PCSK9 Inhibition to Reduce Cardiovascular Events

Since the discovery in 2003 that gain-of-function mutations in the gene encoding proprotein convertase subtilisin–kexin type 9 (PCSK9) cause autosomal dominant hypercholesterolemia, which was followed by the identification in 2005 of loss-of-function mutations in PCSK9 as a cause of lower low-density lipoprotein (LDL) cholesterol levels, interest in the PCSK9 pathway has exploded. PCSK9 is a secreted serine protease that binds to the extracellular domain of the LDL receptor and targets the LDL receptor to the lysosomal compartment for degradation.1 Consequently, PCSK9 prevents recycling of the LDL receptor to the cell surface, thereby attenuating LDL clearance. PCSK9 is present in human . . .