Key facts
- Drug / target: tirzepatide (GIP + GLP-1 receptor agonist) versus semaglutide (GLP-1 receptor agonist), both once weekly by subcutaneous injection.
- Sponsor: Eli Lilly and Company.
- Design: randomized, open-label, phase 3b head-to-head comparative trial.
- Population + n: 751 adults with obesity (or overweight with a weight-related complication) and without type 2 diabetes.
- Duration: 72 weeks.
- Primary endpoint: percent change in body weight from baseline to week 72.
- Headline result: −20.2% with tirzepatide versus −13.7% with semaglutide (P<0.001).
- Registration: NCT05822830 (ClinicalTrials.gov).
- Publication: New England Journal of Medicine, 2025 — PMID 40353578.
What was the SURMOUNT-5 trial?
SURMOUNT-5 was the first large randomized trial to compare the two dominant obesity drugs — tirzepatide and semaglutide — directly against each other rather than against placebo.
Until it reported, the field only had cross-trial inference: tirzepatide's roughly 21% mean loss in SURMOUNT-1 and semaglutide's roughly 15% in STEP 1 came from separate studies with different participants, so comparing the two figures was suggestive rather than definitive. SURMOUNT-5 removed that ambiguity by randomizing the same population to one drug or the other. It was a phase 3b, open-label trial funded by Eli Lilly and published in the New England Journal of Medicine in 2025 (PMID 40353578), registered as NCT05822830.
Who was in it?
The trial randomized 751 adults who had obesity — or overweight with a weight-related complication — and who did not have type 2 diabetes. Excluding people with diabetes matters: diabetes has historically blunted the weight response to this drug class, so studying a non-diabetic population isolates the obesity-treatment effect and makes the comparison with earlier obesity trials cleaner. As in the wider SURMOUNT and STEP programs, both groups received the drug alongside lifestyle support, so the trial measures the difference between two active drugs, not the difference between a drug and doing nothing.
What did participants receive?
Participants were assigned to one drug or the other, each given once weekly as a subcutaneous injection and titrated to the maximum tolerated dose within its approved range. For tirzepatide that meant a maintenance dose of 10 mg or 15 mg; for semaglutide it meant 1.7 mg or 2.4 mg. Reporting these doses describes what the trial administered — it is not a dosing instruction. The two drugs differ mechanistically: tirzepatide is a dual agonist at both the GIP and GLP-1 receptors, while semaglutide acts at the GLP-1 receptor alone, which is the leading hypothesis for why the tirzepatide arm lost more weight.
Primary results
The primary endpoint was the percent change in body weight from baseline to week 72. Tirzepatide won on that measure, and by a clear margin.
| Group | Mean weight change at week 72 | 95% confidence interval |
|---|---|---|
| Tirzepatide (10 or 15 mg weekly) | −20.2% | −21.4 to −19.1 |
| Semaglutide (1.7 or 2.4 mg weekly) | −13.7% | −14.9 to −12.6 |
The difference between the two arms was statistically significant (P<0.001). In plain terms, the average participant on tirzepatide lost roughly half again as much weight as the average participant on semaglutide over the same 72 weeks. The confidence intervals do not overlap, which underlines that this was a consistent group-level advantage rather than a coin-flip.
Secondary results
The secondary endpoints moved in the same direction as the primary one. Only figures reported in the published trial are listed here.
| Secondary measure at week 72 | Tirzepatide | Semaglutide |
|---|---|---|
| Change in waist circumference | −18.4 cm (95% CI −19.6 to −17.2) | −13.0 cm (95% CI −14.3 to −11.7) |
| Reached weight reduction of at least 10%, 15%, 20% and 25% | More participants on tirzepatide reached each threshold than on semaglutide | |
Waist circumference — a marker of the abdominal fat most tied to cardiometabolic risk — fell further with tirzepatide (P<0.001), consistent with the larger overall weight loss. Tirzepatide participants were also more likely to reach each responder threshold, including the demanding 25% mark. The published abstract states that tirzepatide bettered semaglutide at each of these cut-offs but does not give the exact proportions in the summary, so specific responder percentages are omitted here rather than estimated.
Safety and side effects reported
Both drugs showed the safety profile already established for the GLP-1-based obesity class. The most common adverse events in both groups were gastrointestinal — the nausea, diarrhoea, vomiting and constipation typical of this class — and the trial reported that most were mild to moderate and occurred primarily during dose escalation, easing as the dose stabilized. The published summary does not break out exact side-effect rates by group, so no adverse-event percentages are stated here. Nothing in the trial suggested a new or unexpected safety signal for either drug beyond what their existing labels describe.
Limitations and what it does not prove
Three limitations frame how far the result travels. First, SURMOUNT-5 was open-label: participants and investigators knew which drug was given, which can influence behaviour and reporting even though the weight measurements themselves are objective. Second, it enrolled adults with obesity and without type 2 diabetes, so it does not speak to people with diabetes, where the weight response to this class is typically smaller. Third, it measured weight and body-composition outcomes over 72 weeks — it was not a cardiovascular-outcomes trial and does not show that the extra weight loss translates into fewer heart attacks, strokes or deaths. It also reports a group average: individual response varies widely, and greater average efficacy does not settle tolerability, cost, insurance coverage or suitability for any particular person.
Why the SURMOUNT-5 trial matters
Before SURMOUNT-5, the question "which works better, tirzepatide or semaglutide?" could only be answered by lining up separate trials and hoping the populations were comparable. This trial answered it directly, in one randomized comparison, and gave clinicians and patients a like-for-like number: about 20% versus about 14% mean weight loss at 72 weeks. That makes it the anchor citation for the head-to-head question and a natural companion to the single-drug write-ups. For the mechanism and the wider evidence base, see our tirzepatide vs semaglutide comparison, the individual tirzepatide and semaglutide summaries, the placebo-controlled SURMOUNT-1 trial, and the pillar guide to peptides for weight loss. It does not, on its own, make either drug the right choice for a given individual — that remains a clinical decision.
Frequently asked questions
What was the SURMOUNT-5 trial?
SURMOUNT-5 was a randomized, open-label, phase 3b trial funded by Eli Lilly that directly compared tirzepatide with semaglutide for the treatment of obesity. It enrolled 751 adults with obesity but without type 2 diabetes and ran for 72 weeks. It was the first large head-to-head comparison of the two leading obesity drugs, published in the New England Journal of Medicine in 2025.
Did tirzepatide beat semaglutide in SURMOUNT-5?
Yes, on the primary weight-loss endpoint. At week 72, participants on tirzepatide lost a mean 20.2% of body weight versus 13.7% on semaglutide, and the difference was statistically significant (P<0.001). Tirzepatide participants were also more likely to reach weight reductions of at least 10%, 15%, 20% and 25%. This is a comparison of two approved drugs against each other, not a comparison against no treatment.
What doses of tirzepatide and semaglutide were used in SURMOUNT-5?
Participants received the maximum tolerated dose within each drug's approved range, given once weekly by subcutaneous injection: tirzepatide at 10 mg or 15 mg, and semaglutide at 1.7 mg or 2.4 mg. This reflects how the drugs are titrated in practice rather than a single fixed dose for everyone.
Was SURMOUNT-5 blinded?
No. SURMOUNT-5 was an open-label trial, meaning participants and investigators knew which drug was being given. Open-label design is common in head-to-head trials of injectables that use different devices and titration schedules, but it is a limitation because expectations can influence behaviour and reporting. The weight measurements themselves were objective.
Does SURMOUNT-5 mean tirzepatide is the right drug for everyone?
No. SURMOUNT-5 reports a group average in adults with obesity and without type 2 diabetes; individual results vary widely, and tolerability, cost, coverage and medical history all factor into which drug a clinician prescribes. The trial shows tirzepatide produced greater mean weight loss in this population, not that it is the correct choice for any particular person. Prescribing decisions belong with a licensed clinician.
Where was SURMOUNT-5 published and how can I verify it?
SURMOUNT-5 was published in the New England Journal of Medicine in 2025 and is indexed on PubMed under PMID 40353578. The trial is registered on ClinicalTrials.gov under identifier NCT05822830. Both records are linked in the Sources section of this page so you can read the original.
Sources
This summary traces to the peer-reviewed publication and the trial registration:
- Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5), New England Journal of Medicine, 2025 — PubMed 40353578
- SURMOUNT-5 (tirzepatide vs semaglutide) — ClinicalTrials.gov NCT05822830
- Drug reference records: tirzepatide and semaglutide.