Weight loss on GLP-1 drugs reached up to 6%–19% above placebo, depending on the agent

Design

Updated systematic review of randomised controlled trials (no quantitative pooling)

Population

38 trials, 25,816 adults with overweight or obesity without diabetes

Primary outcome

Placebo-subtracted percentage weight loss and adverse events

Effect

Liraglutide −5.8%, semaglutide SC −14.8%, oral −14.3%, orforglipron −12.4%, tirzepatide −19.0%

This updated systematic review in Annals of Internal Medicine included 38 randomised trials of at least 16 weeks in 25,816 adults with overweight or obesity but no diabetes, adding 14 trials since the previous version. Heterogeneity prevented pooling, so results are reported per drug.

Placebo-subtracted weight loss reached 5.8% with liraglutide, 14.8% with subcutaneous semaglutide, 14.3% with oral semaglutide, 12.4% with orforglipron and 19.0% with tirzepatide. Emerging multi-agonists went further (amycretin 23.9%, retatrutide 22.1%) but are not licensed. Gastrointestinal adverse events occurred in 76% vs 40% on placebo; stopping because of adverse events was 10.7% vs 3.4%. Serious adverse events were 6.5% vs 5.2%, with no new safety signals.

For the physician managing a patient with obesity and several other conditions, the practical choice is now among drugs of clearly different potency and route. In India, the arrival of generic semaglutide and the cost of tirzepatide will often decide more than the ranking does.

• Tirzepatide gave the largest placebo-subtracted weight loss among licensed drugs (up to about 19%).
• Oral semaglutide, at the doses used in these obesity trials, performed similarly to injectable semaglutide (up to about 14%); check the dose before applying this to a patient on the diabetes formulation.
• Liraglutide is clearly less effective (up to about 6%) than newer agents.
• Warn patients that nausea and other gastrointestinal effects are common, and titrate slowly.
• About 1 in 10 stopped because of side effects; plan follow-up in the first months.

Why it matters

Choice among these drugs is now a question of how much weight loss is needed and which route the patient can manage.

Don't overread it

Cross-trial comparisons are not head-to-head; the per-drug figures are the best reported, not pooled estimates.

The statistics, in plain English

'Placebo-subtracted' means the extra weight lost beyond what the placebo group lost. These figures come from different trials in different populations, so comparing drugs across trials is only approximate; direct head-to-head trials (tirzepatide over semaglutide, semaglutide over liraglutide) are more reliable.

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