How much weight each incretin drug removes, side by side

Design

Updated systematic review of randomised trials (≥16 weeks)

Population

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

Primary outcome

Placebo-subtracted percent weight change and adverse events

Effect

Up to −19.0% tirzepatide, −14.8% semaglutide, −5.8% liraglutide; GI effects 76% vs 40%

An 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 and without diabetes, adding 14 trials since the previous version.

Among drugs on the market, the best placebo-subtracted weight loss reported was 5.8% for liraglutide, 14.8% for subcutaneous semaglutide, 14.3% for oral semaglutide, 12.4% for orforglipron and 19.0% for tirzepatide. Gastrointestinal adverse events occurred in 76% of treated participants against 40% on placebo; 10.7% stopped because of adverse events against 3.4%. Serious adverse events (6.5% vs 5.2%) and deaths were rare. Head-to-head trials favoured semaglutide over liraglutide and tirzepatide over semaglutide.

For a physician managing obesity alongside other conditions, the useful message is the ranking and the cost of tolerability. Heterogeneity meant the figures could not be pooled, so these are the best results from individual trials, not averages.

Match the drug to the weight loss needed, the patient's other conditions, the route they will accept and what they can afford. Plan for nausea from the first dose and titrate slowly.

• Expect placebo-subtracted weight loss of roughly 6% with liraglutide, 14–15% with semaglutide and 19% with tirzepatide
• Warn patients that about three in four have gastrointestinal effects and about one in ten stop because of side effects
• Titrate slowly and review hydration and kidney function in patients prone to vomiting or dehydration
• Choose by the weight loss needed, comorbidities, route of administration and cost
• Remember these are figures from trials in people without diabetes; weight loss is usually smaller in type 2 diabetes

Why it matters

Choosing an obesity drug is now a comparison between options, not a yes-or-no decision.

Don't overread it

The figures are the best single-trial results, not pooled estimates, so cross-drug comparisons are approximate.

The statistics, in plain English

Placebo-subtracted weight loss is the extra loss beyond what the placebo group achieved. Because the trials differed too much to pool, each figure comes from one or a few trials, and the intervals around them (for tirzepatide, 16.4% to 21.6%) show the uncertainty.

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