SURMOUNT-5 confirms tirzepatide beats semaglutide on weight in a head-to-head trial

A direct comparison of the two leading obesity drugs found that tirzepatide (sold as Zepbound and Mounjaro) produced greater weight and waist reductions than semaglutide (sold as Wegovy, Ozempic and Rybelsus) over 72 weeks. The SURMOUNT-5 results were published in the New England Journal of Medicine and summarized by the American College of Cardiology on July 10, 2025 ^[1][2].

What the trial did

SURMOUNT-5 was a phase 3b, open-label trial \u2014 meaning participants and investigators knew which drug was being used \u2014 that randomly assigned 751 adults with obesity but without type 2 diabetes in a 1:1 ratio to the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg), injected once weekly for 72 weeks ^[1]. Participants had a BMI of 30 or higher, or 27 or higher with at least one obesity-related complication, and had a mean age of 45. They were enrolled at 32 sites in the U.S. and Puerto Rico between April 2023 and November 2024 ^[2]. The trial was funded by Eli Lilly, which makes tirzepatide ^[1].

The numbers

At week 72, the least-squares mean change in body weight was \u221220.2% (95% confidence interval, \u221221.4 to \u221219.1) with tirzepatide and \u221213.7% (95% CI, \u221214.9 to \u221212.6) with semaglutide (P<0.001) ^[1]. In absolute terms, that worked out to an average loss of 22.8 kg with tirzepatide and 15.0 kg with semaglutide \u2014 roughly 50 pounds versus 33 pounds ^[2].

Waist circumference fell by a least-squares mean of 18.4 cm with tirzepatide and 13.0 cm with semaglutide (P<0.001) ^[1]. Tirzepatide participants were also more likely to hit weight-loss thresholds of at least 10%, 15%, 20% and 25% ^[1][2]. The published abstract and the ACC summary do not report the share of participants who lost at least 30% of body weight, so those specific figures are not confirmed by the sources reviewed here.

On side effects, the most common adverse events in both groups were gastrointestinal, and most were mild to moderate and happened mainly during dose escalation ^[1]. Gastrointestinal side effects that led people to stop treatment were more common with semaglutide (5.6%) than tirzepatide (2.7%) ^[2].

One notable pattern: weight loss was about 6 percentage points lower in men than in women in both treatment groups. The trial enrolled a higher share of men (35%) than most obesity trials, and the authors think that may explain why overall weight loss looked slightly lower here than in earlier studies ^[2]. In an accompanying editorial, Frank L. Greenway, MD, wrote that the finding "raises a question about the body constituents involved in weight loss and why these may vary according to sex," and said the trial "provides helpful guidance to physicians treating patients with obesity" ^[2].

Why it matters for patients

Most obesity drug trials compare a medication with placebo, which leaves patients and clinicians guessing about how two active drugs stack up. SURMOUNT-5 tested them against each other in the same population, so the roughly 6.5-percentage-point gap in average weight change is a direct comparison rather than an estimate pieced together across separate studies ^[1].

Several limits are worth keeping in mind. The trial was open-label, not blinded ^[1]. It was funded by the maker of the winning drug ^[1]. It enrolled people with obesity and no type 2 diabetes, so the results do not speak to blood-sugar control in diabetes ^[1]. And averages hide wide individual variation \u2014 the sex difference in response is one example ^[2]. The trial measured weight and waist size, not long-term outcomes like heart attacks or deaths ^[1].

Cost, insurance coverage and supply are not addressed by this trial at all. Neither is tolerability for any one person: while stopping because of gastrointestinal side effects was about twice as common with semaglutide, GI complaints were the most common problem with both drugs ^[1][2].

What happens next

The results were posted online May 11, 2025, and appeared in the July 3, 2025 issue of the New England Journal of Medicine, pages 26\u201336 ^[1]. Whether payers or treatment guidelines shift in response is not addressed in these sources.