome | Estimate |
|---|---|
| HFSubcutaneous semaglutide vs Lifestyle modification | 0.43 (CI 0.21–0.84) |
| HFTirzepatide vs Lifestyle modification | 0.49 (CI 0.27–0.88) |
- All cause mortality: only drug associated with reduced mortality; largely informed by CV outcome trials in high risk populations
Weight loss, emerging agents (ecnoglutide, mazdutide, retatrutide)
- May produce similar or greater reductions (very low to low certainty)
- 13.1-14.6%
Fat and lean mass
- Tirzepatide reduced fat mass the most
- 25.7%
- Tirzepatide reduced lean mass the most
- 8.3%
Kidney failure and quality of life
- No drugs convincingly reduced kidney failure or improved quality of life beyond minimally important differences (43 trials, 45 663 participants)
- all mean differences <5 points; minimally important difference 10
Subgroup analyses
- No credible differences by drug dosage or key patient characteristics, except larger weight reductions in longer trials (subcutaneous semaglutide)
Safety
Discontinuation because of adverse events
- Highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, cagrilintide-semaglutide (CagriSema) and oral semaglutide (RR)
- 1.9 to 4.2
- Moderate to high certainty evidence
Gastrointestinal events
- Most increased with naltrexone-bupropion, oral semaglutide, orforglipron and tirzepatide (RR)
- 3.1 to 4.2
Fatigue · one year
- Naltrexone-bupropion RR; 331 more per 1000
- 8.9
- Orforglipron RR; 100 more per 1000
- 3.4
- CagriSema RR; 92 more per 1000
- 3.2
Original publication
Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis. BMJ. Published 8 July 2026. doi:10.
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