SURMOUNT-5: The Head-to-Head, Run Properly
Last verified May 2026 · Phase 3b · Finished; headline results out May 2025, in print that July · NCT05822830 ↗
Cross-trial comparison is the most common analytical error in this market, and it is usually made in good faith: STEP-1 said 14.9%, SURMOUNT-1 said 20.9%, so tirzepatide must be six points better. Different protocols, populations, durations and titration schedules make that inference shakier than it looks. SURMOUNT-5 removed the guesswork by randomizing the same adults to one drug or the other in an open-label design over 72 weeks. The gap it found — 6.5 points — is close to the cross-trial estimate, which is reassuring, but the reason to cite this trial rather than that arithmetic is that this one actually measured it.
- Enrollment
- 751
- Duration
- 72 weeks on treatment, everyone knowing which drug they were on, with the first 24 weeks spent climbing the dose and safety follow-up after
- Drug
- Tirzepatide (vs semaglutide head-to-head)
- Population
- Adults 18 and over with a BMI of 30 or more — or 27 or more if a weight-related complication came with it — and no type 2 diabetes, meaning an HbA1c under 6.5% at screening. Average starting weight around 113 kg at a BMI near 39, roughly 65% women and about 78% white. ⚠ Prior bariatric surgery, recent weight-drug use, and a cardiac event in the previous six months all ruled people out, so this is a healthier group than the average clinic caseload.
Primary endpoint
How much body weight came off over 72 weeks, on each drug
Treatment arm
−20.2% (95% CI −21.4 to −19.1)
Comparator
−13.7% (95% CI −14.9 to −12.6)
Treatment difference: Estimated treatment difference −6.5 percentage points; P<0.001 for tirzepatide superiority
★ The first randomized proof that tirzepatide takes off roughly half again as much weight as semaglutide when each is pushed to the highest dose the patient can handle. Everything else on this page is commentary on that one line.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Lost a tenth of their body weight or more Almost nine in ten on tirzepatide got there, against two in three on semaglutide. | 87.7% | 66.7% | P<0.001 favoring tirzepatide |
| Lost at least 15% Seven in ten against fewer than half — the band where drug results start to overlap what sleeve gastrectomy delivers at a year. | 71.7% | 45.0% | P<0.001 favoring tirzepatide |
| Lost at least a fifth ★ More than half on tirzepatide reached surgery-range loss; fewer than a third did on semaglutide. If a specific target is the goal rather than an average, this is the row to read. | 55.0% | 31.1% | P<0.001 favoring tirzepatide |
| Lost at least a quarter Roughly twice as many — a magnitude historically reached only after gastric bypass. | 36.5% | 18.6% | P<0.001 favoring tirzepatide |
| Lost at least 30% ⚠ Nearly one in four against fewer than one in twelve. This threshold was exploratory rather than pre-planned, so treat it as descriptive. | 23.0% | 8.2% | Nominal P<0.001 favoring tirzepatide |
| Inches off the waist The waist gap follows the weight gap — about 5 cm more on tirzepatide. | −18.4 cm (95% CI −19.6 to −17.2) | −13.0 cm (95% CI −14.3 to −11.7) | Estimated treatment difference −5.4 cm; P<0.001 favoring tirzepatide |
| BMI points lost 2.5 BMI points separated the arms, which for many people is the difference between two coverage categories. | −8.5 kg/m² | −6.0 kg/m² | Estimated treatment difference −2.5 kg/m²; P<0.001 |
| The same comparison, limited to people who reached the top dose of each drug ★ This is the analysis that closes the obvious objection. If the gap existed only because more tirzepatide patients tolerated their top dose, restricting to top-dose users on both sides would shrink it. It did not — 6.4 points against 6.5. | −21.8% (15 mg tirzepatide subset) | −15.4% (2.4 mg semaglutide subset) | Estimated treatment difference approximately −6.4 percentage points; consistent with the primary analysis |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Nausea The leading complaint on both drugs, at effectively the same rate, and concentrated while doses were being raised. | 43.6% (163/374) | 44.4% (167/376) |
| Diarrhea Indistinguishable between the two. | 23.5% (88/374) | 23.4% (88/376) |
| Constipation Slightly more frequent on semaglutide, but within noise. | 27.0% (101/374) | 28.5% (107/376) |
| Vomiting ★ Less common on tirzepatide — 15.0% against 21.3%. That reverses what comparing the two drugs' separate trials would have led you to expect, and it is the kind of thing only a head-to-head can establish. | 15.0% (56/374) | 21.3% (80/376) |
| Acid reflux Roughly half the rate on tirzepatide. | 6.1% (23/374) | 10.6% (40/376) |
| Belching Slightly more common on tirzepatide; minor either way. | 9.9% (37/374) | 7.7% (29/376) |
| Reaction where the injection went in ⚠ The biggest gap in this table, and the one that runs the other way: 8.6% against 0.3%. If you inject weekly for years, this is worth weighing rather than skipping past. | 8.6% (32/374) | 0.3% (1/376) |
| Hair loss Slightly higher on tirzepatide, mostly in women, and generally temporary — it tracks how fast weight is coming off rather than which drug did it. | 8.3% (31/374) | 6.1% (23/376) |
| Serious adverse events of any kind Uncommon on both, with no organ system standing out, and lower overall than most earlier trials of either drug reported. | 4.8% (18/374) | 3.5% (13/376) |
| Stopped the drug over a side effect Similar on both — around 6% and 8% — with stomach and bowel problems the reason in each case. | Approximately 6% | Approximately 8% |
Clinical significance
For a reader choosing between the two most-prescribed weight-management drugs, this is the trial that answers the question asked. It answers only that question. It does not compare cardiovascular outcomes, where semaglutide holds SELECT and tirzepatide holds nothing yet. It does not compare cost, where the manufacturer cash tiers are close and the compounded markets are not. And an open-label design, chosen for practical reasons, is a weaker guard against expectation effects than a blinded one. ⚠ Read it as decisive on weight and silent on everything else.
Who sells semaglutide, and for how much
This trial tested Tirzepatide (vs semaglutide head-to-head). Across the 556 sellers on this register, 283 publish a standing monthly cash price for compounded semaglutide, from $79 a month, with a median of $174.
⛔ None of those sellers was in this trial. A compounded preparation is not the product studied here: no agency has reviewed that specific preparation for safety, effectiveness or manufacturing quality, and its concentration is set by whichever pharmacy filled it. The result above is the strongest evidence available for semaglutide and it was generated on something else. Every seller, with its price record.
Frequently Asked Questions
References
- 1.Aronne LJ, Horn DB, le Roux CW, et al.; SURMOUNT-5 Trial Investigators. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025. PMID: 40353578.
- 2.Eli Lilly and Company. Study Results: A Study of Tirzepatide Compared to Semaglutide in Participants With Obesity (SURMOUNT-5, NCT05822830). ClinicalTrials.gov. 2025. https://clinicaltrials.gov/study/NCT05822830?tab=results
- 3.Jastreboff AM, Aronne LJ, Ahmad NN, et al.; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022. PMID: 35658024.
- 4.Wilding JPH, Batterham RL, Calanna S, et al.; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021. PMID: 33567185.
- 5.Lincoff AM, Brown-Frandsen K, Colhoun HM, et al.; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023. PMID: 37952131.