Chasing LDL cholesterol to the bottom — PCSK9 in perspective

Low-density lipoprotein (LDL) indubitably contributes causally to atherosclerosis, a leading challenge to health worldwide. Interventions that lower LDL cholesterol (LDL-C) have made remarkable inroads against this global scourge. Recent therapeutic advances have achieved ever lower levels of LDL-C. Improved cardiovascular outcomes continue to accrue from these interventions. In particular, the discovery of the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) as the causal gene in autosomal-dominant hypercholesterolemia has led with remarkable speed to the development of novel agents to lower LDL-C concentrations beyond prior measures, and to alleviate further cardiovascular risk. We review how this story, and its position in the broader landscape of therapy to prevent atherosclerotic events, represents a notable victory of contemporary cardiovascular medicine and reflects successful partnerships between basic scientists, the pharmaceutical and biotechnology sectors, and clinical investigators. Continued cooperation in this manner promises to yield further progress in combating cardiovascular diseases beyond interventions on LDL-C. Libby and Tokgözoğlu discuss the management of atherogenic lipoproteins, notably low-density lipoprotein, with an emphasis on the role of strategies that target PCSK9.