Association of cancer incidence and cancer mortality with statins, ezetimibe, and statin–ezetimibe therapy: a pairwise and bayesian network meta-analysis of randomized controlled trials

Background

Potential cancer risk of statins and ezetimibe remains debated despite ASCVD benefit. Prior analyses focused on statin vs. placebo, and did not assess LDL-C–lowering intensity, ezetimibe monotherapy, or statin–ezetimibe combination therapy. We conducted a pairwise and Bayesian network meta-analysis of RCTs to evaluate cancer risk across these strategies.

Purpose

To evaluate associations of statin therapy by intensity, ezetimibe monotherapy, and statin+ezetimibe therapy with overall cancer incidence and cancer-related mortality.

Methods

PubMed, Embase, and Cochrane Central were searched through January 20, 2026, for RCTs evaluating statins, statin–ezetimibe therapy, ezetimibe monotherapy, or placebo reporting cancer. Records were deduplicated in Rayyan and screened using ASReview. Bayesian random-effects network meta-analysis integrated direct and indirect comparisons; pairwise random-effects meta-analysis was used when connectivity was insufficient. Effects were expressed as risk ratios (RRs) with 95% credible intervals (CrIs) or 95% confidence intervals (CIs).

Results

After screening 45,146 records and removing 31,673 duplicates, 44 RCTs were included in the meta-analysis (n=219,006; median follow-up ~4 years; 64% men, 35.4% women; DM 18.9%; HTN 55.4%; 58% secondary, 33% primary, and 9% mixed prevention population).

Cancer incidence (44 RCTs, n=219,006: 17,856 high-intensity statin, 116,312 moderate-intensity statin, 905 low-intensity statin; 17,418 statin + ezetimibe; 66,515 placebo) showed no differences. Compared with high-intensity statin therapy, RRs were 1.0 (95% CrI 0.68–1.5) for moderate-intensity, 1.1 (95% CrI 0.67–1.9) for moderate-intensity + ezetimibe, and 1.0 (95% CrI 0.70–1.5) for placebo; moderate-intensity + ezetimibe vs moderate-intensity RR 1.1 (95% CrI 0.72–1.7); moderate-intensity vs placebo RR 1.0 (95% CrI 0.85–1.2); moderate-intensity + ezetimibe vs placebo RR 0.93 (95% CrI 0.62–1.4). Cancer-related mortality (37 RCTs, n=203,995: 16,292 high-intensity statin, 111,808 moderate-intensity statin, 460 low-intensity statin; 14,661 statin + ezetimibe; 1,716 ezetimibe alone; 59,058 placebo) showed no differences. Compared with high-intensity statin therapy, RRs were 1.1 (95% CrI 0.94–1.2) for moderate-intensity and 1.1 (95% CrI 0.93–1.2) for placebo; moderate-intensity + ezetimibe vs moderate-intensity RR 1.1 (95% CrI 0.97–1.3); moderate-intensity vs placebo RR 1.0 (95% CrI 0.93–1.1); moderate-intensity + ezetimibe vs placebo RR 0.83 (95% CrI 0.67–0.99), overall RR 0.89 (95% CrI 0.76–1.0).

No differences were observed for gastrointestinal (8 RCTs, n=94,883), breast (11 RCTs, n=99,076), or genitourinary cancers (10 RCTs, n=69,581). Lung cancer (6 RCTs, n=30,846) pooled RR 0.95 (95% CI 0.74–1.21); hematological cancer (8 RCTs, n=61,319) pooled RR 0.95 (95% CI 0.74–1.22).

Conclusion

Statins across intensities and statin–ezetimibe therapy were not associated with increased overall or site-specific cancer risk.Figure 1.League tables and network plotsFigure 2.Forest plots