SURMOUNT-5: tirzepatide against semaglutide, head to head

Until 2025, every "tirzepatide beats semaglutide" claim in obesity was a cross-trial comparison, which is a weak kind of evidence. SURMOUNT-5 ran the two drugs against each other in one trial.

What the trial asked

Whether tirzepatide is superior to semaglutide for weight reduction in adults with obesity who do not have type 2 diabetes.

Design

Phase 3b, open-label, randomised 1:1. Participants received the maximum tolerated dose of tirzepatide (10 or 15 mg) or the maximum tolerated dose of semaglutide (1.7 or 2.4 mg), injected once weekly for 72 weeks.

Open-label means nobody was blinded. That is a real limitation for a subjective-behaviour outcome like body weight, and the paper's authors accept it as a trade-off for using both drugs' own pens.

Who was enrolled

751 adults with obesity and without type 2 diabetes. The abstract gives no further baseline detail (weight, BMI, age, sex), so none is reported here.

Primary endpoint and result

Primary endpoint: percent change in weight from baseline to week 72.

P less than 0.001 for the comparison.

Key secondary results

Waist circumference fell by 18.4 cm (95% CI -19.6 to -17.2) with tirzepatide and 13.0 cm (-14.3 to -11.7) with semaglutide (P less than 0.001). Participants on tirzepatide were more likely to reach reductions of at least 10, 15, 20 and 25 percent; the abstract does not give the percentages.

Adverse events and discontinuation

Gastrointestinal events were the most common adverse events in both groups, mostly mild to moderate and mainly during dose escalation. The abstract gives no discontinuation percentages.

Funding and registration

Eli Lilly. ClinicalTrials.gov NCT05822830.

What this trial does not show

• It was funded by the maker of tirzepatide and was not blinded. Neither fact invalidates the result, but both belong next to it.
• "Maximum tolerated dose" means the arms mix doses. The trial does not tell you how 15 mg tirzepatide compares with 2.4 mg semaglutide specifically.
• Both drugs' arm means here are within the ranges of their own placebo-controlled trials (SURMOUNT-1 15 mg: -20.9 percent; STEP 1: -14.9 percent). The head-to-head confirms the gap; it does not enlarge it.
• Nothing about diabetes, cardiovascular outcomes, cost, or what happens after stopping.

Where the numbers come from

PubMed abstract of the primary paper (PubMed 40353578), fetched 4 September 2026. For the older semaglutide-versus-liraglutide head-to-head, see STEP 8. If you are weighing the two drugs for yourself, FormBlends compares compounded tirzepatide and compounded semaglutide on price and dosing; note that neither compounded product was studied in this trial and compounded drugs are not FDA approved.