Real-world evidence on the additional cancer risk reduction of ezetimibe: a 10-year nationwide retrospective cohort study emulating a target trial

Lipid-lowering therapies, particularly statins, have been associated with a reduced risk of cancer. However, the potential additional protective effects of ezetimibe remain unclear in real-world settings. This study investigated whether statin/ezetimibe combination therapy provided further cancer risk reduction beyond statin monotherapy. A nationwide retrospective cohort study was conducted using the Korean National Health Insurance Service database. Patients with dyslipidemia (total cholesterol ≥ 240 mg/dL) diagnosed between 2004 and 2009 were included and categorized into statin users, statin/ezetimibe users, and nonusers. Cancer incidence over 5- and 10-year follow-up periods was assessed using Cox proportional hazards models adjusted for demographic, clinical, and lifestyle factors. Inverse probability of treatment weighting (IPTW) was applied to account for potential confounders, and sensitivity analyses were performed to assess the stability of the findings. Among 68,353 patients, 9,267 were statin users, 383 were statin/ezetimibe users, and 58,703 were nonusers. Statin users exhibited a reduced cancer risk at 5 years (adjusted hazard ratio [aHR], 0.84; 95% confidence interval [CI] 0.80–0.89) and 10 years (aHR, 0.91; 95% CI 0.87–0.94). Statin/ezetimibe users demonstrated a greater reduction in cancer risk (5 years: aHR, 0.30; 95% CI 0.28–0.32; 10 years: aHR, 0.70; 95% CI 0.67–0.73). Trend analysis confirmed an incremental trend in cancer risk reduction with increasing lipid-lowering therapy intensity (P for trend < 0.001). This real-world study suggests that ezetimibe, when combined with statins, is associated with additional cancer risk reduction beyond statin monotherapy, as observed across both overall and direct comparative analyses. Further research is warranted to confirm the independent effects of ezetimibe and its potential role in cancer prevention.