The discovery of PCSK9 as a pivotal point in the prevention of cardiovascular disease

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important component in the regulation of low-density lipoprotein-cholesterol (LDL-C) metabolism, discovered more than two decades ago. The discovery of PCSK9 and subsequent development of PCSK9 inhibitors (PCSK9i) have helped usher a new era of non-statin lipid-lowering therapy for atherosclerotic cardiovascular disease (ASCVD) risk reduction. In addition to individuals with clinical ASCVD, there have been evolving recommendations for the clinical use of PCSK9i to extend to individuals with familial hypercholesterolemia as well as high-risk primary prevention patients, including those with advanced subclinical atherosclerosis. Beyond the initial development of PCSK9 monoclonal antibodies (mAb), this class of therapies has expanded to include several different modes of administration that are currently being studied for efficacy and safety, including small interfering RNA (siRNA), adnectins, oral, and potentially even CRISPR-based methods. Such scientific advancement and enthusiasm have been moderated by public health challenges involving cost and access of therapy, which we hope will continue to improve in an era emphasizing earlier and greater utilization of combination lipid-lowering therapy. In this review, we will summarize PCSK9 biology, followed by an assessment of completed and ongoing randomized controlled trials involving PCSK9i. This will then be followed by a review of current clinical recommendations for the utilization of PCSK9i, future directions, and concluded with clinical and public health impact. Through this process, we hope to highlight the integral role of PCSK9i in the prevention of ASCVD.