PCSK9 Inhibition and Atherosclerosis: Current Therapeutic Option and Prospection

Low-density lipoprotein cholesterol (LDL-C) is a pivotal factor in atherosclerotic cardiovascular disease (ASCVD), the leading cause of worldwide mortality. The limitations of statin therapy require alternative treatment strategies to achieve target LDL-C level. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in LDLR recycling, consequently regulating plasma cholesterol levels. Monoclonal antibodies targeting PCSK9 increased expression of LDLRs at the cell surface and therefore decreased circulating LDL-C. PCSK9 inhibitors have shown great efficacy in reducing plasma LDL-C levels, which needs to inject once or twice monthly. Though SPIRE sponsors concern the immunogenicity and terminate trials early, FOURIER and ODYSSER OUTCOME trials improved the efficacy of PCSK9 inhibitors in LDL-C reduction. Inclisiran actually is a small interfering RNA (siRNA) developed to inhibit PCSK9 messenger RNA, leading to reduced concentrations of the PCSK9 protein and thereby lower concentrations of LDL-C. Inclisiran is a latest alternative treatment to cholesterol-lowering therapeutics. Twice injections of inclisiran durably reduced LDL-C levels over 1 year. siRNA therapeutics provided a simple, novel, and less frequent approach to LDL-C reduction in phase I and II trials, which may be used either as in combination with statin therapeutics or a stand-alone therapy in the future.