Perspective:

PCSK9 is a protease that targets low-density lipoprotein (LDL) receptors for destruction, leading to reduced LDL clearance capacity and elevated LDL levels. Recent clinical trials have demonstrated that antibody-mediated inhibition of PCSK9 leads to marked reduction in LDL levels, even in statin-treated patients. Because loss and gain of function mutations of PCSK9 have been associated with reduced and increased CVD respectively, PCSK9 inhibition is a promising approach for lowering LDL and reducing CV events. Interestingly, statin therapy leads to both up-regulation of LDL receptors and also PCSK9 expression, which could limit the therapeutic effect of statins. Although this study demonstrated that PCSK9 levels were not associated with lipid levels in patients on statins, and not predictive of risk in patients on high-dose atorvastatin, this does not mean that inhibition of PCSK9 will not have beneficial effects when added to statins. The impact of PCSK9 inhibitors on clinical events in patients on statins will require additional trials. PCSK9 inhibition could be particularly useful in statin-intolerant patients and in patients who do not reach LDL goals on high-dose statins.