SURMOUNT-5
SURMOUNT-5 is the first published head-to-head randomised controlled trial comparing tirzepatide directly against semaglutide 2.4mg (Wegovy) in adults with obesity but without Type 2 diabetes. Published in NEJM 2025 (PMID 40353578), it enrolled 751 participants and ran for 72 weeks. The primary endpoint was percentage body weight reduction.
Primary result: Tirzepatide reduced body weight by −20.2% vs −13.7% for semaglutide 2.4mg — an absolute difference of −6.5 percentage points (P<0.001). This confirms tirzepatide’s superiority for weight loss in the obesity-without-T2D phenotype, consistent with the mechanistic hypothesis that dual GIP+GLP-1 agonism produces greater weight loss than GLP-1 agonism alone.
Ontology SURMOUNT-5 [compares] Tirzepatide SURMOUNT-5 [compares] Semaglutide SURMOUNT-5 [evidence_for] Weight Loss in T2D
Tolerability: GI-related discontinuation was 2.7% for tirzepatide vs 5.6% for semaglutide. GI adverse events (nausea, vomiting, diarrhoea) were comparable between arms overall, but fewer patients stopped tirzepatide due to GI effects.
Vault context — important limitation for T2D inference: SURMOUNT-5 enrolled patients without T2D. This is the SURMOUNT programme (obesity trials), not SURPASS (T2D trials). Results cannot be directly applied to T2D patients for several reasons: (1) T2D is associated with metabolic insulin resistance that attenuates weight loss pharmacotherapy response; (2) glycaemic control is an additional primary goal in T2D that changes the treatment value equation; (3) the relevant comparator for T2D patients would be semaglutide 1mg or 2mg (Ozempic doses), not semaglutide 2.4mg (Wegovy dose). No published head-to-head trial of tirzepatide vs semaglutide 2mg in T2D exists.
Ontology SURMOUNT-5 [relates] Type 2 Diabetes SURMOUNT-5 [part-of] Tirzepatide
Key Numbers
| Endpoint | Tirzepatide | Semaglutide 2.4mg | Effect |
|---|---|---|---|
| Weight change (%) | −20.2% | −13.7% | Δ −6.5 pp; P<0.001 |
| GI discontinuation | 2.7% | 5.6% | Lower with tirzepatide |
| Duration | 72 weeks | 72 weeks | — |
| Population | Obesity, no T2D | Obesity, no T2D | NOT T2D |
Connections
- Semaglutide — comparator
- Tirzepatide — intervention
- Weight Loss in T2D — relates (obesity-only caveat applies)