title: Lipid lowering with PCSK9 inhibitors.
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.
authors: Sections of Cardiovascular Research and Cardiology, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS A601, Houston, TX 77030, USA.
authors: Razvan T
authors: RT
authors: Dadu
authors: Sections of Cardiovascular Research and Cardiology, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, MS A601, Houston, TX 77030, USA.
authors: Christie M
authors: CM
authors: Ballantyne
mesh_terms: D017209:Apoptosis; D002318:Cardiovascular Diseases / Q000097:blood / Q000517:prevention & control*; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases
chemical_list: D000960:Hypolipidemic Agents; D008055:Lipids; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases