- In SURMOUNT-5, adults with obesity and without diabetes lost an average of 20.2% of their weight on tirzepatide and 13.7% on semaglutide over 72 weeks.1
- Waist size fell by 18.4 cm vs 13.0 cm. More people on tirzepatide reached every weight-loss milestone the trial tracked.1
- Side effects were similar in type: mostly stomach-related, mostly mild to moderate, mostly during dose increases.1 Both are effective. Which one fits you is a decision for you and your prescriber.
Why this trial matters
Before 2025, people compared the STEP trials of semaglutide with the SURMOUNT trials of tirzepatide. Those trials enrolled different people at different times, so the comparison was always rough. For those results, see STEP 1 and SURMOUNT-1.
SURMOUNT-5 was the first head-to-head phase 3b trial. It randomly assigned 751 adults with obesity but without type 2 diabetes to one of the two medicines, once weekly, for 72 weeks, alongside diet and activity advice.1 Each person was taken up to the highest dose they could tolerate:
- Tirzepatide (sold for weight loss as Zepbound): 10 mg or 15 mg. It acts on two gut-hormone receptors, GIP and GLP-1.2
- Semaglutide (sold for weight loss as Wegovy): 1.7 mg or 2.4 mg. It acts on the GLP-1 receptor only.2
Doses were stepped up in line with each medicine's approved label. The aim was to reach the top dose, but a lower dose was allowed if stomach side effects persisted.3 So the trial compares each medicine as it is typically used, at the highest dose a person can live with, rather than fixed doses.
At the start, participants averaged 44.7 years old, 113.0 kg (about 249 lb) and a BMI of 39.4. About 65% were women, and 56.7% had prediabetes.2
The main result: weight
The gap was about 6.5 percentage points in favor of tirzepatide, and it was statistically clear.1 For a person starting at 113 kg, that works out to roughly 23 kg vs 15.5 kg. Individual results varied widely in both groups.
The trial also counted how many people lost at least 10%, 15%, 20% and 25% of their weight. People on tirzepatide were more likely to reach each of these.1 A later analysis of the 425 participants with prediabetes, more than half of the trial, reports the exact shares for that group:3
| Lost at least | Tirzepatide | Semaglutide |
|---|---|---|
| 10% | 87.6% | 65.1% |
| 15% | 73.3% | 41.2% |
| 20% | 51.4% | 26.2% |
| 25% | 33.6% | 13.3% |
| 30% | 21.1% | 4.8% |
In that group, average weight loss was 21.5% vs 14.5%, and blood sugar returned to the normal range in 89.9% on tirzepatide vs 76.2% on semaglutide.3
Side effects
The main paper reports that the most common side effects in both groups were gastrointestinal, mostly mild to moderate, and mainly during dose escalation.1 In the prediabetes analysis, rates were close between the two medicines:3
| Tirzepatide | Semaglutide | |
|---|---|---|
| Nausea | 46% | 44% |
| Constipation | 27% | 31% |
| Diarrhea | 25% | 25% |
| Vomiting | 15% | 21% |
This fits a point made in a 2025 joint advisory: differences in side-effect rates between the earlier, separate trials may partly reflect different placebo-group rates, and the increase over placebo looked similar for the two medicines.4 More on timing and what helps: GLP-1 nausea and stomach side effects.
How people felt
A quality-of-life analysis found that physical health scores improved on both medicines. The "general health" score improved more with tirzepatide (5.45 vs 4.20 points), and people who lost the most weight tended to report the biggest gains in physical functioning, pain and general health.2
Caveats worth knowing
- Open-label. Participants and doctors knew which medicine was being given. Weight is an objective measure, but side-effect reporting can be influenced by expectations.1
- Funded by Eli Lilly, which makes tirzepatide.1
- No diabetes. People with type 2 diabetes were not included. In earlier trials they tended to lose less weight on both medicines. See GLP-1s in type 2 diabetes.
- Weight is not everything. SURMOUNT-5 did not test heart attacks or strokes. Semaglutide has been tested in a large cardiovascular outcomes trial; see the SELECT trial.
- It did not cover cost, insurance coverage, supply or what happens after stopping. Those often decide the choice in practice.
Averages also hide a lot of spread. Some people on semaglutide lost more than some people on tirzepatide, and the reverse. A trial can tell you which medicine tends to do more for a group, not exactly what either will do for you.
Bottom line: in the only head-to-head trial so far, tirzepatide led to more weight loss on average. Semaglutide still produced substantial weight loss. The right choice depends on your health history, how you tolerate a medicine and what you can access, which is a conversation for your care team.
Sources
- Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). N Engl J Med. 2025;393(1):26-36. PubMed · doi:10.1056/NEJMoa2416394
- 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 Obes Metab. 2026;28(1):452-462. PubMed · Full text (PMC)
- Galindo RJ, Aronne LJ, Horn DB, et al. Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5. J Endocrinol Invest. 2026;49(7):1611-1620. PubMed · Full text (PMC)
- Mozaffarian D, Agarwal M, Aggarwal M, et al. Nutritional priorities to support GLP-1 therapy for obesity: A joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society. Obesity (Silver Spring). 2025;33(8):1475-1503. PubMed · Full text (PMC)
