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.

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

“…Anti-PCSK9 antibody therapeutics markedly reduce plasma LDL in patients at high-risk of cardiovascular events (45). Given the impressive LDL-lowering efficacy of PCSK9 inhibition, and the prevalence of the underlying disease against which this strategy is targeted, the need for additional PCSK9 inhibitory treatment modalities is well-justified (38,46,47). Currently, pharmacologic inhibition of PCSK9 proteolysis to induce its retention in the ER has proven to be a major pharmacological challenge.…”

Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, a post-commercialization study

“…[29] Failure to reach optimal LDLC lowering is predominantly related to statin intolerance [30–34]. In the current study, 67% of patients were statin intolerant, a very common, outcome limiting problem in treatment of hypercholesterolemia [22, 23, 32–35].…”

Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management

“…To date, PCSK9 has been targeted using a variety of techniques, such as antisense nucleotide therapy and monoclonal antibodies aiming in uninterrupted LDLR expression and, subsequently, substantial clearance of circulating LDL (by up to 70%; Hovingh et al, 2013 ; Seidah et al, 2014 ), with reduction of ASCVD-related morbidity and mortality being the ultimate benefit in atherosclerotic and FH patients (Eisen and Giugliano, 2016 ; Navarese et al, 2016 ; Sabatine et al, 2016 , 2017 ).…”