Lipid lowering with PCSK9 inhibitors

Nat Rev Cardiol. 2014 Oct;11(10):563-75. doi: 10.1038/nrcardio.2014.84. Epub 2014 Jun 24.

Abstract

Statins are the most-effective therapy currently available for lowering the LDL-cholesterol (LDL-C) level and preventing cardiovascular events. Additional therapies are necessary for patients who cannot reach the target LDL-C level when taking the maximum-tolerated dose of a statin. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme with an important role in lipoprotein metabolism. Rare gain-of-function mutations in PCSK9 lead to a high LDL-C level and premature coronary heart disease, whereas loss-of-function variants lead to a low LDL-C level and a reduced incidence of coronary heart disease. Furthermore, the PCSK9 level is increased with statin therapy through negative feedback, which promotes LDL-receptor degradation and decreases the efficacy of LDL-C lowering with statins. PCSK9 inhibition is, therefore, a rational therapeutic target, and several approaches are being pursued. In phase I, II, and III trials, inhibition of PCSK9 with monoclonal antibodies has produced an additional 50-60% decrease in the LDL-C level when used in combination with statin therapy, compared with statin monotherapy. In short-term trials, PCSK9 inhibitors were well tolerated and had a low incidence of adverse effects. Ongoing phase III trials will provide information about the long-term safety of these drugs, and their efficacy in preventing cardiovascular events.

Publication types

  • Review

MeSH terms

  • Apoptosis
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / prevention & control*
  • Humans
  • Hypolipidemic Agents / therapeutic use*
  • Lipids / blood*
  • Proprotein Convertase 9
  • Proprotein Convertases / antagonists & inhibitors*
  • Serine Endopeptidases

Substances

  • Hypolipidemic Agents
  • Lipids
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases