Analysis estimates 28% lower heart risk for tirzepatide versus imputed placebo
An indirect analysis links tirzepatide to a 28% lower relative risk of major cardiovascular events versus a calculated placebo, but the estimate comes from statistics, not a randomized trial.
Researchers estimate that tirzepatide (sold as Mounjaro and Zepbound) was associated with a 28% lower risk of major cardiovascular events than a calculated placebo, using a statistical technique that links results from two separate trials rather than comparing the drug with placebo directly [1]. The analysis reported a hazard ratio of 0.72 (95% CI 0.55, 0.94) for MACE-3, the composite measure of major adverse cardiovascular events that served as the primary outcome [1]. It was published in Diabetes Care, the journal of the American Diabetes Association [1].
The estimate is indirect. SURPASS-CVOT compared tirzepatide with dulaglutide, a GLP-1 receptor agonist, and REWIND compared dulaglutide with placebo [1]. By multiplying the hazard ratio for tirzepatide versus dulaglutide from SURPASS-CVOT by the hazard ratio for dulaglutide versus placebo from REWIND, the researchers produced what the paper calls an imputed placebo comparison for tirzepatide [1]. Propensity score methods were used to adjust for differences in participant characteristics between the two studies [1].
The analysis used data from 2,055 of 9,901 REWIND participants who would have been eligible for SURPASS-CVOT, plus all 13,165 SURPASS-CVOT participants [1]. Beyond MACE-3, the researchers estimated hazard ratios of 0.70 (95% CI 0.51, 0.96) for death from cardiovascular causes or heart failure events and 0.61 (95% CI 0.45, 0.82) for death from any cause [1].
Sensitivity analyses that dropped the adjustment, used the entire REWIND population, or drew on a recent GLP-1 receptor agonist meta-analysis that included REWIND produced generally consistent results, according to the paper [1]. The authors describe the work as a prespecified exploratory indirect comparison and conclude that tirzepatide, compared with imputed placebo, was associated with reduced cardiovascular outcomes and all-cause mortality in participants with type 2 diabetes and established atherosclerotic cardiovascular disease [1]. The study was funded by Eli Lilly and Company, which makes tirzepatide [1].
Why it matters for patients
The population studied is narrow. Participants had type 2 diabetes and established atherosclerotic cardiovascular disease, meaning narrowed or blocked arteries — not the broader group of people who take tirzepatide for other reasons [1]. Findings in this high-risk group do not automatically extend to everyone else [1].
The 28% figure is not the same as a result from a randomized trial in which some patients received a placebo. It comes from multiplying one trial's hazard ratio by another's, a method the paper labels an indirect comparison, and such designs can be affected by differences between study populations even after statistical adjustment [1].
The abstract does not report absolute risk reductions, the number of cardiovascular events in each group, or a number needed to treat, so what the relative risk reduction would mean for an individual patient has not been reported [1]. Whether the estimate will affect drug labeling or treatment guidelines has not been reported [1].
What happens next
No dated next steps — regulatory review, label changes, or guideline updates — have been reported in connection with this analysis [1]. Whether additional analyses or a dedicated placebo-controlled cardiovascular trial of tirzepatide will follow has not been disclosed [1].
Sources
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