What are the results of the cardiovascular (CV) outcome trial of Tirzepatide (a glucagon-like peptide-1 (GLP-1) receptor agonist) in patients with type 2 diabetes?

Tirzepatide Cardiovascular Outcome Trial: SURPASS-CVOT

Current Status and Design

The cardiovascular outcome trial for tirzepatide (SURPASS-CVOT) is currently ongoing and has not yet reported results. 1 This is a critical distinction from other GLP-1 receptor agonists like semaglutide and liraglutide, which have completed cardiovascular outcome trials demonstrating significant MACE reduction.

Trial Design Specifications

• Study design: Randomized, double-blind, active-controlled trial comparing tirzepatide (up to 15 mg weekly) versus dulaglutide 1.5 mg weekly 1
• Primary endpoint: Time to first occurrence of MACE (cardiovascular death, myocardial infarction, or stroke) 1
• Enrollment: 13,299 participants across 640 sites in 30 countries, completed over 2 years 1
• Event-driven design: Trial continues until ≥1,615 participants experience an adjudication-confirmed MACE component 1

Baseline Characteristics of Enrolled Patients

• Mean age 64.1 years with diabetes duration of 14.7 years 1
• Mean HbA1c 8.4% and BMI 32.6 kg/m² 1
• High cardiovascular risk population: 65.0% had coronary disease (47.3% prior MI, 57.4% prior revascularization), 19.1% prior stroke, 25.3% peripheral artery disease 1

Available Evidence Prior to CVOT Completion

Pre-Specified Meta-Analysis Results

A pre-specified cardiovascular meta-analysis of seven SURPASS trials (4,887 tirzepatide participants vs 2,328 controls) demonstrated cardiovascular safety but not definitive efficacy 2:

• MACE-4 hazard ratio: 0.80 (95% CI, 0.57-1.11) - showing no increased cardiovascular risk 2
• Cardiovascular death HR: 0.90 (95% CI, 0.50-1.61) 2
• All-cause death HR: 0.80 (95% CI, 0.51-1.25) 2

Critical limitation: Only 142 total MACE-4 events occurred across all trials, with 109 from the single high-risk trial, providing insufficient power for definitive efficacy conclusions 2

Current Guideline Positioning

What Guidelines Say About Tirzepatide for Cardiovascular Protection

Guidelines explicitly state that tirzepatide does not currently have proven cardiovascular benefit for MACE reduction. 3, 4 This contrasts sharply with established GLP-1 receptor agonists:

• Semaglutide: 26% MACE reduction (HR 0.74, P<0.001 in SUSTAIN-6) 3, 4
• Liraglutide: 13% MACE reduction (HR 0.87, P<0.001 in LEADER) 3, 5

Guideline Recommendations for Patients Requiring CV Protection

For patients with type 2 diabetes and established atherosclerotic cardiovascular disease requiring cardiovascular risk reduction, GLP-1 receptor agonists with proven cardiovascular benefit (semaglutide, liraglutide, dulaglutide) should be preferred over tirzepatide until SURPASS-CVOT results are available. 5

• The 2024 ESC guidelines recommend GLP-1 receptor agonists with proven CV benefit (Class I, Level A) for patients with type 2 diabetes and chronic coronary syndromes 3
• The 2024 ACC/AHA guidelines note that tirzepatide cardiovascular outcome study is ongoing, distinguishing it from agents with completed trials 3
• The American College of Physicians found that tirzepatide does not reduce all-cause mortality or MACE compared to usual care, with low to high certainty of evidence 4

Clinical Decision Algorithm

When to Use Tirzepatide vs. Proven CV Benefit GLP-1 RAs

Primary goal is cardiovascular risk reduction in established ASCVD:

• Choose: Semaglutide or liraglutide (proven 13-26% MACE reduction) 3, 4, 5
• Avoid: Tirzepatide as first-line (no proven CV benefit) 4, 5

Primary goal is glycemic control and weight loss without established ASCVD:

• Consider: Tirzepatide (superior HbA1c reduction of -1.87% to -2.59% and weight loss of -6.2 to -12.9 kg) 6
• Rationale: Cardiovascular safety demonstrated (HR 0.80), though efficacy unproven 2

High-risk primary prevention (age ≥55 with coronary/carotid stenosis >50%, LVH, eGFR <60, or albuminuria):

• Preferred: GLP-1 RAs with proven CV benefit can be considered 5
• Alternative: Tirzepatide acceptable if glycemic/weight goals prioritized over CV risk reduction 5

Critical Caveats

Common Pitfall: Assuming Class Effect

Do not assume tirzepatide shares the cardiovascular benefits of other GLP-1 receptor agonists. 3 Guidelines explicitly note that cardiovascular benefits are not a class effect, as demonstrated by neutral trials of lixisenatide, exenatide, and albiglutide 3

Timing Considerations

The SURPASS-CVOT is event-driven and ongoing 1. Until results are published:

• Tirzepatide remains appropriate for glucose lowering and weight management 6, 7
• For cardiovascular protection specifically, use agents with completed positive CVOTs 3, 5

Unique Trial Design Feature

SURPASS-CVOT uses an innovative active-controlled design comparing tirzepatide to dulaglutide (a GLP-1 RA with proven CV benefit) rather than placebo 8. The trial aims to demonstrate:

1. Non-inferiority to dulaglutide (preserving ≥50% of dulaglutide's CV benefit) 8
2. Superiority to an imputed placebo using hierarchical Bayesian meta-analysis 8

This design addresses ethical concerns about withholding proven CV-protective therapy but complicates interpretation compared to traditional placebo-controlled trials 8.