Estimating the True MACE Benefits From Tirzepatide in SURPASS-CVOT Using an Imputed Placebo Analysis of REWIND

Q: What is the clinical evidence from this study?

Population: Type 2 diabetes and established atherosclerotic cardiovascular disease (n=15220). Intervention: Tirzepatide vs. Imputed placebo. Primary outcome: MACE-3 (composite of cardiovascular death, myocardial infarction, or stroke) (HR 0.72, 95% CI 0.55, 0.94, p=0.016).

Q: What does this research mean for the field?

Tirzepatide is associated with reduced cardiovascular outcomes and all-cause mortality compared to an imputed placebo in patients with type 2 diabetes and established atherosclerotic cardiovascular disease. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Naveed Sattar; Hertzel C. Gerstein; David A. D’Alessio; Deepak L. Bhatt; John B. Buse; Stefano Del Prato; Steven E. Kahn; A. Michael Lincoff; D K Mcguire; Michael A. Nauck; Steven E. Nissen; B Zinman; Sophia Zoungas; Amy Bartee; Debra L. Miller; Hiroshi Nishiyama; Yongming Qu; Govinda Weerakkody; Russell J. Wiese; Imre Pávó; S. Nicholls

doi:10.2337/dc26-0298

Key result

Tirzepatide cuts MACE-3 by ~28% vs imputed placebo in indirect comparison.

HR 0.72
95% CI 0.55, 0.94
P=0.016
NNT 23.6
n=15,220

Diabetes Care published a graphical abstract

Its licence doesn't allow us to show a copy here.

View on journal site ↗

Why the study?

Does tirzepatide reduce MACE-3 compared with imputed placebo in patients with type 2 diabetes and established atherosclerotic cardiovascular disease?

Key Points

To estimate the cardiovascular treatment effect of tirzepatide compared with an imputed placebo using participant-level data from SURPASS-CVOT and REWIND.
The indirect comparison evaluated all 13,165 participants from SURPASS-CVOT and 2,055 of 9,901 participants from REWIND who met SURPASS-CVOT eligibility criteria.
Propensity score weighting and multiple imputation for missing covariates adjusted for baseline clinical differences between trial cohorts.
Treatment effects were derived by multiplying the hazard ratio (HR) of tirzepatide versus dulaglutide in SURPASS-CVOT by the HR of dulaglutide versus placebo in REWIND.
In SURPASS-CVOT, MACE-3 occurred in 801 participants (12.2%; 3.19 per 100 person-years) on tirzepatide versus 862 (13.1%; 3.47 per 100 person-years) on dulaglutide (HR 0.92; 95% CI 0.83, 1.01; P = 0.085); in the REWIND target group, MACE-3 occurred in 165 (16.3%; 3.52 per 100 person-years) on dulaglutide versus 210 (20.1%; 4.47 per 100 person-years) on placebo (HR 0.78; 95% CI 0.61, 1.01; P = 0.056), yielding an indirect HR for tirzepatide versus placebo of 0.72 (95% CI 0.55, 0.94; P = 0.016).
Tirzepatide versus imputed placebo significantly lowered the risk of CV death or heart failure events (HR 0.70; 95% CI 0.51, 0.96; P = 0.025) and all-cause death (HR 0.61; 95% CI 0.45, 0.82; P = 0.001).
The estimated indirect absolute risk reduction in MACE-3 cumulative incidence was 4.2% (number needed to treat of 23.6 over 4 years), with consistent findings across unadjusted cohorts and GLP-1RA meta-analysis models.

Structured PICO

Does tirzepatide reduce MACE-3 compared with imputed placebo in patients with type 2 diabetes and established atherosclerotic cardiovascular disease?

P

Population

15,220 adults with type 2 diabetes and established atherosclerotic cardiovascular disease from the SURPASS-CVOT and REWIND trials, followed for a median of 4.0 years.

I

Intervention

Tirzepatide 15 mg or maximum tolerated dose weekly

C

Comparator

Imputed placebo (derived from dulaglutide vs placebo in REWIND)

O

Outcome

Time to first occurrence of MACE-3 (cardiovascular death, myocardial infarction, or stroke) at median 4.0 years follow-upcomposite

Main Result

Hazard Ratio: 0.72 (95% CI 0.55–0.94)

Absolute Risk Reduction: 4.2%

Number Needed to Treat: 23.6

p-value: p=0.016

This indirect comparison suggests tirzepatide provides significant cardiovascular benefits, including reduced MACE and all-cause mortality, compared to placebo in high-risk patients with type 2 diabetes.

Limitations

Relied on the assumption of no interaction between background standard of care (including SGLT-2i use) and treatment effect
Different inclusion criteria resulted in exclusion of ~80% of the REWIND population
Trials were performed at different times with different background therapies and secular event rates
Assumption of no interaction between background standard of care and treatment effect
Exclusion of ~80% of REWIND population due to different inclusion criteria
Trials performed at different times with different background therapies and secular event rates

Implication

Supports CV benefit of tirzepatide in T2D with ASCVD; leaves open direct RCT confirmation.

Abstract

OBJECTIVE: In prespecified analyses, the treatment effect for major adverse cardiovascular event (MACE) of tirzepatide compared with imputed placebo was estimated using SURPASS-Cardiovascular Outcomes Trial (SURPASS-CVOT) and Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial data. RESEARCH DESIGN AND METHODS: The indirect comparison with placebo was conducted for primary (MACE-3) and secondary outcomes of SURPASS-CVOT. The analysis included data from REWIND participants who would have been eligible for SURPASS-CVOT and all participants from SURPASS-CVOT. Propensity score estimation was used to adjust for differences in participant characteristics between studies. The 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. Sensitivity analyses were performed using unadjusted analyses, including both the selected REWIND and the entire REWIND populations, and adjusted analysis in the entire REWIND population. Post hoc sensitivity analyses used data from a recent glucagon-like peptide 1 receptor agonist (GLP-1RA) meta-analysis that included REWIND. RESULTS: Analyses included 2,055 of 9,901 participants from REWIND and all 13,165 participants from SURPASS-CVOT. In indirect treatment effect comparisons, tirzepatide versus placebo was associated with lower MACE-3 (HR 0.72; 95% CI 0.55, 0.94), death from CV cause or heart failure events (HR 0.70; 95% CI 0.51, 0.96), and all-cause death (HR 0.61; 95% CI 0.45, 0.82). Sensitivity analyses, including nonadjusted or the entire REWIND cohort data or meta-analysis data for GLP-1RAs, were generally consistent. CONCLUSIONS: In this indirect prespecified exploratory comparison, tirzepatide compared with imputed placebo was associated with reduced CV outcomes and all-cause mortality in participants with type 2 diabetes and established atherosclerotic CV disease.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Sattar et al. (2026) studied Type 2 diabetes and established atherosclerotic cardiovascular disease (n=15,220). Tirzepatide vs. Imputed placebo was evaluated on MACE-3 (composite of cardiovascular death, myocardial infarction, or stroke) (HR 0.72, 95% CI 0.55, 0.94, p=0.016). In an indirect treatment comparison, tirzepatide significantly reduced the risk of MACE-3 by 28% compared with imputed placebo (HR 0.72, 95% CI 0.55-0.94, p=0.016) in patients with type 2 diabetes and established cardiovascular disease.

synapsesocial.com/papers/69d5f0ee74eaea4b11a7a5a4 https://doi.org/10.2337/dc26-0298

View at Publisher

Ask AI

Bookmark

Share

Estimating the True MACE Benefits From Tirzepatide in SURPASS-CVOT Using an Imputed Placebo Analysis of REWIND

Diabetes Care published a graphical abstract

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Estimating the True MACE Benefits From Tirzepatide in SURPASS-CVOT Using an Imputed Placebo Analysis of REWIND

Diabetes Care published a graphical abstract

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Keep reading

Keep reading