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

Sep 22, 2026

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) lower LDL cholesterol and may affect cancer through immunomodulatory pathways, yet their impact on human cancer incidence is unclear. A retrospective propensity score-matched real-world cohort from Clalit Health Services (Israel, 2010–2023) compared PCSK9 mAbs with ezetimibe in adults without prior cancer using a 1-year latency. Over a median 4.6-year follow-up, overall cancer incidence was similar, while all-cause mortality was significantly lower with PCSK9 mAbs.

LanguageEnglish

CategoryHealthcare

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Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and Cancer Risk: Insights from a Large Propensity-Matched Cohort Study Inbar Nardi Agmon 1,2,3,4,* , Chen Gurevitz 1,2, Tzippy Shochat5, Shiri Kushnir5, Guy Witberg1,2, Amos Levi 1,2, Dan Gilon6, Ran Kornowski 1,2, Paaladinesh Thavendiranathan3, Husam Abdel Qadir3 and Zaza Iakobishvili7,8 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 toezetimibe-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-cancerdiagnosis 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ; Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) are potent low-density lipoprotein cholesterol (LDL-C) lowering agents. Preclinical studies suggest that PCSK9 may influence cancer biology by modulating tumor cell cholesterol metabolism and immune evasion mechanisms, specifically by downregulating major histocompatibility complex class I (MHC-I) expression on tumor cells. However, clinical evidence regarding the impact of long-term PCSK9 inhibition on human cancer incidence has been limited to post-hoc analyses of short-term randomized trials. WHAT QUESTION DID THIS STUDY ADDRESS? ; This study investigated whether long-term therapy with PCSK9 mAbs (evolocumab or alirocumab) is associated with an altered incidence of newly diagnosed malignancies compared to treatment with ezetimibe, an LDL-C lowering agent without known immunomodulatory effects, in a large, real-world cohort of patients without prior cancer. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ; In a propensity score-matched cohort of nearly 10,000 patients followed fora median of 4.6 years, PCSK9 mAb therapy was not associated with a significant difference in overall or site-specific cancer incidence compared to ezetimibe. Sexstratified analysis revealed a mildly higher cancer incidence in men, which likely reflects a higher baseline prevalence of shared cardiovascular and oncologic risk factors. Notably, PCSK9 mAb users experienced a significant 35% reduction in all-cause mortality, a benefit that was independent of concomitant statin use and likely driven by cardiovascular protection rather than anticancer activity. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ; These findings suggest that while PCSK9 mAbs provide a robust survival benefit, the subtle divergence in cancer incidence among men warrants continued long-term surveillance. The results reinforce the importance of intensive lipid management while suggesting that any hypothesized “protective” anticancer effects may be context-specific or require combination with other immunotherapies to manifest clinically. Received October 22, 2025; accepted January 28, 2026. doi:10.1002/cpt.70232 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 119

FAQs

How did PCSK9 mAb therapy affect mortality?

All-cause mortality was significantly lower in the PCSK9 mAb group (3% vs. 5%; HR 0.65; 95% CI, 0.54–0.80), and post-cancerdiagnosis mortality did not differ.

Sep 22, 2026

Uploaded by Putri