Chronic PCSK9 inhibitor therapy leads to sustained improvements in endothelial function, arterial stiffness, and microvascular function

Abstract

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively decrease low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events in patients at very high cardiovascular risk. Recent short-term studies suggest a partially LDL-C independent beneficial effect of PCSK9 inhibitor (PCSK9i) therapy on endothelial function and arterial stiffness, whereas it is unknown if this effect persists and what the effect is on microcirculation.

Objective: To investigate the effects of PCSK9i therapy on vascular parameters beyond its lipid lowering effect.

Methods: In this prospective trial, 32 patients at very high cardiovascular risk and indication for PCSK9i therapy were included. Measurements were performed at baseline and after 6 months of PCSK9i treatment. Endothelial function was assessed as flow-mediated dilation (FMD). Arterial stiffness was measured as pulse wave velocity (PWV) and aortic augmentation index (AIx). Peripheral tissue oxygenation (StO₂) as a marker of microvascular function was assessed at the distal extremities using near-infrared spectroscopy camera.

Results: Six months of PCSK9i therapy decreased LDL-C levels from 141 ± 54 to 60 ± 30 mg/dl (-56 ± 21 %, p < 0.001), FMD significantly increased from 5.4 ± 1.7 % to 6.4 ± 1.9 % (+19 ± 10 %, p < 0.001), PWV decreased in male patients significantly from 8.9 ± 2.1 to 7.9 ± 1.5 m/s (-12 ± 9 %, p = 0.025). AIx decreased from 27.1 ± 10.4 % to 23.0 ± 9.7 % (-16 ± 14 %, p < 0.001), StO₂ significantly increased from 67 ± 12 % to 71 ± 11 % (+7 ± 6 %, p = 0.012). Brachial and aortic blood pressure showed no significant changes after six months. There was no correlation between LDL-C reduction and changes in vascular parameters.

Conclusions: Chronic PCSK9i therapy is associated with sustained improvements in endothelial function, arterial stiffness, and microvascular function independent from lipid lowering.

Keywords: Arterial stiffness; Endothelial function; Lipid lowering therapy; Microcirculation; PCSK9 inhibitor; Pleiotropic effects; Very high cardiovascular risk.