PCSK9 Inhibitors: Mechanisms of Action, Metabolic Effects, and Clinical Outcomes

Abstract

Atherosclerotic cardiovascular disease (ASCVD) is associated with significant morbidity and mortality worldwide. Increased serum levels of low-density lipoprotein cholesterol (LDL-C) are an independent risk factor for ASCVD, and clinical trial data have shown that lowering LDL-C generally reduces cardiovascular risk. Until recently, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been the main therapy for lowering LDL-C. However, some statin-treated patients have persistently elevated residual cardiovascular risk due to inadequate lowering of LDL-C levels or non-LDL-related dyslipidemia. In addition, adverse effects of statins may limit their tolerability and therefore the ability to attain effective doses in some patients. A new class of drugs that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed to treat hyperlipidemia. This review discusses the history and mechanism of action of PCSK9 inhibitors, their metabolic effects, and clinical outcomes associated with these medications, highlighting recent large cardiovascular outcome trials investigating these therapies.