Lowering cholesterol with statins has shown consistent cardiovascular (CV) outcome benefits, including a reduction in heart attacks and strokes, across a wide range of baseline cholesterol levels. Is it possible to improve CV outcomes by additional lipid-lowering therapy, which will enable lower levels of cholesterol to be attained, particularly in patients at higher CV risk, including those with established CV disease, and those with hypercholesterolaemia, in whom optimal levels of cholesterol cannot be achieved with existing statin therapies? A further unmet need is the optimal management of subjects who are statin intolerant, although true statin intolerance is much less common than has been claimed by some reviewers.
PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) and Inhibitors of PCSK9
A receptor (the LDL receptor) on the surface of liver cells plays a central role in influencing cholesterol balance. Circulating LDL-cholesterol binds to the LDL receptor and the complex is internalized in the liver cells and degraded (Figure 1). The LDL receptor is, however, recycled to the cell surface where it can bind with more LDL-cholesterol molecules (Figure 2) and the process is repeated.
PCSK9 is a protein synthesized by the liver cells which binds to the LDL receptor component of the LDL receptor/LDL-cholesterol complex. However, when this complex is internalized in the liver, the resultant degradation does not permit the LDL receptor to be recycled to the cell membrane (Figure 3). Thus, the number of LDL receptors on the surface of the liver cells is reduced and serum levels of LDL-cholesterol increase. The more PCSK9 produced by the liver, the higher the LDL-cholesterol level ( Figure 4).
Monoclonal antibodies have been developed which bind to PCSK9 and prevent its interaction with the LDL receptor (Figure 5), thereby preserving receptor numbers and lowering LDL-cholesterol.
In early clinical trials, the administration of human monoclonal antibodies to PCSK9 has been associated with impressive reductions of LDL-cholesterol (50-70%)
Human monoclonal antibodies have been shown to be not only effective, but safe and well tolerated. Because of their nature they have to be administered by subcutaneous injection either 2 weekly or 4 weekly. Novel autoinjector devices make subcutaneous administration of the antibody relatively simple and cause minimal discomfort.
- Sever P, Mackay J. Brit. J Cardiol. 2014;21:91-3. New opportunities for cholesterol lowering: Focus on PCSK9 inhibitors
Kexin Type 9 (PCSK9) mode of action
Learn about the role of the PCSK9 protein in the regulation of LDL-cholesterol.
Video kindly supplied thanks to AMGEN.