Proprotein convertase subtilisin/kexin type 9 inhibition in cardiovascular disease: current status and future perspectives

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets the degradation of low-density lipoprotein (LDL) receptors; it has been proved that its inhibition improves cardiovascular outcomes in patients with established atherosclerotic cardiovascular disease (ASCVD). Herein, we review the current status of PCSK9 inhibitors in clinical practice and the future scope of PCSK9 inhibition. The results of two recent large clinical trials reveal that two PCSK9 monoclonal antibodies evolocumab and alirocumab reduce the risk of a cardiovascular event on top of background statin therapy in patients with stable ASCVD and those with recent acute coronary syndrome, respectively. However, there are several ongoing concerns regarding the efficacy in reducing mortality, cost-effectiveness, and long-term safety of extremely low LDL cholesterol levels with PCSK9 inhibition. The results of ongoing cardiovascular outcomes trials with PCSK9 monoclonal antibodies for primary prevention and with small interfering RNA to PCSK9 for secondary prevention may help to shape the use of this new therapeutic class.

Keywords: Antibodies, monoclonal; Cardiovascular diseases; Cholesterol, LDL; PCSK9 protein, human.

Figure 1.

Proprotein convertase subtilisin/kexin type 9 (PCSK9)-mediated regulation of low-density lipoprotein receptors (LDL-Rs) and representative targets for therapeutics. (1) Sterol regulatory element-binding protein-2 (SREBP-2) increases the transcription of both LDL-Rs and PCSK9. PCSK9 is processed in the endoplasmic reticulum (2) and packaged in the Golgi apparatus (3) before being secreted. The LDL-Rs bind LDL cholesterol (LDL-C) on the cell surface, and the complex is internalized by the cells via the endosome (4). LDL-C is displaced from the LDL-Rs for use elsewhere and the LDL-Rs are recycled to the cell surface (5). Secreted PCSK9 binds to the LDL-Rs and the complex enters into the endosome (6), resulting in the lysosomal degradation of the LDL-Rs (7). There are two representative approaches to PCSK9 inhibition: small interfering ribonucleic acids (siRNAs) and PCSK9 monoclonal antibodies (MoAbs). siRNAs inhibit the translation of PCSK9 (right lower area), while MoAbs block PCSK9 binding to the LDL-Rs on the cell surface (right upper area).