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Clinical science · NEJM 2025

SURMOUNT-5: tirzepatide outperformed semaglutide, head-to-head

The first direct comparison of the two leading obesity drugs gave a clear answer on average weight loss — with the usual caveats about what an average can and can't tell you.

Researched by the editorial team · Source: NEJM (Aronne et al., 2025)
The short version

What the trial compared

SURMOUNT-5 was a 72-week head-to-head study in adults with obesity or overweight and weight-related conditions, but without type 2 diabetes. Participants received the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg), once weekly, alongside lifestyle support. The primary endpoint was percent weight change at week 72.

SURMOUNT-5 — mean weight loss at 72 weeks

Head-to-head, maximum tolerated dose
0%10%20% 20.2%13.7% TirzepatideSemaglutide
Source: SURMOUNT-5, Aronne et al., New England Journal of Medicine, 2025. Tirzepatide 10/15 mg vs semaglutide 1.7/2.4 mg, 72 weeks.

What it means — and doesn't

SURMOUNT-5 settles the average-efficacy question: in this population, tirzepatide led to greater mean weight and waist reduction. But "greater on average" is not "right for everyone." Individual response varies widely, and tolerability, side-effect profile, cost, insurance coverage, and other approved indications (semaglutide carries cardiovascular, kidney, and MASH indications; tirzepatide carries a sleep-apnea indication) all factor into a real prescribing decision.

Don't over-read one trial. A single 72-week study in non-diabetic adults doesn't capture long-term durability, every patient type, or every endpoint. It's strong evidence on one question, not a universal verdict.

How this fits the bigger picture

Stacked against registrational trials, the class keeps climbing: semaglutide ~14.9% (STEP-1), tirzepatide ~22.5% (SURMOUNT-1), and the investigational triple agonist retatrutide ~28.3% (TRIUMPH-1) — though those are separate trials, not head-to-head. SURMOUNT-5 is valuable precisely because it removes the cross-trial guesswork for two of them.

FAQ

Is tirzepatide always better than semaglutide?
It produced greater average weight loss in this trial, but the best choice depends on the individual, tolerability, cost, coverage, and which other indications matter for that patient.
Were these the compounded versions?
No. The trial studied FDA-approved branded products at defined doses. Compounded versions are not FDA-approved finished drug products and were not what was tested.

Sources

Note. Educational content, not medical advice. Treatment decisions are made by a licensed clinician. Disclosure appears at the top of the page.