Weight-loss drugs work, but nausea common Glucagon-like peptide-1–based drugs produced substantial weight loss in adults without diabetes.
*Systematic review of randomized trials; Level 1 (OCEBM).

Citation

Moiz A, Filion KB, Samuels AE, et al. Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists and Co-agonists for Weight Loss Among Adults Without Diabetes. Ann Intern Med. Published September 1, 2026. doi:10.7326/ANNALS-25-05519

Background

Weight-loss medicines acting on gut-hormone pathways are increasingly used for obesity treatment. This review updates prior evidence as newer oral and combination drugs have been studied.

Patients

Adults with overweight plus weight-related illness or obesity, without diabetes. Trials in specific clinical populations and those lasting under 16 weeks were excluded.

Intervention

Glucagon-like peptide-1–based weight-loss medicines, including semaglutide, liraglutide, tirzepatide, orforglipron, and newer combination agents.

Control

Mainly placebo, usually with lifestyle counseling.

Outcome

Main outcome: percent body-weight change. Safety outcomes included digestive side effects, stopping treatment, serious side effects, and death.

Follow-up Period

16 to 104 weeks.

Results

Thirty-eight randomized trials included 25,816 participants. Quantitative pooling was not done.
Finding Result versus placebo
Liraglutide Up to −5.8% body weight (95% CI −8.0 to −3.6)
Subcutaneous semaglutide Up to −14.8% (95% CI −16.2 to −13.4)
Oral semaglutide Up to −14.3% (95% CI −17.2 to −11.4)
Orforglipron Up to −12.4% (95% CI −15.1 to −9.7)
Tirzepatide Up to −19.0% (95% CI −21.6 to −16.4)
Digestive side effects 76.0% versus 40.1%; number needed to harm about 3
Stopping due to side effects 10.7% versus 3.4%; number needed to harm about 14

When feasible, outcomes used intention-to-treat analyses. A 5% weight loss is often clinically meaningful; most approved drugs exceeded this threshold versus placebo.

Limitations

Trial differences prevented pooled estimates. Safety reporting was inconsistent, follow-up was usually short, and direct comparisons between drugs remain limited.

Funding

None; no apparent funder bias.

Clinical Application

Offer these medicines to appropriate adults with obesity, balancing meaningful weight loss against frequent digestive side effects and long-term safety uncertainty.