Lipid Lowering Therapy and Circulating PCSK9 Concentration

• Published in: Journal of Atherosclerosis and Thrombosis 2017/09/01, Vol.24(9), pp.895-907
• Main Author: Nozue, Tsuyoshi
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - therapeutic use; Biomarkers - blood; Cholesterol, LDL - blood; Ezetimibe - therapeutic use; Familial hypercholesterolemia (FH); Fibric Acids - therapeutic use; Gene Silencing; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia - blood; Hypercholesterolemia - drug therapy; Hypercholesterolemia - therapy; Hypolipidemic Agents - therapeutic use; Lipid Metabolism; Low-density lipoprotein cholesterol (LDL-C); Low-density lipoprotein receptor (LDLR); Niacin - therapeutic use; PCSK9 Inhibitors; Proprotein Convertase 9 - blood; Proprotein Convertase 9 - genetics; Proprotein convertase subtilisin/kexin type 9 (PCSK9); Review; Statin
• ISSN: 1340-3478; 1880-3873
• DOI: 10.5551/jat.RV17012

Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid-modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events.