PCSK9 inhibitors and LDL reduction: pharmacology, clinical implications, and future perspectives

PCSK9 inhibitors are monoclonal antibodies to proprotein convertase-subtilisin/kexin type 9 which significantly reduce LDL cholesterol concentration in vivo by inhibiting degradation of the LDL receptor in hepatocytes. The introduction of PCSK9 inhibitors heralded a new era of intensive LDL-C reduction with LDL-C concentrations lowered below levels ever thought possible with conventional treatments such as statins. With their introduction considerations regarding cost, clinical outcomes and long-term safety are paramount. Areas covered: This review examines the pharmacology of PCSK9 inhibitors and summarizes the current evidence base for use in clinical practice from an efficacy, safety, and cardiovascular outcome perspective including recently presented data on alirocumab. It also examines the potential role of these agents into the future. Potential issues with PCSK9 inhibitors are examined and future pharmacologic targets are examined including siRNA and PCSK9 vaccination. Expert commentary: It is clear that the PCSK9 inhibitors are highly effective in the lowering of LDL cholesterol. However, this reduction comes at a large financial cost, and although early outcome data has been positive, the role of PCSK9 inhibition remains confined to limited patient groups at present. As more long-term data is gathered on clinical outcomes and safety, the role for these agents may expand.