SURMOUNT-5: Tirzepatide Beats Semaglutide Head-to-Head
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The first direct comparison of the two leading obesity drugs is in, and tirzepatide came out ahead. Here are the full SURMOUNT-5 results and what they mean for treatment choice.
By Dr. Parmis, Lead Medical Researcher · Medically reviewed by Adam Kennah, M.D. · Last reviewed July 9, 2026 · Sources cited at the end.
Direct answer
In SURMOUNT-5, the first head-to-head trial of the two leading obesity drugs, tirzepatide (Zepbound) beat semaglutide (Wegovy): participants lost 20.2% of body weight on average at 72 weeks versus 13.7% with semaglutide. Tirzepatide won the primary endpoint and all five key secondary endpoints. The trial enrolled 751 adults with obesity (without diabetes), used each drug at its maximum tolerated dose, and was published in the New England Journal of Medicine and presented at the European Congress on Obesity.
The headline numbers
Full results
| Endpoint | Tirzepatide | Semaglutide |
|---|---|---|
| Mean weight loss (72 wk) | 20.2% | 13.7% |
| Average weight lost | ~22.8 kg | ~15.0 kg |
| ≥ 25% weight loss | 31.6% | 16.1% |
| Waist reduction | −18.4 cm | −13.0 cm |
| GI discontinuation | 2.7% | 5.6% |
Source: SURMOUNT-5, New England Journal of Medicine; American College of Cardiology summary.
Why tirzepatide pulled ahead
Tirzepatide is a dual GIP/GLP-1 receptor agonist, while semaglutide acts on GLP-1 alone. Researchers noted the result was consistent with the two drugs’ separate prior trials. Both had similar overall safety, with gastrointestinal effects most common; notably, GI-related discontinuations were lower with tirzepatide.
What it means for patients
For many people, tirzepatide offers a larger average weight-loss ceiling — but semaglutide remains highly effective, and choice depends on tolerability, cost, coverage, and clinical history. A new oral GLP-1 pill now adds a third option. For a patient-facing decision guide, see our tirzepatide vs semaglutide vs the pill comparison and our brand vs compounded overview.
How the trial was designed
SURMOUNT-5 was a randomized, open-label, phase 3b trial of 751 adults with obesity or overweight and at least one weight-related condition, 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 for 72 weeks. Comparing each drug at its top tolerated dose is what makes the result a fair, direct test rather than a mismatched comparison, and the findings closely tracked what each drug had shown in its own earlier trials.
Caveats worth noting
A few limitations matter. The trial was open-label, meaning participants knew which drug they received. It enrolled a higher share of men than most obesity trials, and men lost slightly less weight in both groups, which may have modestly lowered the overall figures. And it studied FDA-approved products, not compounded tirzepatide. None of this undercuts the headline — tirzepatide was superior across the board — but individual results still depend on tolerability, cost, and adherence, so semaglutide remains a strong option for many patients.
Frequently asked questions
Which drug won SURMOUNT-5? Tirzepatide. Participants lost 20.2% of body weight on average at 72 weeks versus 13.7% with semaglutide — tirzepatide was superior on the primary endpoint and all key secondary endpoints.
How big was the difference? About 6.5 percentage points, or roughly 7.8 kg more weight lost on average. And 31.6% of tirzepatide users reached at least 25% weight loss versus 16.1% on semaglutide.
Was it a fair comparison? Yes — it was a randomized, head-to-head trial of 751 adults using each drug at its maximum tolerated dose, published in the New England Journal of Medicine.
Does this apply to compounded tirzepatide? The trial studied FDA-approved tirzepatide (Zepbound). Compounded tirzepatide is not FDA-approved and was not the product tested.
July 9, 2026: Published; results verified against NEJM/ACC/Weill Cornell reporting of SURMOUNT-5.
May 11, 2025: SURMOUNT-5 published in the New England Journal of Medicine.
Sources
- New England Journal of Medicine / Weill Cornell — SURMOUNT-5 head-to-head trial
- American College of Cardiology — SURMOUNT-5 weight and waist results
- HCPLive — SURMOUNT-5: tirzepatide bests semaglutide
Important: Compounded tirzepatide is not FDA-approved and is not the same medicine as Mounjaro or Zepbound, the only FDA-approved tirzepatide products (Eli Lilly and Company). This page is educational and is not medical or legal advice. Weight-loss medications require evaluation and, when appropriate, a prescription from a licensed clinician. Individual results and side effects vary. Confirm current FDA status, pricing, and clinical guidance directly before acting.