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Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Feb 26, 2017; 9(2): 76-91
Published online Feb 26, 2017. doi: 10.4330/wjc.v9.i2.76
PCSK9 inhibitors: A new era of lipid lowering therapy
Rahul Chaudhary, Jalaj Garg, Neeraj Shah, Andrew Sumner
Rahul Chaudhary, Department of Medicine, Sinai Hospital of Baltimore, Johns Hopkins University, Baltimore, MD 21209, United States
Jalaj Garg, Neeraj Shah, Andrew Sumner, Division of Cardiology, Lehigh Valley Health Network, Allentown, PA 18103, United States
Author contributions: Chaudhary R and Garg J contributed equally to the paper; all authors contributed to this paper.
Conflict-of-interest statement: All authors report no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Jalaj Garg, MD, FESC, Division of Cardiology, Lehigh Valley Health Network, 1250 S Cedar Crest Blvd, Allentown, PA 18103, United States. garg.jalaj@yahoo.com
Telephone: +1-585-7660898 Fax: +1-610-4023225
Received: August 15, 2016
Peer-review started: August 16, 2016
First decision: September 6, 2016
Revised: November 23, 2016
Accepted: December 7, 2016
Article in press: December 9, 2016
Published online: February 26, 2017
Processing time: 192 Days and 11.1 Hours
Abstract

Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein (LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsin-kexin type 9 (PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9.

Keywords: Hyperlipidemia; Statins; Proprotein convertase subtilsin-kexin type 9

Core tip: Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD). However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. The Food and Drug Administration has approved two novel medications for low-density lipoprotein (LDL)-cholesterol reduction in this patient population: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsin-kexin type 9 (PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. PCSK9 inhibitors are an exciting agent for reducing LDL-C and have ushered in a new era of lipid lowering therapy.