Estimating the True MACE Benefits From Tirzepatide in SURPASS-CVOT Using an Imputed Placebo Analysis of REWIND
Year: 2026
Type: article
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.
Source: Diabetes Care
DOI: 10.2337/dc26-0298
Authors: Naveed Sattar, Hertzel C. Gerstein, David D’Alessio, Deepak L. Bhatt, John B. Buse, Stefano Del Prato, Steven E. Kahn, A. Michael Lincoff, Darren K. McGuire, Michael A. Nauck, Steven E. Nissen, Bernard Zinman, Sophia Zoungas, Amy Bartee, Debra Miller, Hiroshi Nishiyama, Yongming Qu, Govinda Weerakkody, Russell J. Wiese, Imre Pavo, Stephen J. Nicholls
Institutions: University of Glasgow, Population Health Research Institute, Hamilton Health Sciences, McMaster University, Duke Medical Center, Icahn School of Medicine at Mount Sinai, University of North Carolina at Chapel Hill, Scuola Superiore Sant'Anna, University of Washington, VA Puget Sound Health Care System, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Parkland Health & Hospital System, The University of Texas Southwestern Medical Center, St. Josef-Hospital, Katholisches Klinikum Bochum, Ruhr University Bochum, Cleveland Clinic, Mount Sinai Hospital, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Monash University, Eli Lilly (United States)
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7150941934