Future role of proprotein convertase subtilisin/kexin type 9 inhibitors in preventive cardiology

Purpose of review The use of therapeutic monoclonal antibodies to target proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel approach to the management of hypercholesteremia and prevention of atherosclerotic cardiovascular disease. We review the most recent literature relevant to PCSK9 inhibition with emphasis on how recent results and ongoing trials have and will continue to shape the use of this new therapeutic class in preventive cardiology. Recent findings PCSK9 inhibitors reduce plasma lipoprotein(a) concentrations but a mechanistic understanding remains elusive. Evaluation of evolocumab for use in patients without prior myocardial infarction or stroke is underway (NCT03872401). Concerns regarding the cost-effectiveness of PCSK9 inhibitors have continued to thwart access to these drugs, though innovative models of care delivery and price reductions have improved this situation. Inclisiran, a small interfering ribonucleic acid (siRNA), reduces translation of PCSK9 and demonstrates more durable reductions in low-density lipoprotein-cholesterol (LDL-C). It is currently evaluated in the context of a phase III cardiovascular outcome trial in patients with established vascular disease (NCT03705234). The current scope of PCSK9 inhibitor therapy in preventive cardiology is limited to patients with familial hypercholesterolemia and/or established atherosclerotic cardiovascular disease. Future cardiovascular outcome trial results with PCSK9 blocking antibodies in primary prevention and with siRNA to PCSK9 in secondary prevention, improved understanding of the drivers of lipoprotein(a) reduction with PCSK9 inhibition, and cost-effectiveness will determine the future role of this therapeutic class.