Pleiotropic Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors?
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Treatment with statins is the standard of care for individuals at increased risk for cardiovascular disease and has been shown to significantly reduce cardiovascular events across a wide range of pretreatment low-density lipoprotein (LDL) cholesterol levels and cardiovascular risk. Further lowering of LDL cholesterol (LDL-C) by adding ezetimibe to statin provides incremental benefit, but event rates among such optimally treated patients remain high.
PCSK9 (proprotein convertase subtilisin/kexin type 9) is a serine protease that is secreted by the liver, binds to the LDL receptor, and directs the LDL receptor toward lysosomal degradation. Decreased availability of LDL receptors on the cell surface leads to decreased cellular LDL-C uptake and higher plasma LDL-C levels. The observation that PCSK9 loss-of-function mutations are associated with lifelong lower LDL-C levels and markedly decreased cardiovascular risk led to the development of monoclonal antibodies to PCSK9 that lower LDL-C by increasing LDL receptor expression on the cell surface and enhancing LDL-C clearance from plasma. These agents achieve LDL-C reductions of ≥50% to 60%, whether administered alone or in combination with a statin.1 Total …