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Drugs in development: targeting high-density lipoprotein metabolism and reverse cholesterol transport

Duffy, Daniellea; Rader, Daniel Jb

Current Opinion in Cardiology: July 2005 - Volume 20 - Issue 4 - p 301-306
doi: 10.1097/01.hco.0000168532.69342.26
HDL cholesterol

Purpose of review This review summarizes currently available therapies for raising high-density lipoprotein cholesterol (HDL-C) and expands on therapies currently in development that target high-density lipoprotein cholesterol.

Recent findings In the realm of new high-density lipoprotein-raising therapies, there is a strong focus on high-density lipoprotein metabolism and the reverse cholesterol transport pathway. Several infusions of recombinant apoA-I Milano/phospholipid complexes appeared to reduce atheroma volume as measured by intravascular ultrasound. Both intravenous and oral apoA-I mimetic peptides are in early clinical trials. Next generation PPAR-α agonists are more potent at high-density lipoprotein-raising than currently available fibrates, and dual PPAR-α/PPAR-γ agonists are under investigation to help correct atherogenic dyslipidemia seen in many diabetics. Two small molecule inhibitors of the cholesteryl ester transfer protein have shown promise in clinical trials at substantially raising high-density lipoprotein cholesterol.

Summary Larger scale clinical trials, including those with additional surrogate outcome measures as well as cardiovascular event outcomes are needed to further assess the benefit of newer high-density lipoprotein-raising therapies. Additional therapeutics are currently in development that target other parts of the reverse cholesterol transport pathway and, in addition to providing new potential pharmaceuticals, will help to further elucidate the atheroprotective mechanisms of high-density lipoprotein cholesterol.

aDepartment of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania and bInstitute for Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

Correspondence to Daniel J. Rader, Institute for Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, 654 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, USA

Tel: 215 573 4176; fax: 215 573 8606; e-mail:

© 2005 Lippincott Williams & Wilkins, Inc.