Evaluation of proprotein convertase subtilisin/kexin type 9: focus on potential clinical and therapeutic implications for low-density lipoprotein cholesterol lowering

Reduction in low-density lipoprotein cholesterol (LDL-C) is associated with a decrease in coronary heart disease (CHD). Statins are currently the most effective medications for LDL-C lowering; however, there continues to be a residual risk for cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that promotes LDL receptor degradation, leading to an increase in LDL-C blood levels. Patients with PCSK9 gain-of-function mutations can have up to a 20-fold increase in associated CHD compared with patients without these mutations. Conversely, patients with PCSK9 loss-of-function mutations can have up to an 88% reduction in CHD without any deficits in neurologic or physiologic functions. PCSK9 can be modulated by current antihyperlipidemic therapies. In particular, statins lead to an increase in PCSK9, which may attenuate their full lipid-lowering effects. These attributes have made PCSK9 inhibition a desirable target for future drug therapies. Current investigational modalities inhibiting PCSK9 will also be discussed.