Editorial: Adding evolocumab to statin therapy can benefit patients with peripheral arterial disease and claudication

Lowering blood cholesterol levels efficiently reduces the risk of developing atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease (CAD), which is the main cause of death worldwide. CAD is caused by plaque formation, comprising cholesterol deposits in the coronary arteries. Proprotein convertase subtilisin kexin/type 9 (PCSK9) was discovered in the early 2000s and later identified as a key regulator of cholesterol metabolism. PCSK9 induces lysosomal degradation of the low-density lipoprotein (LDL) receptor in the liver, which is responsible for clearing LDL-cholesterol (LDL-C) from the circulation. Accordingly, gain-of-function PCSK9 mutations are causative of familial hypercholesterolemia, a severe condition with extremely high plasma cholesterol levels and increased ASCVD risk, whereas loss-of-function PCSK9 mutations are associated with very low LDL-C levels and protection against CAD. Since the discovery of PCSK9, extensive investigations in developing PCSK9 targeting therapies have been performed. The combined delineation of clear biology, genetic risk variants, and PCSK9 crystal structures have been major drivers in developing antagonistic molecules. Today, two antibody-based PCSK9 inhibitors have successfully progressed to clinical application and shown to be effective in reducing cholesterol levels and mitigating the risk of ASCVD events, including myocardial infarction, stroke, and death, without any major adverse effects. A third siRNA-based inhibitor has been FDA-approved but awaits cardiovascular outcome data. In this review, we outline the PCSK9 biology, focusing on the structure and nonsynonymous mutations reported in the PCSK9 gene and elaborate on PCSK9-lowering strategies under development. Finally, we discuss future perspectives with PCSK9 inhibition in other severe disorders beyond cardiovascular disease.