In a propensity score-matched TriNetX analysis of 5,665 patients per arm (adults 45 or older, BMI 27 or higher, established ASCVD, no diabetes), semaglutide and tirzepatide produced statistically indistinguishable cardiovascular outcomes. Five-point MACE occurred in 19.5% versus 17.1% (HR 1.03, 95% CI 0.94-1.12), and 3-point MACE in 17.4% versus 15.4% (HR 1.04, 95% CI 0.95-1.14). No individual component, including mortality, myocardial infarction, stroke, heart failure exacerbation or revascularization, differed significantly.
The result fits what the pharmacology predicts. Semaglutide already has randomized proof of benefit in this exact population: SELECT cut MACE by 20% in people with obesity and prior cardiovascular disease. Tirzepatide's cardiovascular trials in obesity are still maturing, so a head-to-head comparison against a proven comparator is useful, and parity is reassuring. Tirzepatide's larger weight loss did not translate into a detectable cardiovascular edge here, which hints that benefit may depend on more than kilograms lost.
Treat this with caution. Retrospective electronic-record data carry residual confounding, since prescribers choose drugs based on insurance, patient characteristics and timing, and tirzepatide's later market entry means shorter follow-up. The raw event rates numerically favored tirzepatide, and the confidence intervals cannot rule out a modest difference in either direction, so this is absence of evidence rather than proof of equivalence. For patients, the practical takeaway is that both drugs are reasonable options after a heart event, and cost, tolerability and access can reasonably guide the choice. Confirmatory rather than paradigm-shifting.