Obesity Drugs Present Diverse Benefits, Harms, and Discontinuation Rates

A systematic review and network meta-analysis published in The BMJ examined 262 trials involving 99,791 participants and 19 obesity drugs. Researchers found substantial weight loss after one year with tirzepatide, CagriSema, oral and subcutaneous semaglutide, orforglipron, and…

Study Overview and Methods

As pharmacotherapies become increasingly available for treating obesity, there is a growing need to evaluate outcomes beyond simple weight loss when measuring treatment success. However, limited knowledge has existed regarding the comparative risks, benefits, and differences among various obesity drugs across these broader outcomes.

To address this gap, Kailei Nong and colleagues conducted a systematic review and network meta-analysis published in The BMJ. The researchers searched data sources including Medline, Embase, and Cochrane Library up to November 12, 2025. They identified 262 trials that included a total of 99,791 participants. These trials evaluated 19 different drugs, with follow-up periods ranging from 12 to 172 weeks.

Weight Loss Efficacy

The results showed moderate to high certainty evidence of substantial weight loss compared to lifestyle modification after one year in participants taking several specific drugs. Tirzepatide led to a mean difference of -14.9% 95% confidence interval -16.0% to -13.9% . Cagrilintide-semaglutide, known as CagriSema, resulted in a mean difference of -14.8% 95% CI -16.9% to -12.7% . Oral semaglutide produced a mean difference of -10.9% 95% CI -12.7% to -9.1% , and orforglipron gave -9.9% 95% CI -12.4% to -7.5% .

Subcutaneous semaglutide showed a mean difference of -9.8% 95% CI -10.6% to -9.1% , while phentermine-topiramate resulted in -8.1% 95% CI -9.7% to -6.5% . Emerging agents such as ecnoglutide, mazdutide, and retatrutide demonstrated similar or greater reductions ranging from 13.1% to 14.6%, though this evidence was at a lower certainty. Tirzepatide was associated with the greatest reductions in both fat mass 25.7% and lean mass 8.3% .

Outcomes Beyond Weight Loss

When examining outcomes beyond weight loss, the researchers found that subcutaneous semaglutide was the only drug associated with reduced all-cause mortality risk ratio 0.81, 95% CI 0.72 to 0.93 . It also reduced the risk of myocardial infarction risk ratio 0.72, 95% CI 0.61 to 0.85 . Both subcutaneous semaglutide risk ratio 0.43, 95% CI 0.21 to 0.84 and tirzepatide risk ratio 0.49, 95% CI 0.27 to 0.88 reduced the risk of heart failure.

No drugs had a significant impact on kidney failure. For quality of life, the analysis included 43 trials with 45,663 participants. All mean differences were less than 5 points, while the minimally important difference is 10 points, indicating no clinically meaningful improvement across the drugs studied.

Adverse Events and Discontinuation Rates

Discontinuation due to adverse events was highest with several drugs. For orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide, risk ratios for discontinuation ranged from 1.9 to 4.2.

When reviewing specific adverse events, gastrointestinal events were increased most in participants taking naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide, with risk ratios ranging from 3.1 to 4.2. Fatigue was particularly high with naltrexone-bupropion risk ratio 8.9; absolute increase of 331 per 1000 people over one year , orforglipron risk ratio 3.4; absolute increase of 100 per 1000 , and CagriSema risk ratio 3.2; absolute increase of 92 per 1000 .

Conclusion and Clinical Implications

Overall, the researchers concluded that larger benefits were typically accompanied by greater harms and a higher likelihood of discontinuation. Because of this trade-off, they note that decisions about prescribing these drugs should be made through shared decision-making processes that carefully weigh the potential benefits against the potential harms.

Peptides referenced: Semaglutide, Tirzepatide, Retatrutide, Liraglutide, Cagrilintide, Mazdutide, Orforglipron.