Reducing plasma levels of low-density lipoprotein cholesterol (LDL) is central in both primary and secondary prevention of cardiovascular disease (CVD).1 But despite widespread use of intensive statin therapy, a substantial proportion of high-risk patients with hypercholesterolemia fail to achieve adequate LDL reduction. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising target to reduce residual cardiovascular disease risk.2

Two separate lines of research have led to the development of drugs targeting PCSK9.  The first began with the discovery of a family with familial hypercholesterolemia—ie, elevated low-density-lipoprotein (LDL) cholesterol levels—and increased risk of myocardial infarction (MI). Surprisingly, this family did not have a mutation in the LDL receptor. This led to the discovery of PCSK9, a locus for this gene.3,4 A second line of research explored the structure and function of proprotein convertases that activate a wide range of proteins responsible for regulating key cellular pathways.2 The convergence of this research led to the development of the PCSK9 inhibitors.

Mechanism of Action of PCSK9 Inhibitors

Hepatic endocytosis is a process mediated by the binding of LDL to LDL receptors (LDL-Rs) on the hepatocyte cell membrane that are responsible for removal of LDL from the blood.2 PCSK9 is a serine protease that binds to LDL-Rs. Overexpression of PCSK9 leads to accelerated degradation of LDL-Rs, resulting in increased circulating LDL. Inhibiting PCSK9 frees up more receptors to remove LDL cholesterol from the blood, leading to less circulating LDL.2

Monoclonal antibodies are agents that target specific proteins—in this case, PCSK9. PCSK9 inhibitors are injected monoclonal antibodies.2 Monoclonal antibodies are extensively used to target highly specific proteins in areas of medicine such as rheumatology and oncology,5,6 but these are the first such agents to be introduced into cardiology.