Abstract Body (Do not enter title and authors here): Cardiovascular outcomes trials of the glucagon-like peptide-1 receptor agonist-based agents tirzepatide and semaglutide are evaluating effects in populations at varying levels of cardiovascular risk. While early trial results for tirzepatide are promising, indirect comparisons across heterogeneous placebo or active-comparator-controlled studies offer limited clinical guidance, leaving optimal treatment choice uncertain.

We conducted a three-stage comparison of tirzepatide vs semaglutide in patients at cardiovascular risk with type 2 diabetes and obesity using three US national claims databases. The primary end point was the composite of all-cause mortality, myocardial infarction, or stroke. First, we emulated the two cardiovascular outcome trials SUSTAIN-6 and SURPASS-CVOT to predict and benchmark findings, building confidence in our design, data, and analytic framework. Second, we expanded upon these findings to assess the effectiveness of each drug across populations routinely seen in clinical practice. Third, we directly compared tirzepatide vs semaglutide in patients at elevated and high cardiovascular risk.

After propensity score adjustment, we observed high concordance between emulated and reported trial results (HR for semaglutide vs sitagliptin = 0.68, 95% CI, 0.60-0.77; HR for tirzepatide vs dulaglutide = 0.81, 95% CI, 0.67-0.98). Estimates for both agents remained consistent in populations more reflective of routine care. The head-to-head comparison of tirzepatide vs semaglutide is still ongoing and will be completed in September. ClinicalTrials.gov Identifier: NCT06659744, NCT07088718, NCT07096063.