PCSK9 Inhibition: Discovery, Current Evidence, and Potential Effects on LDL-C and Lp(a)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that binds to low-density lipoprotein receptors (LDL-Rs), leading to their accelerated degradation and increased low-density lipoprotein cholesterol (LDL-C) levels. Therefore, PCSK9 levels play a critical role in cholesterol metabolism by reducing LDL-R levels and thus increasing levels of plasma LDL-C. Recently, investigational agents inhibiting PCSK9 have been shown to lower LDL-C and also, potentially, an important secondary target, lipoprotein(a). Therefore, several pharmaceutical companies have initiated drug-development programs that target PCSK9 and are built on a solid foundation of basic science, genetic studies, and epidemiological observations. PCSK9 inhibition with monoclonal antibodies demonstrated LDL-C lowering of up to 57% when the PCSK9 antibodies are used as monotherapy and up to 73% when added to background lipid-lowering therapy. In addition, long-term cardiovascular outcome studies are currently under way to confirm the longer term safety and efficacy of PCSK9 inhibitors and to determine whether PCSK9 inhibition lowers the incidence of major cardiovascular events. PCSK9 inhibitors may provide safe and effective lipid-lowering therapy, especially for patients with inadequate LDL-C lowering on lipid-lowering treatments, those who are statin intolerant or have contraindications to statin therapy, and those with hereditary hypercholesterolemia/familial hypercholesterolemia and severely elevated LDL-C.