There is one randomised trial that gave the two drugs to comparable people at the same time, and it is SURMOUNT-5. Over 72 weeks in 751 adults with obesity and no type 2 diabetes, tirzepatide produced a least-squares mean weight reduction of 20.2% and semaglutide 13.7% (PMID 40353578). Waist circumference fell 18.4 cm against 13.0 cm.
Almost every other semaglutide-versus-tirzepatide comparison online is built by putting a number from one trial next to a number from a different trial, which is not a comparison. This page starts with the head-to-head, says what it did and did not settle, then adds the one other randomised comparison and the largest real-world one.
- SURMOUNT-5, the only randomised head-to-head in obesity, gave -20.2% on tirzepatide against -13.7% on semaglutide over 72 weeks.
- It was open-label, and each arm used the maximum tolerated dose: 10 or 15 mg tirzepatide, 1.7 or 2.4 mg semaglutide.
- SURPASS-2 compared them in type 2 diabetes over 40 weeks, where HbA1c was the primary endpoint and weight a secondary one.
- A 6-month US cohort of 2396 adults without diabetes found -11.15% on tirzepatide against -8.83% on semaglutide in ordinary practice.
The head-to-head: SURMOUNT-5
A phase 3b trial randomised participants 1 to 1 to the maximum tolerated dose of tirzepatide or the maximum tolerated dose of semaglutide, once weekly, for 72 weeks. Everyone had obesity and nobody had type 2 diabetes.
| Outcome at week 72 | Tirzepatide (10 or 15 mg) | Semaglutide (1.7 or 2.4 mg) |
|---|---|---|
| Mean weight change | -20.2% | -13.7% |
| Waist circumference | -18.4 cm | -13.0 cm |
| Reaching 10%, 15%, 20% and 25% loss | More likely, all four thresholds | Reference group |
| Most common adverse events | Gastrointestinal, mostly mild to moderate, mainly during escalation | Gastrointestinal, mostly mild to moderate, mainly during escalation |
The 6.5 percentage point gap is the number worth carrying away, because it is the only one measured under one protocol with one set of eligibility criteria and one follow-up schedule. Everything else in this article is weaker evidence than that row.
What SURMOUNT-5 did not settle
- It was open-label. Participants and investigators knew which drug they were taking, which matters more for reported symptoms and adherence than for a scale reading, but it is not a blinded result.
- The doses were maximum tolerated, not matched. Part of the semaglutide arm was on 1.7 mg rather than the 2.4 mg maintenance dose, and part of the tirzepatide arm was on 10 mg rather than 15 mg. That is a pragmatic design that reflects practice, not a fixed-dose comparison.
- Safety was not the comparison. The trial reports that gastrointestinal events were most common in both arms and mostly mild to moderate. It was not powered to rank the two drugs on tolerability.
- No outcomes beyond weight and waist. It is a 72-week weight trial, not a cardiovascular outcomes trial.
The other randomised comparison, in type 2 diabetes
SURPASS-2 ran four years earlier and answered a different question. It randomised 1879 adults with type 2 diabetes to tirzepatide 5 mg, 10 mg or 15 mg, or semaglutide 1 mg, open-label, for 40 weeks, with HbA1c as the primary endpoint (PMID 34170647).
| Measure at week 40 | Tirzepatide 5 mg | Tirzepatide 10 mg | Tirzepatide 15 mg | Semaglutide 1 mg |
|---|---|---|---|---|
| HbA1c change | -2.01 points | -2.24 points | -2.30 points | -1.86 points |
| Weight difference vs semaglutide | -1.9 kg | -3.6 kg | -5.5 kg | Reference |
| Nausea | 17% to 22% across doses | 18% | ||
| Serious adverse events | 5% to 7% across doses | 3% |
Two caveats keep this trial in its lane. The semaglutide comparator was 1 mg, the diabetes dose, not the 2.4 mg weight-management dose, so the weight gap here is not the gap between the two drugs at their weight-loss ceilings. And the population had type 2 diabetes, where both drugs produce less weight loss than they do in people without it.
Why the cross-trial comparison keeps getting made
The temptation is obvious. Both drugs have a flagship obesity trial with a big headline number, and the two numbers sit near each other in every search result.
| STEP 1 (PMID 33567185) | SURMOUNT-1 (PMID 35658024) | |
|---|---|---|
| Drug and dose | Semaglutide 2.4 mg | Tirzepatide 15 mg |
| Population | Overweight or obesity, no diabetes | Obesity or overweight with a complication, no diabetes |
| Duration | 68 weeks | 72 weeks |
| Mean weight change | -14.9% | -20.9% |
| Placebo arm | -2.4% | -3.1% |
Those are two separate trials, run years apart, with different eligibility criteria, different baseline weights, different durations and different placebo responses. Subtracting one percentage from the other produces a number that no trial measured. It happens to point the same way SURMOUNT-5 does, which is reassuring, but it is not evidence in its own right. Our separate write-ups cover what STEP 1 measured for Wegovy and what SURMOUNT-1 measured for Zepbound.
Put both trial percentages against your own weight
See what -20.2% and -13.7% work out to in pounds from your starting point, rather than comparing two abstractions.
What happens outside a trial
A retrospective cohort study using US electronic health records followed 2396 adults with overweight or obesity and no diabetes who started one of the two drugs between December 2023 and June 2024, and measured weight at six months (PMID 41661445).
| At 6 months | Tirzepatide (n=1003) | Semaglutide (n=1393) |
|---|---|---|
| Mean weight change | -11.15% | -8.83% |
| Lost 5% or more | 85.7% | 75.2% |
| Lost 10% or more | 59.0% | 38.0% |
| Lost 15% or more | 31.2% | 14.0% |
Both figures are well below the 72-week trial results, which is what you would expect at six months on drugs that take four to five months to reach their top dose. The adjusted difference of 2.32 percentage points also runs smaller than SURMOUNT-5's gap at that point in treatment. This is observational data, so prescribing was not randomised and the two groups may differ in ways the adjustment did not capture.
Which brand is which
| Molecule | Type 2 diabetes brand | Weight management brand | Maximum dose |
|---|---|---|---|
| Semaglutide | Ozempic | Wegovy | 2 mg for Ozempic, 2.4 mg for Wegovy, 7.2 mg for Wegovy HD |
| Tirzepatide | Mounjaro | Zepbound | 15 mg for both |
This is where a lot of comparisons go wrong, because a 2.4 mg semaglutide result is a Wegovy result and cannot be attributed to Ozempic, whose ceiling is 2 mg. The two ladders are side by side in our semaglutide dosage chart, and tirzepatide's six strengths in the tirzepatide dosage chart.
Tolerability is not a tiebreaker either way
SURPASS-2 is the only randomised per-symptom comparison, and its numbers were close: nausea 17% to 22% across the tirzepatide doses against 18% on semaglutide 1 mg, diarrhoea 13% to 16% against 12%, vomiting 6% to 10% against 8%. Serious adverse events were 5% to 7% against 3%.
Both drugs concentrate their gastrointestinal events in the dose-escalation window and both carry the same boxed warning for thyroid C-cell tumours. We set out the recorded rates for each separately in semaglutide side effects and tirzepatide side effects.
FAQ
Is tirzepatide better than semaglutide for weight loss?
On the one randomised head-to-head in obesity, yes on weight. SURMOUNT-5 reported -20.2% on tirzepatide against -13.7% on semaglutide over 72 weeks in 751 adults with obesity and no diabetes, along with a larger reduction in waist circumference.
Is there a real head-to-head trial?
Two. SURMOUNT-5 compared them for weight over 72 weeks in adults with obesity and no diabetes. SURPASS-2 compared them over 40 weeks in type 2 diabetes with HbA1c as the primary endpoint and semaglutide dosed at 1 mg. Both were open-label.
How does Zepbound compare with Wegovy?
Those are the weight-management brands of the two molecules, and SURMOUNT-5 is the trial that compared them, using the maximum tolerated dose of tirzepatide (10 or 15 mg) against the maximum tolerated dose of semaglutide (1.7 or 2.4 mg). The result was -20.2% against -13.7% at 72 weeks.
Do the two drugs differ in side effects?
Not by much in the only randomised per-symptom comparison. In SURPASS-2, nausea was 17% to 22% across the tirzepatide doses against 18% on semaglutide 1 mg, and diarrhoea 13% to 16% against 12%. Serious adverse events were 5% to 7% against 3%.
Why do cross-trial comparisons give a different gap?
Because they are not measuring one thing. STEP 1 ran 68 weeks and SURMOUNT-1 ran 72, with different eligibility criteria, baseline weights and placebo responses, so the difference between -14.9% and -20.9% is an artefact of two protocols as much as of two drugs.
What do the drugs do outside a trial?
A 6-month US cohort study of 2396 adults without diabetes recorded -11.15% on tirzepatide and -8.83% on semaglutide, with 59.0% against 38.0% losing at least 10%. Both are lower than the trial figures, partly because six months is not long enough to complete dose escalation and hold the top dose.
This article compares what the published trials report. It is not medical advice and not a recommendation of either drug. Which treatment is appropriate, and at what dose, is a decision for your prescriber.
Sources
- Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). <em>N Engl J Med</em>. 2025;393(1):26-36. PMID: 40353578
- Frias JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). <em>N Engl J Med</em>. 2021;385(6):503-515. PMID: 34170647
- Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). <em>N Engl J Med</em>. 2021;384(11):989-1002. PMID: 33567185
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). <em>N Engl J Med</em>. 2022;387(3):205-216. PMID: 35658024
- le Roux CW, Done N, Brnabic AJM, et al. Comparative effectiveness of tirzepatide and semaglutide for obesity management in US clinical practice: a 6-month retrospective cohort study. <em>J Endocrinol Invest</em>. 2026;49(2):413-423. PMID: 41661445