Statin–Ezetimibe Therapy and Incident Myocardial Infarction Across Modified Cardiovascular–Kidney–Metabolic Risk Groups: A Nationwide Target Trial Emulation

BACKGROUND: Cardiovascular-kidney-metabolic syndrome integrates metabolic risk, kidney dysfunction, and cardiovascular disease. Whether statin-ezetimibe combination therapy is associated with lower subsequent myocardial infarction risk than statin monotherapy among patients across modified cardiovascular-kidney-metabolic risk groups remains uncertain. METHODS: Using the Korean National Health Insurance Service database, we emulated separate two-arm landmark target trials within modified early and late cardiovascular-kidney-metabolic risk groups. Adults aged 30-74 years with dyslipidemia who received prescriptions covering a total of 180 days with statin monotherapy or a fixed-dose statin-ezetimibe combination were eligible. Treatment was assigned at the 180-day landmark. Stabilized inverse probability of treatment weighting and cause-specific Cox regression were used to calculate hazard ratio (HR) and 95% confidence interval (CI), with death treated as a competing event for cumulative incidence estimation. RESULTS: Among 309,371 treated participants, 239,954 had modified early risk and 69,417 had modified late risk. Compared with statin monotherapy, statin-ezetimibe therapy was associated with lower myocardial infarction risk after weighting in both early-risk participants (HR 0.87, 95% CI 0.81-0.95) and late-risk participants (HR 0.88, 95% CI 0.79-0.98). 10-year weighted cumulative incidence was 1.97% versus 2.23% in the early-risk group and 3.52% versus 3.94% in the late-risk group. In same-intensity comparisons, the association was most evident with moderate-intensity therapy, particularly in the early CKM group (HR, 0.87; 95% CI, 0.79-0.95). CONCLUSION: Among adults with dyslipidemia who received prescriptions covering a total of 180 days, statin-ezetimibe combination therapy was associated with a lower subsequent risk of myocardial infarction than statin monotherapy across modified CKM risk groups. The association was most evident in moderate-intensity comparisons.