Adverse effect

Biology

Cholesterol

Clinical trial

Endocrinology

Coronary artery disease

Bioinformatics

Lipoprotein

PCSK9

LDL receptor

Internal medicine

Medicine

Disease

Diabetes mellitus

Nature Reviews Cardiology

The gene encoding PCSK9 was first identified and linked to the phenotype of familial hypercholesterolaemia approximately 15 years ago. Soon after, studies uncovered the role of PCSK9 in the regulation of LDL-receptor recycling and identified loss-of-function variants of PCSK9 that were associated with low circulating levels of LDL cholesterol (LDL-C) and a reduced risk of coronary artery disease. With amazing rapidity, monoclonal antibodies against PCSK9 were developed and studied in large clinical programmes. These PCSK9 inhibitors lowered plasma LDL-C levels by approximately 60%, even in patients already receiving maximum-dose statin therapy. In the past year, three cardiovascular outcome trials were completed and showed that PCSK9 inhibitors significantly reduce the risk of major vascular events. Reassuringly, this benefit comes with no major offsetting adverse events, such as an excess of myalgias, elevation of hepatic aminotransferases levels in the plasma, incident diabetes mellitus or neurocognitive adverse events. The clinical benefit of PCSK9 inhibitors seen in these trials occurred in the setting of reducing LDL-C levels to unprecedentedly low levels, suggesting that more aggressive LDL-C targets should be adopted. New technologies to inhibit PCSK9 are now being harnessed and might further revolutionize our treatment of dyslipidaemia. Three cardiovascular outcome trials have now demonstrated the clinical benefit of achieving lower plasma LDL-cholesterol levels with the addition of PCSK9 inhibitors to statin therapy. In this Review, Marc Sabatine discusses the safety and efficacy data from these trials and their possible implications, such as the definition of new plasma LDL-cholesterol targets.

PCSK9 inhibitors: clinical evidence and implementation