Translating the effect of dual lipid reduction with PCSK9 inhibitors on a mechanical vascular instrumental biomarker in familial hypercholesterolemia subjects

Familial hypercholesterolemia (FH) is characterized by lifelong elevated LDL-C levels and increased cardiovascular risk. PCSK9 inhibitors (PCSK9i) reduce LDL-C and Lp(a), however, the effect of dual lipid reduction on mechanical vascular function remains unclear. The aim of this study was to evaluate the efficacy of PCSK9i in reducing LDL-C and Lp(a) and to assess the relationship between the dual lipid reduction and the mechanical vascular profile improvement in FH subjects. This prospective observational study included 301 genetically confirmed FH subjects treated with PCSK9i added to high-intensity statins and ezetimibe. Biochemical and PWV measurements were performed at baseline and after six months. Subjects were stratified into four groups based on median values of ΔLDL-C and ΔLp(a). After six months of add-on PCSK9i, 44.9% of FH subjects achieved their LDL-C targets. Reductions were observed in LDL-C (− 49.8%, p < 0.001), Lp(a) (− 21.4%, p < 0.001), and PWV (Δ − 22.7%, p < 0.001). PWV improvement increased across groups with greater lipid reductions (p for trend < 0.01); Group 3 and Group 4 exhibited a similar mechanical vascular benefit. Logistic regression showed that subjects with the greatest combined lipid reduction (ΔLDL-C ≤ − 45.22% and ΔLp(a) ≤ − 11.49%) had the strongest association with PWV improvement (OR: 5.12; 95% CI: 2.08–11.02). Dual lipid reduction with PCSK9i was associated with a pronounced mechanical vascular profile improvement in FH subjects; however, an intensive Lp(a) reduction may be needed to achieve a greater mechanical vascular benefit.