Targeting PCSK9 for hypercholesterolemia

Co-administering ezetimibe with PCSK9 inhibitors produces an additional lipid-lowering effect.

“Co-administration of ezetimibe with PCSK9 inhibitors also results in an additional effect [265].”

PCSK9 has become a therapeutic target for potently reducing LDL-C in humans.

“First identified in 2003 and shown to be related to autosomal-dominant hypercholesterolaemia, PCSK9 has become a therapeutic target for potently reducing LDL-C in humans.64,65”

PCSK9 inhibitors reduce LDL-C by 50-60% in a variety of patient groups, including those identified as statin intolerant.

“Studies have consistently shown large LDL-C reductions of 50–60% in a variety of patient groups,64,65 including those identified as statin intolerant,66–68”

PCSK9 inhibitors have a very low rate of muscle symptoms.

“with a very low rate of muscle symptoms”

PCSK9 inhibitors work by reducing plasma PCSK9, preventing it from binding LDLR, which reduces intracellular degradation of LDLR, leading to higher LDLR expression and lower circulating LDL-C.

“The mechanism of action relates to the reduction of plasma levels of PCSK9, which in turn is not available to bind the LDLR. Since this interaction triggers the intracellular degradation of the LDLR, lower levels of circulating PCSK9 will result in a higher expression of LDLRs at the cell surface and therefore in a reduction of circulating LDL-C levels.”

Elevated PCSK9 levels/functions reduce LDL receptor expression by promoting lysosomal catabolism of LDLR, increasing plasma LDL-C; lower PCSK9 levels/functions are associated with lower plasma LDL-C.

“Elevated levels/functions of this protein in plasma reduce LDLR expression by promoting, upon binding, the LDLR lysosomal catabolism and increase plasma LDL-C concentration, while lower levels/functions of PCSK9 are related to lower plasma LDL-C levels.”