Among available drugs for obesity, tirzepatide and cagrilintide-semaglutide (CagriSema) yield the largest decrease in body weight, regardless of diabetes status, suggest the results of a systematic review and network meta-analysis.
“Most agents do not improve quality of life meaningfully and few show cardiovascular benefits,” the investigators said. “Decisions in clinical practice should consider trade-offs between benefits and harms within the context of shared decision making.”
A total of 262 trials comprising 99,791 participants and evaluating 19 obesity drugs, with follow-up from 12 to 172 weeks, were included in the network meta-analysis. [BMJ 2026;394:e372161]
At 1 year, weight substantially decreased following treatment with tirzepatide (mean difference [MD], ‒14.9 percent, 95 percent confidence interval [CI], ‒16.0 to‒13.9), CagriSema (MD, ‒14.8 percent, 95 percent CI, ‒16.9 to ‒12.7), oral semaglutide (MD, ‒10.9 percent, 95 percent CI, ‒12.7 to ‒9.1), orforglipron (MD, ‒9.9 percent, 95 percent CI, ‒12.4 to ‒7.5), subcutaneous semaglutide (MD, ‒9.8, 95 percent CI, ‒10.6 to ‒9.1), and phentermine-topiramate (MD, ‒8.1, 95 percent CI, ‒9.7 to ‒6.5) relative to lifestyle modification alone, based on moderate- to high-certainty evidence.
“Emerging agents (ie, ecnoglutide, mazdutide, retatrutide) may produce similar or greater reductions (13.1 percent to 14.6 percent; very low to low certainty),” the investigators said.
Safety
Discontinuation due to adverse events was highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide (risk ratios [RR] ranging from 1.9 to 4.2), based on moderate- to high-certainty evidence. Gastrointestinal events occurred most frequently with naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide (RRs from 3.1 to 4.2).
Fatigue also occurred, showing an increased risk with naltrexone-bupropion (RR, 8.9; absolute increase 331 per 1,000 people over 1 year), orforglipron (RR, 3.4; 100 more per 1,000 people), and CagriSema (RR, 3.2; 92 more per 1,000 people).
Fat mass and lean mass decreased most substantially with tirzepatide (by 25.7 percent and 8.3 percent, respectively). Furthermore, subcutaneous semaglutide was the only drug that contributed to reductions in all-cause mortality (RR, 0.81, 95 percent CI, 0.72‒0.93) and myocardial infarction (RR, 0.72, 95 percent CI, 0.61‒0.85), with estimates mostly informed by cardiovascular outcome trials in high-risk populations. Tirzepatide (RR, 0.49, 95 percent CI, 0.27‒0.88) and subcutaneous semaglutide (RR, 0.43, 95 percent CI, 0.21‒0.84) also reduced the risk of heart failure.
“No drugs convincingly reduced kidney failure or improved quality of life (43 trials with 45,663 participants) beyond established minimally important differences (all mean differences <5 points; minimally important difference 10),” the investigators said.
Pharmacotherapy
In subgroup analyses for drug dosages and key patient characteristics, no credible differences in relative effects of treatment were observed across drugs, except for greater weight loss in trials with longer duration (shown for subcutaneous semaglutide).
“Obesity drugs produce variable weight loss at 1 year, with larger benefits generally accompanied by greater harms and discontinuation,” the investigators said.
“Emerging drugs with substantial weight lowering effects require large, long-term trials to determine their impact on cardiovascular, kidney, and other patient important outcomes. Pharmacotherapy should be integrated with lifestyle interventions and strategies to preserve lean mass,” they added.
This systematic review and network meta-analysis used frequentist random effects models and Bayesian dose-response models, the GRADE approach, and the Cochrane Risk of Bias 2 tool. The investigators searched Medline, Embase, and Cochrane Library up to 12 November 2025 and identified randomized controlled trials of 12 weeks’ duration or longer comparing one or more obesity drugs with lifestyle modification, placebo, or another agent.