Novel Hypolipidemic Agents: the Role of PCSK9 Inhibitors

Abstract

Hyperlipidemia is a major cause of cardiovascular disease despite the availability of first-line cholesterol lowering agents such as statins. Although statin therapy is very efficient to reduce cholesterol, nearly 10-20% of individuals on statins, experience side effects, such myopathy, which hinder the drugs ability to achieve target low-density lipoprotein (LDL) cholesterol (LDL-C) levels. Statin-intolerant patients require more effective therapies for lowering LDL-C. As proprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLR) and prevents it from recycling to the membrane, a new therapeutic approach to lowering LDL-C acts by blocking LDL-receptor degradation by serum PCSK9. Humanized monoclonal antibodies which target PCSK9 and its interaction with the LDL receptor (REGN727/SAR23653, AMG145, and RN316), as well as agents that inhibit PCSK9 synthesis, such as ALN-PCS, are now in clinical trials. The latter is a small interfering RNA (siRNA) that directs sequence-specific messenger RNA for PCSK9 leading to reduced hepatocyte-specific synthesis of PCSK9. Ongoing phase III trials’ results are awaited with great interest in order to define these agents’ long-term safety, tolerability and efficacy for reducing cardiovascular events.