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

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.