Benefits and Harms of Pharmacologic Treatments in Adults With Overweight or Obesity: A Living Systematic Review and Network Meta-analysis for the American College of Physicians
*Living systematic review and network meta-analysis of RCTs; Level 1a.
Citation
Damen JAA, Idema DL, Vernooij RWM, et al. Benefits and Harms of Pharmacologic Treatments in Adults With Overweight or Obesity. Ann Intern Med. 2026;179:1140-1155.
Background
Obesity is common and increases risks for diabetes, heart disease, stroke, and death. Medication is often added when lifestyle changes alone do not produce lasting weight loss.
Patients
Adults with body mass index at least 25 kg/m²; trials had at least 52 weeks of treatment and follow-up. Non-English and shorter trials were excluded.
Intervention
Weight-loss medications, with or without lifestyle changes.
Control
Placebo, lifestyle changes, or another eligible medication.
Outcome
Weight loss, death, major heart events, quality of life, blood sugar, serious harms, and stopping treatment because of side effects.
Follow-up Period
52 to 281 weeks.
Results
The review included 69 randomized trials with 112,511 participants.
| Treatment vs placebo/lifestyle | Achieved at least 10% weight loss | Stopped because of side effects |
|---|---|---|
| Semaglutide | Risk ratio 5.14 (95% CI 4.49 to 5.88); NNT 2 | Risk ratio 1.89 (95% CI 1.56 to 2.29); NNH 28 |
| Tirzepatide | Risk ratio 6.68 (95% CI 5.21 to 8.56); NNT 2 | Risk ratio 1.88 (95% CI 1.35 to 2.61); NNH 29 |
| Liraglutide | Risk ratio 2.42 (95% CI 2.01 to 2.92); NNT 6 | Risk ratio 1.96 (95% CI 1.51 to 2.53); NNH 32 |
| Naltrexone-bupropion | Risk ratio 2.65 (95% CI 2.04 to 3.44); NNT 8 | Risk ratio 2.21 (95% CI 1.72 to 2.84); NNH 8 |
Tirzepatide generally produced the greatest weight loss. Semaglutide probably reduced major heart events: odds ratio 0.80 (95% CI 0.72 to 0.88). Most controls were placebo plus lifestyle advice, not active medication.
Limitations
Few direct drug-to-drug trials were available, so many comparisons were indirect. Doses and lifestyle programs varied. Rare harms and long-term stopping effects remain uncertain. Most included trials were industry funded.
Funding
American College of Physicians; most included trials were industry funded.
Clinical Application
Consider semaglutide or tirzepatide when medication is appropriate, while counseling about side effects, cost, and likely need for ongoing treatment.
Discussion
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In this living systematic review and network meta-analysis of RCTs, tirzepatide achieved ≥10% weight loss more often than placebo/lifestyle intervention (RR 6.68), but discontinuations due to adverse events were higher (RR 1.88). Given sparse head-to-head data, should this change first-line pharmacotherapy choices? In this review, many comparisons between obesity medications were based on network meta-analysis rather than direct head-to-head RCTs. Which statement best describes an important limitation of interpreting those indirect comparisons?