Evidence comparison

Tirzepatide against semaglutide: the evidence

Two randomized trials have compared the two medications head to head. They enrolled different people, ran for different lengths of time and used different semaglutide doses, and the difference between them is the whole point.

The two trials that made the comparison directly

Everything else circulating as a tirzepatide-versus-semaglutide result is either an indirect comparison across separate trials or an observational analysis. Those can be informative, but they are not the same class of evidence and this page does not treat them as such.

What SURPASS-2 found, in people with diabetes

Source: SURPASS-2, New England Journal of Medicine 2021

Over 40 weeks in 1,879 adults with type 2 diabetes, glycated hemoglobin fell by 2.01, 2.24 and 2.30 percentage points on tirzepatide 5, 10 and 15 mg against 1.86 points on semaglutide 1 mg. Tirzepatide was noninferior and then superior at every dose.

Weight was secondary here. Tirzepatide participants lost more than semaglutide participants by an estimated 1.9 kg, 3.6 kg and 5.5 kg at the three doses. The comparator was semaglutide at its diabetes dose of 1 mg, so this trial cannot say what would have happened against the higher dose used for weight. The full summary is on the SURPASS-2 page.

What SURMOUNT-5 found, in people without diabetes

Source: SURMOUNT-5, New England Journal of Medicine 2025

SURMOUNT-5 was built for the question SURPASS-2 could not answer. It randomized 751 adults with obesity and without type 2 diabetes to the maximum tolerated dose of tirzepatide (10 or 15 mg) or the maximum tolerated dose of semaglutide (1.7 or 2.4 mg) for 72 weeks, with percent weight change as the primary endpoint.

At week 72 weight fell by 20.2% on tirzepatide and 13.7% on semaglutide. Waist circumference fell by 18.4 cm and 13.0 cm. Participants on tirzepatide were more likely to reach reductions of at least 10%, 15%, 20% and 25%. The trial was open-label, so nobody was blinded to which medication they were receiving.

The most common adverse events in both groups were gastrointestinal, mostly mild to moderate, and occurred primarily during dose escalation.

What neither trial answers

Neither trial studied a compounded preparation of either medication. Both compared branded, approved products supplied under trial conditions, and neither result transfers automatically to a pharmacy preparation of the same molecule.

Neither ran beyond 72 weeks, so neither says anything about the second or fifth year. Both were open-label, which is a real limitation in a trial whose endpoint is partly behavioral. Both were funded by Eli Lilly, which makes tirzepatide. And both report group means: a difference of 6.5 percentage points between arms does not predict any individual reader’s result.

Most importantly, neither trial measured cost, tolerability over a working life, or what happens on stopping — for that last question the relevant trial is SURMOUNT-4. Which medication suits a particular person is a clinical decision, and this page is neither advice nor a recommendation to start either one.