The Role of PCSK9 in Lipid Metabolism: Clinical Relevance to Treating Cardiac Disease

Abstract

The treatment of atherosclerosis includes changing lifestyle (e.g. changing diet and exercise regimens, loosing weight, stop smoking, managing stress), performing medical procedures (e.g. bypass surgery) and medical interventions involving primarily statins. Despite excellent safety profiles, the major limitation of statins is their muscle and liver toxicity that occurs in some patients. Since non-statin therapies only modestly reduce LDL cholesterol, alternatives are needed for patients not tolerating statins or in clinical cases of familial hypercholesterolemia where even statins are ineffective. Over the past 12 years, an amazing series of studies have identified proprotein convertase subtilisin/kexin type-9 (PCSK9) as a new target to treat high cholesterol that is the underlying cause of atherosclerosis and cardiovascular disease. The liver-derived PCSK9, a gene found on the short arm of chromosome 1 that encodes a 692 amino acid protein, was initially discovered as neural apoptosis-regulated convertase 1 (NARC-1) in cancer cell lines and implicated in the differentiation of cortical neurons in 2003¹. Subsequently, neutralizing PCSK9 antibodies were developed and proven clinically effective in pre-clinical studies. Since then, Phase I, II, and most recently Phase III human trials have tested applied anti-PCSK9 antibodies to patients intolerant of statins and familial hypercholesterolemia. In this review, we discuss the role of PCSK9 in regulating cholesterol and summarize the promising findings of blocking PCSK9 with antibodies in human clinical trials. While the efficacy of blocking PCSK9 using antibodies to treat high cholesterol is still forthcoming in at least 12 ongoing Phase III clinical studies, anti-PCSK9 antibodies appear effective with minimal safety or tolerance issues identified to date. Blocking PCSK9 may offer a viable complement to statin therapies, which are not universally tolerated or effective with all patient populations.