Novel Hypolipidemic Agents: Focus on PCSK9 Inhibitors

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) was recently discovered as the third gene involved in autosomal dominant familial hypercholesterolemia. The encoded PCSK9 protein binds and induces degradation of the low-density lipoprotein (LDL) receptor and thereby modulates the plasma levels of LDL-cholesterol. Some of the naturally occurring PCSK9 mutations increase the function of this protein (gain of function) and cause hypercholesterolemia, whereas loss of function mutations produce hypocholesterolemia. Since the loss of a functional PCSK9 in humans is not associated with apparent deleterious effects, this protease is an attractive target for the development of hypocholesterolemic agents, either alone or in combination with statins. Thus, inhibition of PCSK9 with monoclonal antibodies is emerging as a novel strategy for the treatment of hypercholesterolemia. Other novel hypolipidemic agents include mipomersen, an antisense oligonucleotide inhibitor targeted to human apolipoprotein B-100, and lomitapide, an oral microsomal triglyceride transfer protein inhibitor. Data obtained from preliminary studies show that use of these new therapeutic approaches are effective in reducing LDL-cholesterol. An overview of these novel hypolipidemic agents is herein attempted with a focus on PCSK9 inhibition.