Tirzepatide has demonstrated cardiometabolic benefits in clinical trials, but real-world cardiovascular outcomes among patients without diabetes following acute cardiovascular events or stroke remain understudied. We evaluated clinical outcomes associated with early tirzepatide use after acute myocardial infarction (AMI) or ischemic stroke in patients without diabetes. We conducted a retrospective study using the TriNetX Research Network (110 healthcare organizations). Adults ≥18 years and BMI ≥27 kg/m² without diabetes, with AMI or ischemic stroke from June 2022 to November 2025 were included. Patients treated with tirzepatide within 14 days of AMI/stroke were compared with those not receiving tirzepatide. Propensity score matching (1:1) across 28 covariates balanced demographics, comorbidities, medications, and laboratory values, yielding 833 patients per cohort. Outcomes were assessed over 2 years and included all-cause emergency room (ER) visit or hospitalization, acute kidney injury (AKI), ischemic stroke, heart-failure hospitalization, and major adverse cardiovascular events (MACE). Cox proportional hazard models were used to estimate hazard ratios (HRs). After matching, tirzepatide use was associated with significantly lower risk of all-cause ER visit or hospitalization (HR 0.64, 95% CI 0.548-0.741), AKI (HR 0.65, 95% CI 0.441-0.962), ischemic stroke (HR 0.82, 95% CI 0.703-0.947), and heart-failure hospitalization (HR 0.24, 95% CI 0.0001-0.383). MACE hazard did not differ significantly (HR 0.91, 95% CI 0.814-1.021). In conclusion, early tirzepatide initiation after AMI/stroke in patients without diabetes was associated with fewer hospitalizations and reduced renal, heart-failure, and stroke events. These findings support prospective trials of tirzepatide for secondary cardiovascular prevention in non-diabetic patients.
