Reduction of cerebrovascular and peripheral events with PCSK9 inhibitors: Does it just depend on the lowering of the low-density lipoprotein?

Atherosclerotic cardiovascular disease is a systemic condition involving several vascular districts. The most involved vascular bed, beyond the coronary district, is represented by the peripheral arteries, whose involvement can give rise to cerebrovascular or peripheral events. PCSK9 inhibitors (PCSK9i) have established themselves as safe and effective drugs in reducing cholesterol linked to low-density lipoprotein (LDL-C), a causative factor of disease, with a consequent reduction in cardiovascular events. The two main studies on anti-PCSK9 antibodies, the FOURIER study for evolocumab and the ODYSSEY OUTCOMES study for alirocumab, highlighted the effectiveness in reducing LDL-C levels and its translation in a lower event rate of around 15%. Sub-analysis of these two trials showed how PCSK9i prevent cerebrovascular and/or peripheral events and how patients with already known cerebrovascular or peripheral disease benefit more from the action of these drugs than patients who do not have a widespread disease. Current evidence suggests that the preventive action of cerebrovascular and peripheral events is mainly expressed through reducing LDL-C levels. Although there are data regarding the association of PCSK9 levels and inflammatory status, propensity for thrombosis and platelet aggregation, these are currently less robust and do not justify a cardiovascular event reduction action that is independent of the action on LDL-C.