The history of proprotein convertase subtilisin kexin-9 inhibitors and their role in the treatment of cardiovascular disease

Abstract

A consensus has formed based on epidemiological studies and clinical trials that intervention to reduce low density lipoprotein cholesterol (LDL-C) will reduce cardiovascular disease (CVD) events. This has progressively reduced the thresholds for intervention and targets for treatment. Whist statins are sufficient for many people in primary prevention, they only partially achieve the newer targets of secondary prevention for established CVD. Increasing use of statins has highlighted that 1–2% cannot tolerate these drugs. Other cholesterol-lowering drugs such as ezetimibe add to the benefits of statins but have limited efficacy. The discovery of activating mutations in proprotein convertase subtilisin kexin-9 (PCSK9) as a cause of familial hypercholesterolaemia while inactivating mutations lower LDL-C led to the idea to develop PCSK9 inhibitors as drugs. This article reviews the history of lipid-lowering therapies, the discovery of PCSK9 and the development of PCSK9 inhibitors. It reviews the key trials of the current antibody-based drugs and how these have influenced new guidelines. It also reviews the controversy caused by their cost and the increasing application of health economics to determine the optimum strategy for implementation of novel therapeutic pathways and surveys other options for targeting PCSK9 as well as other LDL-C lowering compounds in late development.