Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and LDL Lowering in the Contemporary Management of Dyslipidemia

Abstract

PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) protein plays an important role in LDL cholesterol (LDL-C) metabolism, due to its role in the degradation of the LDL receptor. Preliminary clinical data of PCSK9 inhibition are quite promising and indicate that PCSK9 inhibition may be a novel strategy for the treatment of dyslipidemia particularly for those with refractory hypercholesterolemia, statin intolerance, or an elevated lipoprotein (a) level and associated cardiovascular diseases. Furthermore, development of PCSK9 inhibitor is an excellent example of "bench to bedside" concept where discovery of a genetic mutation was translated into a novel therapy to address unmet clinical needs. Although several approaches have been attempted to inhibit PCSK9 activity including small molecules, gene silencing and inhibitory antibodies, the most promising approach appears to be the use of monoclonal antibodies with a 50 -70% LDL cholesterol reduction on top of maximal doses of statins. In this article, we review the pharmacology of PCSK9 and summarize findings from key clinical studies using PCSK9 inhibitors.

Recent updates on therapeutic targeting of lipoprotein(a) with RNA interference

“…A multicenter prospective observational study of lipoprotein apheresis is currently underway [28]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors decrease lipoprotein levels by 20–30% [29]. In a prespecified analysis of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial, evolocumab reduced plasma Lp(a) levels by 27% with a 23% reduction in risk of major coronary events in patients with Lp(a) levels above the median [30].…”

Looking into the Crystal Ball—Upcoming Drugs for Dyslipidemia

“…The findings related to inhibition of PCSK9 are burgeoning as an attractive target for reducing LDL-C in both dyslipidemia and cardiovascular diseases. 43,44 Monoclonal antibodies against PCSK9 have opened a newer paradigm in the reduction of LDL-C and have been found to be effective in the treatment of both familial and non-FH. 45 Evolocumab (AMG 145), a fully human monoclonal immunoglobulin G2 antibody specific for human PCSK9, has been shown to prevent degradation of LDL receptor.…”

“…The findings related to inhibition of PCSK9 are burgeoning as an attractive target for reducing LDL-C in both dyslipidemia and cardiovascular diseases. 43,44…”