SURPASS-CVOT
SURPASS-CVOT is the dedicated cardiovascular outcomes trial for tirzepatide, published in the New England Journal of Medicine in December 2025 (Nicholls SJ et al., NEJM 2025;393:2409-2420). It enrolled 13,299 adults with Type 2 diabetes, BMI ≥25 kg/m², and established atherosclerotic cardiovascular disease (ASCVD). Participants were randomised to once-weekly subcutaneous tirzepatide (titrated from 2.5mg up to 15mg) or dulaglutide 1.5mg (an active comparator with established cardiovascular benefit from the REWIND trial), followed for a median of 4 years. Placebo control was considered unethical given strong evidence that GLP-1 receptor agonists reduce cardiovascular events in this population.
Primary endpoint (3-point MACE): CV death, non-fatal MI, or non-fatal stroke occurred in 12.2% of tirzepatide patients vs 13.1% of dulaglutide patients. HR 0.92 (95% CI 0.83–1.01). Noninferiority was met (P=0.003); superiority was NOT met (P=0.09). This establishes cardiovascular safety of tirzepatide — it is at least as cardioprotective as an established GLP-1 RA. It does not establish that tirzepatide is superior to the GLP-1 RA class for preventing cardiovascular events.
Secondary endpoints: The 4-point MACE (adding coronary revascularisation) was significantly reduced with tirzepatide (HR 0.88, 95% CI 0.80–0.96). All-cause mortality was lower with tirzepatide, driven by non-cardiovascular death reduction. Tirzepatide also showed substantially greater metabolic benefits: HbA1c reduction −1.66% vs −0.88%, weight loss −11.6% vs −4.5%, greater triglyceride reduction.
Safety: Adverse events leading to discontinuation were higher with tirzepatide (13.2% vs 10.1%), driven by gastrointestinal side effects — consistent with the GI profile seen in SURPASS trials. The baseline population was clinically complex: 48.8% were on insulin and 30.2% on SGLT2 inhibitors at enrolment.
Interpretation for the vault: SURPASS-CVOT provides the first definitive long-term cardiovascular evidence for tirzepatide in T2D. It does not establish superiority over GLP-1 RAs for heart events, but confirms noninferiority at a level consistent with the class benefit. Clinicians choosing between tirzepatide and semaglutide/dulaglutide for a T2D patient with ASCVD should not expect a cardiac advantage for tirzepatide specifically; the advantage lies in superior glycaemic control and weight reduction. The active-comparator design means there is no direct placebo-arm comparison, making absolute cardiovascular risk reduction calculations impossible from this trial alone.
Ontology SURPASS-CVOT [evidence_for] Tirzepatide SURPASS-CVOT [relates] Cardiovascular Risk SURPASS-CVOT [relates] Dulaglutide SURPASS-CVOT [relates] SURPASS Clinical Trial Programme SURPASS-CVOT [relates] Type 2 Diabetes
Numbers
| Endpoint | Tirzepatide | Dulaglutide | HR (95% CI) | P |
|---|---|---|---|---|
| 3-point MACE (CV death/MI/stroke) | 12.2% | 13.1% | 0.92 (0.83–1.01) | 0.003 (NI); 0.09 (sup) |
| 4-point MACE (+ revascularisation) | — | — | 0.88 (0.80–0.96) | Significant |
| All-cause mortality | Lower | — | Not reported separately | Significant |
| HbA1c change | −1.66% | −0.88% | — | — |
| Weight change | −11.6% | −4.5% | — | — |
| Discontinuation (AEs) | 13.2% | 10.1% | — | — |
Practical Interpretation
- What this confirms: tirzepatide has the same class-level CV protection as established GLP-1 RAs (dulaglutide); expanded MACE-4 significantly lower; all-cause mortality lower
- What this does NOT confirm: superiority over GLP-1 RAs for preventing heart attacks/strokes specifically
- Key limitation: active-comparator design; cannot establish absolute cardiovascular event reduction vs no drug
- Population note: mean age 64, 48.8% on insulin at baseline — this population is broadly representative of advanced T2D with established CVD; results are relevant to the vault’s target patient group
Connections
- Tirzepatide — evidence_for, [2025], SURPASS-CVOT
- Dulaglutide — compared_to (active comparator; same CV protection tier)
- Cardiovascular Risk — evidence_from
- SURPASS Clinical Trial Programme — part_of
- Circulation Claims — resolves (confirms noninferiority; does not confirm superior vascular benefit)