SURMOUNT-5: Tirzepatide versus Semaglutide in Adults with Obesity — SURMOUNT-5 (phase 3b, open-label)

Background + significance

SURMOUNT-5 is the first published head-to-head trial of the two leading obesity medications, comparing maximum-tolerated-dose tirzepatide against maximum-tolerated-dose semaglutide 2.4 mg in adults with obesity and WITHOUT type 2 diabetes. Results were presented at ECO 2025 and published in the New England Journal of Medicine in May 2025. Every prior "Zepbound beats Wegovy" claim relied on comparing separate trials (SURMOUNT-1 vs STEP-1) run in different populations — a comparison that is suggestive but not valid. SURMOUNT-5 is the trial that actually tested it.

Trial design

Sponsor

Eli Lilly

Phase

Phase 3

Participants

751

Duration

72 weeks

ClinicalTrials.gov ID

NCT05822830 (opens in a new tab)

Drugs tested

• Zepbound (tirzepatide)Active comparator
• Wegovy (semaglutide 2.4 mg)Active comparator

Primary outcome

Percentage change in body weight from baseline to week 72

−20.2% on tirzepatide vs −13.7% on semaglutide at week 72

Secondary outcomes

• •Waist circumference: −18.4 cm on tirzepatide vs −13.0 cm on semaglutide
• •≥30% body-weight reduction reached by 19.7% on tirzepatide vs 6.9% on semaglutide
• •Greater improvement on tirzepatide in systolic and diastolic blood pressure
• •Greater improvement on tirzepatide in HbA1c, fasting insulin, triglycerides and HDL cholesterol

Why it matters

1. 1.Tirzepatide produced roughly 6.5 percentage points more weight loss than semaglutide over 72 weeks (−20.2% vs −13.7%) in a direct comparison.
2. 2.The gap is widest at the top end: nearly 1 in 5 tirzepatide patients lost ≥30% of body weight, versus about 1 in 15 on semaglutide.
3. 3.Open-label design is the main methodological limitation — neither patients nor investigators were blinded, which can influence adherence and reported outcomes.
4. 4.The trial excluded people with type 2 diabetes, so it does not answer which drug is better for diabetic patients. That question is covered by the SURPASS and SUSTAIN programs.
5. 5.Superior weight loss does not automatically mean superior for you — coverage, tolerability and cardiovascular indication still differ, and Wegovy carries the SELECT cardiovascular indication tirzepatide does not.