PCSK9 Inhibitors

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an important regulator of cholesterol metabolism. In the United States, 2 fully humanized monoclonal antibodies—alirocumab and evolocumab— have been approved by the US Food and Drug Administration (FDA) to inhibit or reduce PCSK9 activity. Recently, both the European Union and FDA have approved inclisiran, a small interfering mRNA, that inhibits intracellular PCSK9 synthesis. Increased PCSK9 activity correlates with heightened LDL-C levels, while specific gain-of-function mutations lead to autosomal dominant familial hypercholesterolemia characterized by extremely high total and low-density lipoprotein (LDL) cholesterol levels, premature atherosclerotic vascular disease, and the formation of tendon xanthomas. In most cases, this is due to a genetic mutation of the LDL receptor caused by mutations of the apoprotein B100 or PCSK9 genes. Conversely, individuals with reduced PCSK9 activity, whether due to genetic polymorphism or the administration of PCSK9 monoclonal antibodies, exhibit lower cholesterol levels and a reduced risk of cardiovascular disease. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, monitoring, and toxicity of PCSK9 inhibitors. This activity also helps the interprofessional healthcare team tailor patient therapy for optimal outcomes in serum lipid management and improve cardiovascular outcomes.