The Emerging Role of PCSK9 Inhibitors in Preventive Cardiology.

Low-density lipoprotein cholesterol (LDL-C) is a most important risk factor for developing coronary artery disease (CAD) and other forms of atherosclerotic cardiovascular disease (CVD) and a major focus of CVD risk reduction with lifestyle and statins. Unfortunately residual risk of CVD remains in patients with familial hypercholesterolaemia and/or statin intolerance in whom adequate LDL-C lowering is not accomplished with lifestyle and statins. PCSK9 is a serine protease that binds the LDL receptor (LDL-R) and acts as a chaparone for endocytosis and shuttling the PCSK9-LDLR complex to lysosomes for degradation. In the absence of PCSK9 the LDLR-LDL-C complex dissociates and LDL-R is recycled back to the cell surface. Humanised monoclonal antibodies (evolocumab, alirocumab, bocolicumab) have been developed that increase LDL-R by ~2-fold and lower LDL-C by up to 75 percent. This effect is synergistic to that of statins with the only common adverse effect is a local injection site reaction. At present, ongoing Phase III CVD outcome trials with PCSK9 inhibitors offer promise that patients with LDL-C levels that remain elevated can decrease CVD events and related mortality.