Association of Cancer Incidence and Cancer-Related Mortality with Statin Therapy, Ezetimibe, and Statin–Ezetimibe Combination - A Systematic Review and Bayesian Network Meta-analysis of Randomized Controlled Trials

BACKGROUND: Statins and ezetimibe are widely used and safe lipid-lowering therapies for the prevention of atherosclerotic cardiovascular disease. However, concerns persist, especially among the lay public, about the possibility of a long-term association with cancer incidence and cancer-related mortality. OBJECTIVES: To evaluate the association between statin therapy, statin intensity, ezetimibe, and statin-ezetimibe combination therapy with cancer incidence and cancer-related mortality using a network meta-analysis of randomized controlled trials. METHODS: We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials comparing statin monotherapy, statin-ezetimibe combination, or ezetimibe monotherapy with no lipid-lowering therapy (no-LLT), including head-to-head comparisons of statin intensities. PubMed/MEDLINE, Embase, and Cochrane were searched through February 2026. Treatment effects were estimated using random-effects Bayesian models and expressed as risk ratios (RRs) with 95% credible intervals (CrIs). RESULTS: A total of 69 randomized controlled trials, including 238,533 participants, were analyzed, of whom 199,286 received statins, 35,836 received statins plus ezetimibe, and 3,411 received ezetimibe alone. For cancer incidence, high-intensity statins (RR 0.95, 95% CrI 0.87-1.03), moderate-intensity statins (RR 1.01, 95% CrI 0.96-1.05), low-intensity statins (RR 1.06, 95% CrI 0.72-1.61), and moderate-intensity statin plus ezetimibe (RR 1.04, 95% CrI 0.96-1.14) were not associated with a reduction compared with no-LLT. For cancer mortality, no significant differences were observed with high-intensity statins (RR 0.94, 95% CrI 0.79-1.09), moderate-intensity statins (RR 1.00, 95% CrI 0.92-1.08), low-intensity statins (RR 1.70, 95% CrI 0.50-6.06), moderate-intensity statin plus ezetimibe (RR 1.12, 95% CrI 0.97-1.32), or ezetimibe alone (RR 1.32, 95% CrI 0.82-2.15), all compared with no-LLT. All head-to-head comparisons among active treatment nodes (statin intensities, statin-ezetimibe combination, and ezetimibe monotherapy) were similarly null, with point estimates close to unity and 95% CrIs crossing 1.0 for all comparisons. Node-splitting revealed no significant inconsistency between direct and indirect evidence for any evaluable comparison. Subtype analyses for lung, breast, gastrointestinal, genitourinary, hematological, skin, and central nervous system cancers showed no significant differences across treatment strategies. CONCLUSION: In this network meta-analysis of randomized trials, statin therapy across all intensities and ezetimibe, alone or in combination, were not associated with an increased risk of cancer incidence or cancer-related mortality, supporting their oncologic safety within the duration of follow-up available in randomized clinical trials.