Application of PCSK9 Inhibitors in Practice

Abstract

Although the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and development of therapeutic antagonists represent a major triumph of modern clinical medicine, efforts to implement PCSK9 inhibitors (PCSK9i) in patient care have been sobering. This practical guide examines the barriers and opportunities for the successful application of pharmacological inhibition of PCSK9 in clinical practice through introduction of a new model of care delivery—the PCSK9i clinic. Historically, the foundation of primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has consisted of therapeutic lifestyle changes in combination with pharmacological therapy focused on lipid modulation, specifically low-density lipoprotein cholesterol (LDL-C) lowering.1 In 2015, the Food and Drug Administration (FDA) approved a new class of cholesterol-lowering medications, PCSK9i, to great anticipation. The seminal discovery in 2003 by Abifadel et al2 linked gain-of-function mutations in the PCSK9 gene with autosomal dominant hypercholesterolemia. This finding uncovered PCSK9 as a key player in cholesterol homeostasis, a circulating protein with the strongest influence on plasma LDL-C concentration.3 PCSK9 directly interacts with the low-density lipoprotein receptor and enhances its degradation by targeting it for destruction by the lysosome and halting its efficient recycling. Because PCSK9 causes degradation of the low-density lipoprotein receptor, inhibiting its action prolongs the lifespan of the low-density lipoprotein receptor and leads to profound reductions in plasma LDL-C levels. The ultimate culmination of this work was the regulatory approval of 2 monoclonal antibody inhibitors of PCSK9 (alirocumab and evolocumab). More recently, the randomized, placebo-controlled trial, FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), demonstrated improved ASCVD outcomes when evolocumab was added to background treatment with a statin. The combination of statin plus evolocumab resulted in a significant absolute and relative risk reduction in both the primary composite end point (cardiovascular death, myocardial infarction, stroke, and hospitalization …