Proprotein Convertase Subtilisin/Kexin Type 9 ( PCSK9 ) Inhibition and Cancer Risk: Insights from a Large Propensity‐Matched Cohort Study

Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) lower LDL cholesterol and may influence cancer through immunomodulatory pathways. However, their effect on human cancer incidence remains unknown. We conducted a retrospective, propensity score-matched study (Clalit Health Services, Israel, 2010-2023) comparing PCSK9 mAbs to ezetimibe. Adults prescribed PCSK9 mAbs for 6 months or more were matched 1:3 to ezetimibe-treated patients without prior cancer, applying a 1-year latency. The cohort included 9,876 patients (2,469 PCSK9 mAb; 7,407 ezetimibe; mean age 65). During a median 4.6-year follow-up, cancer occurred in 12% of PCSK9 mAb users and 11% of ezetimibe users (HR 1.09 [95% CI, 0.95-1.25]). In sex-stratified analysis, men on PCSK9 mAbs had a higher cancer incidence (12.5% vs. 10.3%, P = 0.03); no difference was observed in women. All-cause mortality was significantly lower in the PCSK9 mAb group (3% vs. 5%; HR 0.65 [95% CI, 0.54-0.80]). Post-cancer-diagnosis mortality did not differ. In this large cohort, PCSK9 mAb therapy appeared safe regarding overall cancer risk and was associated with a significant reduction in all-cause mortality; the slightly higher cancer incidence in men may likely be attributed to a higher prevalence of baseline risk factors.