Lipoprotein(a) reduction with PCSK9-targeting pharmacotherapy: A prospective real-world registry study

BACKGROUND AND AIMS: Lipoprotein(a) is an independent cardiovascular risk factor with limited therapeutic options. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce lipoprotein(a), but comparative real-world data across available agents are scarce. We aimed to evaluate lipoprotein(a) reduction with PCSK9i in a large prospective registry. METHODS: We analysed 1112 patients from a prospective single-centre PCSK9i registry with available baseline lipoprotein(a) measurements and follow-up data. Patients received alirocumab, evolocumab, or inclisiran according to clinical practice. Lipoprotein(a) changes were assessed at 3, 9, and 21 months using mixed-effects models and inverse probability of treatment weighting (IPTW). RESULTS: Clinical atherosclerotic disease was present in 52.4% of patients; median baseline LDL-C and lipoprotein(a) concentrations were 3.8 mmol/L (IQR 2.4-4.9) and 67.3 mg/dL (IQR 13.9-130.8), respectively. PCSK9i therapy resulted in a significant and sustained reduction in lipoprotein(a), with mean changes of -15.3%, -16.7%, and -19.0% at 3, 9, and 21 months, respectively (all p < 0.001). In unadjusted analyses, reductions ranged from -14% to -21% with alirocumab and evolocumab and from -8% to -17% with inclisiran. After IPTW adjustment, similar patterns were observed (-13% to -19% vs -8% to -17%), with no statistically significant differences between treatment groups at any time point (all p > 0.05). CONCLUSIONS: In this large real-world cohort, PCSK9i therapies produced modest but significant reductions in lipoprotein(a). No statistically significant differences between agents were detected, although estimates for inclisiran were less precise because of the smaller sample size. Reductions were smaller than in randomised clinical trials, highlighting the need for targeted therapies.