Arterial Functional and Structural Effects of Pcsk9 Inhibitors: A Comparison Between Antibody and Small Interfering Rna

Background and Objectives Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9–i) are used to reduce LDL cholesterol in dyslipidemic patients who do not adequately respond to traditional therapies. PCSK9 can be inhibited through monoclonal antibodies (Alirocumab, Evolocumab) or siRNA (Inclisiran). Their lipid–lowering efficacy is established, but effects on vascular structure/function remain uncertain. This study evaluated whether these properties change after starting PCSK9–i during a 1–year follow–up, comparing Inclisiran to antibodies. Methods This prospective longitudinal study enrolled all patients who began Evolocumab, Alirocumab, or Inclisiran in our cardiology department. Antibodies were self–administered every 2 weeks, while Inclisiran was administered by healthcare professionals at baseline, 3 months, and then every 6 months. Carotid–femoral Pulse Wave Velocity (cf–PWV), carotid Intima–Media Thickness (cIMT), and brachial Flow–Mediated Dilation (FMD) were assessed at T0 (the day before PCSK9–i start), 6 months (T1), and 12 months (T2). Statistical analysis included 42 patients treated with antibodies and 42 treated with Inclisiran, matched by age, sex, and BMI. Results Both groups had a mean age of 69.1±8.8 years, 78.6% male, BMI 26.9±3.2 kg/m². LDL–C significantly decreased in both groups (Inclisiran ΔT0–T2 = 60.6±37.2 mg/dL; PCSK9i–Ab ΔT0–T2 = 71.1±10.0 mg/dL; p‹0.001). A borderline HDL–C increase (49.4±14.7→52.5±14.5 mg/dL; p=0.032) occurred with antibodies, while a borderline triglyceride reduction (115.3±48.2→100.8±36.6 mg/dL; p=0.048) occurred with Inclisiran. Systolic blood pressure decreased with Inclisiran (131.8±15.3→125.5±11.2 mmHg; p=0.001), whereas diastolic pressure decreased with antibodies (80.1±13.1→75.2±9.3 mmHg; p=0.020). No significant changes were seen in IMT or FMD. PWV significantly decreased only in the Inclisiran group (10.9±2.4→10.4±2.5→10.3±1.8 m/s; p=0.013), unlike the antibody group. Conclusions PCSK9–i confirmed LDL–C reduction in both groups, while only Inclisiran appeared to reduce arterial stiffness. This finding was associated with a significant systolic pressure reduction, the main determinant of PWV. Larger studies are needed to clarify the effects of PCSK9–i on vascular structure and function.