Evan Albert Stein

(2017). Are the PCSK9 inhibitors the panacea of atherosclerosis treatment? Expert Review of Cardiovascular Therapy: Vol. 15, No. 7, pp. 491-494.

This article provides an updated review of the LDL-cholesterol efficacy, safety, and cardiovascular benefits of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. It focuses on evidence from numerous clinical trials and provides clinicians with a basis for understanding, assessing, and selecting these agents for clinical practice. It also provides some perspective on other potential agents in development that target PCSK9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-density lipoprotein receptor (LDLR) resulting in its degradation. Inhibition of PCSK9 results in increased LDLR recycling and a reduction in LDL-cholesterol (LDL-C). The clinical development of monoclonal antibodies (mAbs) that bind to circulating PCSK9 has been rapid with large phase II and III trials demonstrating substantial reductions in LDL-C when given to a very broad group of patients including those with familial and non-familial hypercholesterolemia, diabetes, heart disease, and in those intolerant to statins. Despite sub-cutaneous administration these mAbs are well tolerated and have demonstrated good safety. Two agents, alirocumab and evolocumab, received regulatory approval in 2015 in the US and Europe and evolocumab in 2016 in Japan.

Over the past three decades, statins have become first-line treatment for reducing LDL cholesterol (LDL-C) and cardiovascular disease (CVD). They have provided a clear, robust, and reproducible relationship between the absolute LDL-C reduction and the decrease in CVD; every 1 mmol/L (∼40 mg/dL) in LDL-C reduction results in a 22 % decrease in CVD events. This relationship has recently been extended to reduction in LDL-C with a non-statin, ezetimibe, on top of statin therapy, further consolidating LDL-C as the cornerstone in CVD risk reduction. Despite these two effective and safe LDL-C-lowering drugs, there remains a need for additional drugs to reduce LDL-C, the focus of this review which covers agents which produce sufficient LDL-C reduction to potentially help address this unmet need and are either recently approved or currently in clinical trials.