SURPASS-CVOT
(2025)Objective
To determine whether tirzepatide (dual GLP-1/GIP agonist) is noninferior to dulaglutide (GLP-1 agonist) for cardiovascular outcomes in patients with type 2 diabetes and established atherosclerotic cardiovascular disease
Study Summary
• Did not achieve superiority (p=0.09)
• Greater reductions in HbA1c (-1.66 vs -0.88 percentage points) and weight (-11.6% vs -4.8%) with tirzepatide
Intervention
Tirzepatide SC weekly (titrated up to 15 mg) vs Dulaglutide SC 1.5 mg weekly
Inclusion Criteria
Age ≥40 years, type 2 diabetes with HbA1c 7.0-10.5%, BMI ≥25, established ASCVD in at least one vascular territory, no CV event within 60 days of screening
Study Design
Arms: Tirzepatide (up to 15 mg weekly) vs Dulaglutide (1.5 mg weekly)
Patients per Arm: Tirzepatide: 6586, Dulaglutide: 6579
Outcome
• All-cause death: 8.6% vs 10.2%, HR 0.84 (95% CI 0.75-0.94)
• Stroke: 3.5% vs 3.8%, HR 0.91 (95% CI 0.76-1.09)
Bottom Line
Tirzepatide was noninferior to dulaglutide for the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke (HR 0.92, p=0.003 for non-inferiority) but did not achieve superiority (p=0.09). Tirzepatide produced greater reductions in HbA1c, body weight, blood pressure, and triglycerides. All-cause mortality was lower with tirzepatide in secondary analysis.
Major Points
- Active-comparator non-inferiority trial of 13,165 patients with T2DM and established ASCVD across 640 sites in 30 countries
- Primary endpoint (CV death, MI, stroke): 12.2% tirzepatide vs 13.1% dulaglutide (HR 0.92, 95.3% CI 0.83-1.01, p=0.003 non-inferiority, p=0.09 superiority)
- Non-inferiority margin of 1.05 was chosen to preserve ≥50% of dulaglutide's known efficacy vs placebo
- Median follow-up 4.0 years with 99.0% complete primary endpoint assessment
- All-cause mortality lower with tirzepatide: 8.6% vs 10.2% (HR 0.84, 95% CI 0.75-0.94)
- Non-CV death also lower: 3.0% vs 4.0% (HR 0.75, 95% CI 0.63-0.91)
- Greater metabolic improvements with tirzepatide: HbA1c -1.66 vs -0.88 percentage points; weight -11.6% vs -4.8%
- No significant difference in individual stroke outcome (3.5% vs 3.8%, HR 0.91)
- More gastrointestinal adverse events with tirzepatide (42.5% vs 35.9%)
Study Design
- Study Type
- Active-comparator-controlled, double-blind, randomized, non-inferiority trial
- Randomization
- Yes
- Blinding
- Double-blind (sham dose-escalation for dulaglutide to maintain blinding); outcome adjudication by blinded independent committee
- Sample Size
- 13165
- Follow-up
- Median 4.0 years
- Centers
- 640
- Countries
- 30 countries across North America, South America, Europe, Asia-Pacific
Primary Outcome
Definition: Composite of death from cardiovascular causes, myocardial infarction, or stroke (time to first event)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 862/6579 (13.1%) | 801/6586 (12.2%) | 0.92 (0.83-1.01 (95.3% CI)) | 0.003 (non-inferiority); 0.09 (superiority) |
Limitations & Criticisms
- No placebo arm - active comparator design limits ability to determine absolute CV benefit of tirzepatide
- Did not achieve superiority over dulaglutide (p=0.09) despite greater metabolic improvements
- Limited diversity: >80% White participants, only 29% women - not fully representative of global patient population
- Only evaluated secondary prevention population with established ASCVD - not applicable to primary prevention
- Only one GLP-1 agonist comparator (dulaglutide) evaluated - cannot extrapolate to other GLP-1 agents like semaglutide
- Imbalance in SGLT2 inhibitor addition after randomization (33.8% vs 41.1% at 36 months) may have affected results
- Higher drug discontinuation rate with tirzepatide (21.6% vs 19.8%)
- Limited to patients with type 2 diabetes - placebo-controlled trial in obesity without diabetes is ongoing (SURMOUNT-MMO)
- Mechanism of potential mortality benefit (particularly non-CV mortality) is uncertain and requires further investigation
Citation
N Engl J Med 2025;393:2409-20