PCSK9 inhibitors and association with lower risk of metastasis.

Abstract

10588 Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates degradation of membrane proteins including the low-density lipoprotein (LDL) receptor and major histocompatibility complex class I (MHC-I) independently. Beyond lipid metabolism, preclinical studies have shown that PCSK9 inhibition reduces metastasis in animal models, suggesting potential to suppress tumor cell proliferation, migration, and immune evasion. However, population-level evidence across malignancies is limited. We evaluated whether PCSK9 inhibitor (PCSK9i) use is associated with risk of cancer metastasis in a large real-world cohort. Methods: In this new-user, active-comparator cohort study using the TriNetX U.S. Collaborative Network (≈134 million patients), eligible patients were adults who initiated PCSK9i or statins alone for hyperlipidemia between 01/01/2015 and 01/01/2025 and subsequently received a cancer diagnosis. Index date was first prescription of PCSK9i or statin, with follow-up period continued until occurrence of study outcomes. To reduce reverse causation and early detection bias from intensified workup around drug initiation, patients with any cancer diagnosis within 6 months after index were excluded. 1:1 propensity score matching (PSM) balanced pre-index demographics, ASCVD and liver comorbidities, cancer screening procedures (low-dose chest CT, Pap smear, colonoscopy), BMI, and LDL. Primary outcome was time to any metastatic cancer (ICD-10 C77–C79); secondary outcomes were site-specific metastases (liver, lung, bone, brain, lymph node, adrenal gland). Cox proportional hazards models estimated hazard ratios (HRs) with 95% CIs. Results: Among 1,149,843 adults newly prescribed PCSK9i or statin (mean age 61.7 years, SD 10.6), median follow-up was 2,926 days. After 1:1 PSM, 8,674 patients remained in each cohort with balanced baseline characteristics (all standardized mean differences <0.1). Metastatic cancer was diagnosed in 435 PCSK9i patients versus 741 statin patients. The overall hazard of metastasis did not differ significantly (HR 0.96, 95% CI 0.85–1.08). In site-specific analyses, PCSK9i use was associated with lower hazards of liver metastasis (HR 0.64, 95% CI 0.50–0.85) and lung metastasis (HR 0.78, 95% CI 0.65–0.94); hazards for lymph node, brain, adrenal, and bone metastases were similar between groups. Sensitivity analyses accounting for competing risk of death showed consistent directionality. Conclusions: In this nationwide cohort study, overall metastatic risk was similar between PCSK9i and statin-only users, but PCSK9i use was associated with lower hazards of liver and lung metastases. Further mechanistic and prospective investigation are warranted to elucidate the role of PCSK9 inhibition in tumor progression and metastasis.