Cardiovascular Risk
Tirzepatide’s cardiovascular outcomes are now established through SURPASS-CVOT (NEJM 2025), a dedicated cardiovascular outcomes trial comparing tirzepatide vs dulaglutide in 13,299 adults with T2D and established ASCVD, followed for a median of 4 years. The 3-point MACE primary endpoint (CV death/MI/stroke) occurred in 12.2% of tirzepatide patients vs 13.1% of dulaglutide patients (HR 0.92; noninferiority met, P=0.003; superiority not met, P=0.09).
The expanded 4-point MACE (adding coronary revascularisation) was significantly reduced with tirzepatide (HR 0.88, 95% CI 0.80–0.96). All-cause mortality was also lower with tirzepatide, driven by a reduction in non-cardiovascular deaths — consistent with broad cardiometabolic benefits of tirzepatide in a population highly burdened with diabetes complications.
Dulaglutide was chosen as the active comparator specifically because placebo control was considered unethical for T2D patients with established ASCVD, given the established cardiovascular benefit of GLP-1 receptor agonists (demonstrated in REWIND for dulaglutide, LEADER for liraglutide, SUSTAIN-6/PIONEER-6 for semaglutide, EMPA-REG for empagliflozin). This means SURPASS-CVOT establishes noninferiority to an active cardiometabolic therapy — a strong result — but does not provide a placebo-controlled absolute risk reduction estimate.
Earlier data from SURPASS-4 (n=2002, 104 weeks vs insulin glargine) showed MACE HR 0.74 (95% CI 0.51–1.08) — directionally favourable but underpowered. SURPASS-CVOT supersedes this as the definitive evidence for cardiovascular outcomes.
Ontology Cardiovascular Risk [evidence_from] SURPASS-CVOT Cardiovascular Risk [evidence_from] SURPASS-4 Cardiovascular Risk [relates] Tirzepatide Cardiovascular Risk [relates] GLP-1 Receptor Agonism Cardiovascular Risk [relates] Dulaglutide
Numbers
| Trial | Endpoint | Tirzepatide | Comparator | HR (95% CI) | Conclusion |
|---|---|---|---|---|---|
| SURPASS-CVOT (2025) | 3-point MACE | 12.2% | 13.1% (dulaglutide) | 0.92 (0.83–1.01) | Noninferior; NOT superior |
| SURPASS-CVOT (2025) | 4-point MACE | — | — | 0.88 (0.80–0.96) | Significantly reduced |
| SURPASS-CVOT (2025) | All-cause mortality | Lower | — | Not separately reported | Significant |
| SURPASS-4 (2021) | MACE (underpowered) | — | Insulin glargine | 0.74 (0.51–1.08) | Not significant |
Practical Interpretation
- What is established: tirzepatide is at least as cardioprotective as dulaglutide (an established cardioprotective GLP-1 RA) — confirmed noninferiority
- What is NOT established: tirzepatide is superior to GLP-1 RAs for cardiovascular event prevention
- Who this applies to: T2D with established ASCVD; baseline population resembles advanced T2D (mean 64 years, 48.8% on insulin)
- Clinical implication: prescribers can choose tirzepatide for T2D+ASCVD without CV compromise; advantages lie in superior HbA1c and weight reduction
Confirmed Absent: CV Superiority vs Placebo
gap_status: CONFIRMED_ABSENT — structural design gap, not a search gap
The question “does tirzepatide reduce MACE compared to placebo?” cannot be answered by any existing or planned SURPASS trial. SURPASS-CVOT was designed as active-controlled non-inferiority (dulaglutide) because using placebo in T2D+ASCVD patients would be unethical once GLP-1 RA CV benefit was established. This is a structural design gap: tirzepatide’s absolute CV risk reduction vs no treatment will never be known from the SURPASS programme.
SURMOUNT-MMO (NCT05556512) — Eli Lilly’s ongoing obesity CV outcomes trial of tirzepatide vs placebo in adults with obesity and established CVD (without T2D) — is the only trial that will provide tirzepatide-vs-placebo MACE data. Primary completion estimated October 2027. Results will apply to the obesity population; T2D patients were excluded to avoid confounding.
Clinical implication: For T2D+ASCVD, the pragmatic question is already answered — tirzepatide is at least as protective as dulaglutide, which has established placebo-controlled CV benefit. The “vs placebo” data is scientifically interesting but not the clinically relevant comparison for prescribing decisions in this population.
Ontology Cardiovascular Risk [relates] SURMOUNT-MMO
Connections
- Tirzepatide — confirmed CV safety and noninferiority
- SURPASS-CVOT — evidence_from (primary)
- SURPASS-4 — evidence_from (prior, underpowered)
- Dulaglutide — active comparator in SURPASS-CVOT
- GLP-1 Receptor Agonism — class CV benefit confirmed; tirzepatide shares it
- Circulation Claims — relates (class-level benefit confirmed; superior vascular protection still not established)
- SURMOUNT-MMO — future data source (obesity CV outcomes vs placebo, expected 2027)