Introduction

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 receptor agonist (GLP-1 RA) receptors GIP and GLP-1 receptor agonist, improves glycemic control, lowers glycosylated hemoglobin (HbA1c), body weight, blood pressure (BP), atherogenic lipids, and inflammatory markers, while preserving kidney function in patients with type-2 diabetes mellitus (T2DM). The SURPASS-CVOT trial demonstrated that tirzepatide was noninferior to dulaglutide for reducing major adverse cardiovascular events (MACE-3). Given the proven superiority of dulaglutide over placebo in the REWIND trial, indirect analyses suggest that tirzepatide may reduce MACE-3 risk vs. placebo. Further adjusted modeling using high-risk REWIND participants was thus conducted to better estimate the cardiovascular (CV) benefits of tirzepatide.

Aim

Prespecified analyses evaluated the estimated impact of tirzepatide vs. an imputed placebo on MACE outcomes, using data from SURPASS-CVOT and REWIND.

Patient Profile

• The indirect treatment comparison target group included intention-to-treat (ITT) participants from REWIND who would have been eligible for enrolment in SURPASS-CVOT and all modified ITT (mITT) participants from SURPASS-CVOT (all randomized participants except for those randomized in error). Propensity score estimation was used to adjust for differences in participant characteristics between studies
• Participants form the REWIND who would have been enrolled in SURPASS-CVOT had a baseline HbA1c ≥7.0% and a history of at least one of the following: myocardial infarction (MI), >50% stenosis, coronary revascularization, ischemic stroke, carotid artery revascularization, ankle-brachial index (ABI) <0.9, peripheral revascularization (iliac or femoral artery), or amputation.

Methods

Study Design

• A pre-specified analysis of SURPASS-CVOT and REWIND trials. Indirect analysis of the treatment effect was derived by multiplying the hazard ratio (HR) for MACE-3 between tirzepatide and dulaglutide in SURPASS-CVOT by the HR for dulaglutide versus placebo in REWIND. Post hoc sensitivity analyses used data from a recent GLP-1RA meta-analysis that included REWIND.
• SURPASS-CVOT (compared tirzepatide 10/ 15 mg or maximum tolerated dose with dulaglutide 1.5 mg weekly) and REWIND (compared the same dose of dulaglutide with placebo) were both, randomized, double-blind, event-driven trials.

Outcomes

• Primary and key secondary CV outcomes of SURPASS-CVOT comprised of composite MACE-3, CV death, all-cause death, composite CV death or heart failure (HF) events, and composite MACE-4 (MACE-3 components or coronary revascularization).
• The number needed to treat to composite MACE-3 at a median follow-up of SURPASS-CVOT at 4.0 years was calculated.

Results

• Among the 2,055 REWIND participants eligible for indirect comparison, dulaglutide reduced MACE-3 events vs. placebo (16.3% vs. 20.1%; HR 0.78, 95% CI 0.61-1.01). In SURPASS-CVOT, tirzepatide showed a numerically lower risk of the primary composite outcome than dulaglutide (12.2% vs. 13.1%; HR 0.92, 95% CI 0.83-1.01). The indirect comparison estimated a significant 28% reduction in MACE-3 risk with tirzepatide vs. placebo (HR 0.72, 95% CI 0.55-0.94).
• The indirect comparison showed consistent results in both unadjusted (HR 0.72, 95% CI 0.58-0.91; P=0.005) and adjusted analyses (HR 0.72, 95% CI 0.55-0.94; P=0.016). Compared with imputed placebo, tirzepatide significantly reduced all-cause mortality by 39% (HR 0.61, 95% CI 0.45-0.82) and CV death or HF events by 30% (HR 0.70, 95% CI 0.51-0.96), while reductions in MACE-4 (HR 0.80) and CV death (HR 0.75) did not reach statistical significance.
• For key secondary CV outcomes, indirect treatment effect estimates were consistent between unadjusted and adjusted analyses in the target population. In the overall REWIND population, only minor differences were observed for primary and key secondary outcomes, while MACE-3 results remained comparable across populations and analytical methods. The estimated absolute risk reduction in MACE-3 with tirzepatide vs. imputed placebo was 4.2% over 4 years, corresponding to a number needed to treat (NNT) of 23.6 to prevent one MACE-3 event.
• Post hoc sensitivity analyses using data from a recent meta-analysis of incretin-based therapies in T2DM patients, which demonstrated a 14% reduction in MACE, estimated the CV effect of tirzepatide relative to placebo. Tirzepatide was associated with a significant reduction in MACE-3 with an estimated HR 0.79 (95% CI 0.71-0.88), corresponding to an approximate 21% relative risk reduction. Analyses also consistently suggested benefits of tirzepatide, as compared to placebo, across multiple CV outcomes (including MACE and all-cause mortality).

Conclusion

• An indirect comparison using REWIND and SURPASS CVOT data, supported by sensitivity analyses, suggested that tirzepatide may substantially reduce MACE, the composite of HF events and CV death, and all-cause mortality compared with placebo in patients with T2DM and CVD.

Diabetes Care. 2026 Apr 6:dc260298.  doi: 10.2337/dc26-0298.