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

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.