Clinical Trial Review
SURMOUNT-5 Trial: Tirzepatide vs Semaglutide Results Explained
Updated October 21, 2026
In 2025 the New England Journal of Medicine published SURMOUNT-5 — the first large randomized trial to compare tirzepatide and semaglutide head-to-head for weight loss. This page walks through what the study measured, what it found, and what it did not establish, with every figure tied to the published source.
Educational content published by Surfbound Health. It is not medical advice and does not replace an individual evaluation by a licensed provider.
751 adults
Randomized, open-label, active-controlled
72 weeks
Once-weekly injectable treatments
20.2% vs 13.7%
Mean body-weight change at 72 weeks
What did SURMOUNT-5 find?
SURMOUNT-5 was a phase 3b, randomized, open-label trial that compared once-weekly injected tirzepatide with once-weekly injected semaglutide head-to-head in 751 adults with obesity but without type 2 diabetes. Over 72 weeks, mean body weight fell 20.2% with tirzepatide (10 or 15 mg) and 13.7% with semaglutide (1.7 or 2.4 mg) — a 6.5 percentage-point difference under the trial’s treatment-regimen estimand. Both study drugs were FDA-approved brand-name products; no compounded medication was studied.
Primary publication: Aronne et al., New England Journal of Medicine, May 11, 2025 · PubMed 40353578 · Registry NCT05822830
The trial at a glance
Four numbers carry most of the study. Each one describes the group being studied, not an individual patient’s expected result.
- 751
Adults randomized
Adults with obesity and no type 2 diabetes. Every participant received one of the two active drugs; there was no placebo arm.
- 72
Weeks of treatment
Both drugs were injected once weekly and titrated to a maximum tolerated dose, then continued through week 72.
- 20.2%
Mean weight reduction, tirzepatide
Once-weekly injectable tirzepatide at a maximum tolerated dose of 10 mg or 15 mg.
- 13.7%
Mean weight reduction, semaglutide
Once-weekly injectable semaglutide at a maximum tolerated dose of 1.7 mg or 2.4 mg.
Read these as averages. A mean reduction of 20.2% means some participants lost considerably more and some considerably less, and a small number did not respond meaningfully. Trial averages are not a forecast for one person.
Weight and waist results at 72 weeks
The chart below is an original visualization drawn from the published group means. It is not a reproduction of any figure from the journal.
Percent of baseline body weight, treatment-regimen estimand. Group averages.
6.5 percentage points — the arithmetic difference between the two published means (20.2 − 13.7). This subtraction is our calculation, not a separately reported endpoint.
Published results and derived differences
| Outcome at 72 weeks | Tirzepatide | Semaglutide | Difference |
|---|---|---|---|
| Mean body-weight change (% of baseline) | −20.2% | −13.7% | 6.5 pp |
| Mean body-weight change (kg) | −22.8 kg | −15.0 kg | 7.8 kg |
| Mean waist-circumference change | −18.4 cm | −13.0 cm | 5.4 cm |
| Stopped treatment because of a gastrointestinal adverse event | 2.7% | 5.6% | — |
Weight, kilogram, waist and discontinuation figures are the values reported in the publication. The “Difference” column for weight and waist is an arithmetic subtraction of those reported means, calculated for this page. “pp” means percentage points.
Why a head-to-head trial is different
Most of what gets quoted about these two medications comes from separate trials run at different times. That is an indirect comparison, and it is weaker than it looks.
Randomization removes the choice of who gets which drug
Participants were assigned to tirzepatide or semaglutide at random rather than by a clinician’s judgment or patient preference, which is what allows the two groups to be compared without the selection bias that shapes observational data.
Both groups were treated at the same time, under one protocol
The same eligibility rules, visit schedule and duration applied to both arms. In a comparison across separate trials, differences in enrollment, background care and trial era can all move the numbers — which is why cross-trial percentages should not be subtracted from each other.
The comparison is between two active treatments
There was no placebo arm. SURMOUNT-5 answers “how do these two compare with each other” rather than “does either work versus nothing”; placebo-controlled evidence for each drug comes from its own trial program.
What this still is not: a single trial, in one population, over 72 weeks, funded by the manufacturer of one of the two drugs. It is stronger evidence for comparing these two products than any cross-trial arithmetic — and it is not a lifetime safety study.
What the results mean for patients
Four findings are worth carrying into a conversation with a clinician — and one caution that applies to all of them.
Body weight
Mean weight fell 20.2% with tirzepatide and 13.7% with semaglutide — about 22.8 kg versus 15.0 kg. Tirzepatide also produced a higher likelihood of reaching the 10%, 15%, 20% and 25% thresholds, at group level.
Waist circumference
Mean waist reduction was 18.4 cm with tirzepatide and 13.0 cm with semaglutide. Waist circumference is a practical proxy for abdominal fat, and it changed in the same direction as total body weight in both arms.
Adverse events
Gastrointestinal effects — nausea, vomiting, diarrhea, constipation — were the predominant adverse events in both arms, mostly mild to moderate and concentrated during dose escalation. Treatment stopped for a GI event in 2.7% of the tirzepatide group and 5.6% of the semaglutide group.
Individual variation
The spread inside each arm is wide: some lost far more than the mean, some little. Baseline weight, age, sex, adherence, tolerability, diet and activity all shape the response — a mean cannot be promised to a person.
The caution: a larger average does not make one medication the right choice for a given person. Tolerability, contraindications, other medical conditions, cost and coverage weigh as much as a group mean. Both drugs carry a boxed warning about thyroid C-cell tumors observed in rodents, of unknown human relevance, and are contraindicated with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2.
Limitations, and the compounded-product distinction
A trial result is only as useful as the reader’s understanding of what was and was not tested. Two limits matter most here: the design of the study, and the identity of the products studied.
Open-label design
Participants and investigators knew which drug was being given; there was no placebo and no blinding. Open-label trials can be influenced by expectations and by differences in how care is delivered, even when the endpoint is a measured weight.
A specific population
Participants were adults with obesity and without type 2 diabetes. Results in people with diabetes, in older adults, in pregnancy, or in people with significant kidney, liver or cardiac disease are not established by this trial.
Maximum tolerated doses, 72 weeks
Both drugs were titrated to a maximum tolerated dose of 10 or 15 mg (tirzepatide) or 1.7 or 2.4 mg (semaglutide), and follow-up ended at 72 weeks. The trial does not describe outcomes beyond that window, or what happens after stopping.
Industry sponsorship
The trial was funded by Eli Lilly, which manufactures tirzepatide. Sponsorship does not invalidate a randomized trial, but it is part of how the evidence should be weighed, and it is not evidence of any endorsement of Surfbound.
SURMOUNT-5 did not study compounded medications
The trial studied FDA-approved, brand-name injectable products: tirzepatide (Zepbound) and semaglutide (Wegovy), each at the doses described above. Compounded semaglutide and compounded tirzepatide are different products. They are prepared by licensed compounding pharmacies and are not FDA-approved; the FDA does not review an individual compounded formulation for safety, effectiveness, or quality before it is marketed.
No randomized trial has compared a compounded semaglutide or tirzepatide product head-to-head with either studied drug. Because of that, the 20.2% and 13.7% figures describe the two approved products only. They are not evidence of equivalent safety, efficacy, absorption, or outcomes for any compounded formulation, and they should not be presented as such.
SURMOUNT-5 also implies no relationship with Surfbound. The FDA, the New England Journal of Medicine, the study investigators, and Eli Lilly have not reviewed, endorsed, or approved Surfbound or its products.
If you are considering treatment
Trial results inform a decision; they do not make it. These are the factors a licensed clinician weighs when deciding whether a GLP-1 medication — and which one — is medically appropriate.
Health history and contraindications
History of medullary thyroid carcinoma or MEN 2, pancreatitis, gallbladder disease, significant kidney or liver disease, and pregnancy or breastfeeding plans all change what is appropriate.
Tolerability in practice
A trial reports average tolerability. How an individual handles nausea or constipation during escalation is a practical question, and it sometimes means slowing the schedule.
Treatment goals
Weight targets, coexisting conditions such as prediabetes or hypertension, and how long treatment is intended to continue all shape the choice.
Formulation — approved versus compounded
A licensed provider should state plainly whether a product is FDA-approved or compounded, because the evidence base is different for each.
Cost and coverage
Whether a plan covers an FDA-approved product, and what a cash-pay compounded option costs, decides the practical choice as often as the clinical one.
Eligibility and follow-up
Treatment requires a valid prescription after a real evaluation, plus a plan for monitoring, dose review, and what to do if side effects occur.
Next step
Exploring Your Weight-Loss Treatment Options?
Surfbound connects eligible adults with licensed medical providers who review individual health information and determine which treatment options, if any, may be medically appropriate.
Surfbound’s weight-loss options are compounded medications. They are not FDA-approved and were not the products studied in SURMOUNT-5. Any prescription requires a licensed provider review; not everyone qualifies, and nothing is charged unless a medication is approved.
References and how this page was produced
- 1.Aronne LJ, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). New England Journal of Medicine. Published online May 11, 2025. DOI 10.1056/NEJMoa2416394. New England Journal of Medicine · May 11, 2025
- 2.SURMOUNT-5 — PubMed record (abstract and indexing) for the New England Journal of Medicine publication above. PubMed / National Library of Medicine · 2025
- 3.SURMOUNT-5 registry entry — Tirzepatide Compared With Semaglutide in Participants With Obesity or Overweight. Phase 3b, randomized, open-label, active-controlled trial. ClinicalTrials.gov · 2025
- 4.Zepbound (tirzepatide) injection, for subcutaneous use — U.S. Prescribing Information, current version. Source for the boxed warning, contraindications, and labeled adverse reactions of the FDA-approved tirzepatide product. DailyMed / U.S. National Library of Medicine · Current version
- 5.Wegovy (semaglutide) injection, for subcutaneous use — U.S. Prescribing Information. Source for the boxed warning and labeled adverse reactions of the FDA-approved semaglutide product. Novo Nordisk — U.S. Prescribing Information · Current version
- 6.Compounding and the FDA: Questions and Answers — compounded drugs are not FDA-approved and are not reviewed by the FDA for safety, effectiveness, or quality before marketing. U.S. Food and Drug Administration · Accessed 2026
Methodology
- Every numerical result here is taken from the peer-reviewed publication or its registry record, and is presented next to the population, dosing and estimand that produced it.
- The chart and the two "Difference" figures (6.5 percentage points, 7.8 kg, 5.4 cm) are original visualizations or calculations made from the published group means. No journal figure has been reproduced.
- Statements about the FDA-approved products come from current U.S. prescribing information; statements about compounded products come from the FDA.
- No individual physician review of this page is claimed. Surfbound Health publishes this interpretation and is editorially responsible for it.
Page content revised and verified against the primary publication on 2026-10-21. Published by Surfbound Health (Organization). This page is educational content, not medical advice, and does not replace an individual evaluation by a licensed provider. Compounded medications are not FDA-approved.