Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice

ABSTRACT

Elevation of low-density lipoprotein cholesterol (LDL-C) is an important cause of atherosclerotic cardiovascular disease (ASCVD). Over the years, clinical outcome studies with LDL-C lowering agents have revealed that reducing LCL-C levels is effective in reducing rates of major ASCVD events. Although secondary factors play a role in clinical expression, severe lipid disorders often have a strong genetic component. Genetic revelations have provided novel targets for improving LDL-C management in high-risk individuals. Most recently, researchers have explored how the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) alters LDL metabolism and lowers LDL-C levels to achieve lipid goals and potentially reduce ASCVD risk in patients with severe lipid disorders, including familial hypercholesterolemia (FH). This CMHC Spotlight article summarizes the clinical evidence demonstrating the safety, tolerability, and efficacy of PCSK9 inhibitors in lowering LDL-C levels. Reductions in LDL-C levels by PCSK9 inhibitors alone in patients who are statin intolerant or combined with maximally tolerated statins in patients with severe lipid disorders demonstrate the potential for reduced morbidity and mortality associated with ASCVD.

KEYWORDS:

• PCSK9 inhibitors
• LDL-C
• lipid disorders
• familial hypercholesterolemia
• statin intolerance

Declaration of interest

This paper was funded by Amgen, through support provided to the 2015 Cardiometabolic Health Congress (CMHC); editorial support was arranged by CMHC. Editorial support was provided by Paul Cerrato, Robert E. Lamb, and Erin Franceschini. MS Sabatine has received grants/research support from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi Sankyo, Eisai, Gilead,GlaxoSmithKline, Intarcia, Merck, Roche Diagnostics, Sanofi-Aventis and Takeda, as well as consulting fees from Alnylam, Amgen, AstraZeneca, Cubist, CVS Caremark, Intarcia and Merck. JA Underberg has received grants/research support from Pfizer, Kowa and Aegerion, as well as consulting fees from Amgen, Sanofi, Novartis, Esperion, Liposcience and Amarin, and he has been on the Speakers’ Bureau for Merck, Amarin, Sanofi, Genzyme, Kowa and AstraZeneca. M Koren has received grants/research support from Sanofi, Regeneron, Amgen and Pfizer, and been on the Speakers’ Bureau for Sanofi, Regeneron and Amgen. SJ Baum has received consulting fees from Merck, AstraZeneca, Aegerion Pharmaceuticals Inc., Genzyme and Sanofi, and been on the Speakers’ Bureau for Merck, AstraZeneca, Aegerion Pharmaceuticals Inc., Genzyme and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.