Tirzepatide beat semaglutide head to head for weight loss in SURMOUNT-5

Both semaglutide and tirzepatide produce large weight loss, and both have been studied extensively against placebo. What had not been done until now was to put them directly against each other in people with obesity and no diabetes. SURMOUNT-5 did exactly that, and it reported a clear winner.

The New England Journal of Medicine published on May 11, 2025 the results of SURMOUNT-5, a phase 3b, open-label, controlled trial that randomly assigned 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), both given subcutaneously once weekly for 72 weeks [s1].

Why a head-to-head trial matters

Most of what patients and clinicians "know" about which of these two drugs works better came from comparing separate trials — a tirzepatide study against one placebo group, a semaglutide study against another. That is an unreliable way to rank two drugs, because the trial populations, durations, and dosing schedules differ. A single randomised trial that gives each drug to comparable people, on comparable terms, settles the comparison in a way indirect analyses cannot [s1].

The design choice that makes SURMOUNT-5 credible is also its main limitation. It compared each drug at its maximum tolerated dose rather than a fixed dose, which mirrors how the drugs are actually titrated in practice [s1].

The result

A total of 751 participants underwent randomisation [s1]. At week 72, the least-squares mean percent change in weight was −20.2% (95% confidence interval, −21.4 to −19.1) with tirzepatide and −13.7% (95% CI, −14.9 to −12.6) with semaglutide, a difference that was statistically significant (P<0.001) [s1].

Waist circumference moved in the same direction. The least-squares mean change was −18.4 cm (95% CI, −19.6 to −17.2) with tirzepatide and −13.0 cm (95% CI, −14.3 to −11.7) with semaglutide, again significant (P<0.001) [s1].

The gap widened at the tail of the distribution. Participants in the tirzepatide group were more likely than those in the semaglutide group to reach weight reductions of at least 10%, 15%, 20%, and 25% [s1]. In other words, tirzepatide did not just shift the average — it moved more people into the categories of largest weight loss, which is the part of the distribution that matters most to patients hoping for a decisive result rather than an incremental one.

The waist figure is worth reading separately from body weight. Waist circumference is a rough proxy for central and visceral fat, the fat most strongly tied to metabolic risk, so a larger waist reduction is not simply a restatement of the weight result [s1].

Tolerability

The most common adverse events in both groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation [s1]. That is the familiar profile of this drug class, and the trial did not report a tolerability signal that separated the two drugs the way the efficacy numbers did.

A prespecified secondary analysis of the same trial later examined health-related quality of life using the Short Form-36 survey, reflecting how the trialists themselves framed the comparison as being about more than the number on the scale [s2].

The caveats that matter

It was open-label. Nobody was blinded to which drug they received [s1]. For weight — an objective measurement — that matters less than for symptom reporting; but expectations can still influence adherence, effort, and the decision to push to a higher dose.

Maximum tolerated dose is not a fixed comparison. Because each participant took as much of their assigned drug as they could tolerate, the trial compares two real-world dosing strategies rather than two fixed doses [s1]. That is arguably the more useful question, but it means the result should not be read as "15 mg beats 2.4 mg" in the abstract.

The population is specific. These were adults with obesity but without type 2 diabetes [s1]. People with diabetes typically lose less weight on these drugs, so the numbers here should not be transplanted onto a different group.

The funder makes the winning drug. The trial was funded by Eli Lilly, which manufactures tirzepatide [s1].

What it settles, and what it doesn't

Within its design, SURMOUNT-5 answers the ranking question directly: at maximum tolerated doses over 72 weeks, tirzepatide produced more weight loss and more waist reduction than semaglutide, and moved more participants into the highest response categories [s1]. What a weight-loss trial cannot tell you is whether that advantage translates into fewer heart attacks, strokes, or deaths — endpoints that require dedicated cardiovascular outcome trials, not a 72-week weight study. The trial is registered on ClinicalTrials.gov as NCT05822830 [s1].

This article describes trial results, including doses and adverse events, for informational purposes only. It is not medical advice and not a recommendation about any medication.

Sources

• [s1] Aronne LJ, Horn DB, le Roux CW, et al; SURMOUNT-5 Trial Investigators. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine, published online 2025-05-11.
• [s2] Shukla AP, Dunn JP, Gomez Valderas E, et al. Improved health-related quality of life with tirzepatide versus semaglutide in adults with obesity or overweight from the SURMOUNT-5 trial. Diabetes, Obesity and Metabolism, published online 2025-11-04.