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SURMOUNT-5 deep dive: tirzepatide vs semaglutide head-to-head at 72 weeks

Last verified August 2026 · Phase 3b · Completed; primary results published May 2025 (print July 2025) · NCT05822830 ↗

By Eli Marsden · Founding Editor
Editorially reviewed & fact-checked against primary sources · How we verify contentLast reviewed

SURMOUNT-5 (NCT05822830) is the phase-3b open-label trial Eli Lilly designed to answer the single most-asked question in obesity medicine: does tirzepatide actually outperform semaglutide head-to-head? Cross-trial comparisons of STEP-1 and SURMOUNT-1 had suggested a tirzepatide edge of roughly 5 to 8 percentage points, but those trials enrolled separate cohorts. Aronne and colleagues randomized 751 adults with obesity and no type 2 diabetes 1:1 to maximum tolerated dose tirzepatide (10 mg or 15 mg) or maximum tolerated dose semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. Results published in the New England Journal of Medicine on May 11, 2025 showed tirzepatide producing a least-squares mean weight loss of 20.2% versus 13.7% on semaglutide — a 6.5-percentage-point advantage in a single randomized trial.

Enrollment
751
Duration
72 weeks of treatment (open-label), with a 24-week dose-escalation period and post-treatment safety follow-up
Drug
Tirzepatide (vs semaglutide head-to-head)
Population
Adults aged 18 or older with obesity (BMI ≥30) or overweight (BMI ≥27) plus at least one weight-related complication, and without type 2 diabetes (HbA1c <6.5% at screening). Mean baseline body weight was approximately 113 kg and mean BMI approximately 39 kg/m². Roughly 65% of participants were female, and about 78% were white. Participants with prior bariatric surgery, recent weight-loss-drug use, or significant cardiovascular disease in the preceding 6 months were excluded.

Primary endpoint

Percent change in body weight from baseline to week 72 (efficacy estimand, treatment-regimen)

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

First randomized head-to-head confirmation that tirzepatide produces roughly 50% more relative weight loss than semaglutide at maximum tolerated dose in adults with obesity without diabetes.

Secondary endpoints

EndpointTreatmentComparatorDifference
Body-weight reduction ≥10% at week 72

Almost nine in ten tirzepatide participants reached the conventional clinically meaningful threshold versus two thirds on semaglutide.

87.7%66.7%P<0.001 favoring tirzepatide
Body-weight reduction ≥15% at week 72

Threshold approaching the lower bound of weight loss reported with sleeve gastrectomy at one year.

71.7%45.0%P<0.001 favoring tirzepatide
Body-weight reduction ≥20% at week 72

More than half of tirzepatide participants reached a bariatric-surgery-range weight loss; semaglutide reached this in fewer than one in three.

55.0%31.1%P<0.001 favoring tirzepatide
Body-weight reduction ≥25% at week 72

Roughly twice as many tirzepatide participants reached ≥25% weight loss — a magnitude historically associated with Roux-en-Y gastric bypass.

36.5%18.6%P<0.001 favoring tirzepatide
Body-weight reduction ≥30% at week 72 (exploratory threshold)

Nearly one in four on tirzepatide reached ≥30% weight loss versus fewer than one in twelve on semaglutide.

23.0%8.2%Nominal P<0.001 favoring tirzepatide
Change in waist circumference at week 72 (cm)

Confirms larger reduction in central adiposity tracks with the larger weight effect.

−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
Change in body-mass index (BMI) at week 72 (kg/m²)−8.5 kg/m²−6.0 kg/m²Estimated treatment difference −2.5 kg/m²; P<0.001
Percent change in body weight at week 72 — restricted to participants on the 15 mg tirzepatide and 2.4 mg semaglutide doses

Pre-specified comparison at the top labeled doses rules out the possibility that the headline result depends on dose imbalance between arms.

−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

EventTreatment rateComparator rate
Nausea

Most common adverse event in both arms; rates were essentially identical and clustered in the dose-escalation phase.

43.6% (163/374)44.4% (167/376)
Diarrhea

Identical incidence between arms.

23.5% (88/374)23.4% (88/376)
Constipation27.0% (101/374)28.5% (107/376)
Vomiting

Numerically less common on tirzepatide, a notable reversal of the cross-trial impression that the dual agonist would be more emetogenic.

15.0% (56/374)21.3% (80/376)
Gastroesophageal reflux disease

Roughly half the rate on tirzepatide vs semaglutide.

6.1% (23/374)10.6% (40/376)
Eructation (belching)9.9% (37/374)7.7% (29/376)
Injection-site reaction

Largest between-arm difference of any AE; favors semaglutide on local tolerability.

8.6% (32/374)0.3% (1/376)
Alopecia (hair loss)

Predominantly in female participants; typically transient and tied to the rate of weight loss.

8.3% (31/374)6.1% (23/376)
Serious adverse events (any)

Small absolute difference; no specific organ system dominated, and rates were lower than in most prior obesity trials of these drugs.

4.8% (18/374)3.5% (13/376)
Discontinuation due to adverse event

Drug-discontinuation rates were broadly similar between arms; gastrointestinal events were the dominant reason in both.

Approximately 6%Approximately 8%

Clinical significance

SURMOUNT-5 settled the cross-trial argument with a single randomized comparison: at maximum tolerated dose, tirzepatide produces about 50% more relative weight loss than semaglutide in adults with obesity who do not have type 2 diabetes — 20.2% vs 13.7% at 72 weeks, with roughly twice the proportion reaching ≥20% and ≥25% weight loss. The trial does not address cardiovascular outcomes, durability beyond 72 weeks, or efficacy in adults with type 2 diabetes (SURPASS-2 remains the head-to-head for that population). Adverse-event profiles were broadly similar, with tirzepatide associated with fewer vomiting and reflux events but more injection-site reactions. For clinicians choosing between Wegovy and Zepbound for weight loss in patients without diabetes, SURMOUNT-5 is the strongest single piece of evidence currently available and supports tirzepatide as the more efficacious option on weight outcomes, with cost, insurance coverage, and tolerability still relevant tie-breakers.

Frequently Asked Questions

SURMOUNT-5 shows tirzepatide produced about 6.5 percentage points more weight loss than semaglutide over 72 weeks at maximum tolerated dose. For someone who has not yet started either drug and is choosing between them for weight loss without diabetes, the trial supports tirzepatide as the more efficacious option on weight outcomes. For someone already losing weight on semaglutide and tolerating it well, the case for switching is weaker: the average advantage is on the population level, individual responses vary, and switching means restarting dose escalation with its tolerability burden. Insurance coverage, cost, and any cardiovascular indication (which Wegovy has and Zepbound does not yet) should also factor in. Discuss with the prescribing clinician.
Yes on both counts. The primary endpoint — percent change in body weight from baseline to week 72 — showed −20.2% on tirzepatide vs −13.7% on semaglutide, an estimated treatment difference of −6.5 percentage points with P<0.001 for tirzepatide superiority. Every prespecified threshold endpoint (≥10%, ≥15%, ≥20%, ≥25% weight loss) also favored tirzepatide at P<0.001. The 6.5-percentage-point gap also exceeds the roughly 3-percentage-point threshold typically considered clinically meaningful in obesity trials, and the proportion reaching ≥20% weight loss nearly doubled (55.0% vs 31.1%).
The trial compared maximum tolerated dose to maximum tolerated dose — tirzepatide 10 mg or 15 mg vs semaglutide 1.7 mg or 2.4 mg — which is how both drugs are used in real-world clinical practice. A prespecified secondary analysis restricted to participants on the top labeled doses (15 mg tirzepatide vs 2.4 mg semaglutide) showed −21.8% vs −15.4%, an approximately 6.4-percentage-point gap, essentially identical to the primary result. So the headline finding does not depend on more tirzepatide participants reaching the top dose. The comparison is dose-matched to label, not dose-matched in milligrams (which would be biologically meaningless across two different molecules).
No. SURMOUNT-5 was a 72-week weight and waist-circumference trial. It was not powered or designed to detect cardiovascular events. The cardiovascular evidence base is asymmetric: semaglutide 2.4 mg has the SELECT trial (PMID 37952131) showing a 20% reduction in major adverse cardiovascular events over a mean 40 months in adults with obesity and prior cardiovascular disease, and Wegovy carries an FDA-approved indication for MACE reduction. Tirzepatide has no equivalent reported cardiovascular outcomes trial yet — SURMOUNT-MMO and SURPASS-CVOT are ongoing. So for patients with established cardiovascular disease, semaglutide currently has a labeled cardioprotective indication that tirzepatide does not.
Not directly. SURMOUNT-5 explicitly excluded participants with type 2 diabetes (HbA1c had to be <6.5% at screening). The head-to-head comparison in adults with type 2 diabetes is SURPASS-2 (PMID 34170647), which compared tirzepatide 5/10/15 mg with semaglutide 1 mg (not 2.4 mg) over 40 weeks; tirzepatide produced larger weight reductions there as well, but the populations and dosing schemes differ from SURMOUNT-5. A direct head-to-head of tirzepatide vs semaglutide 2.4 mg at maximum dose in adults with type 2 diabetes has not been reported.
Gastrointestinal adverse events were the dominant tolerability issue in both arms and broadly similar in frequency: nausea (43.6% vs 44.4%), diarrhea (23.5% vs 23.4%), and constipation (27.0% vs 28.5%) were essentially identical. Two notable differences favored tirzepatide on GI tolerability: vomiting (15.0% vs 21.3%) and GERD (6.1% vs 10.6%) were both less common. The trade-off was injection-site reactions, which were much more common on tirzepatide (8.6% vs 0.3%) — the largest between-arm AE difference observed. Serious adverse events were uncommon in both arms (4.8% vs 3.5%). Overall the tolerability profiles were more similar than different.

References

  1. 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. 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. 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. 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. 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.

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