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Therapeutic Targets to Raise HDL in Patients at Risk or with Coronary Artery Disease

[ Vol. 10 , Issue. 6 ]

Author(s):

Thomas F. Luscher, Arnold von Eckardstein and Branko Simic   Pages 720 - 724 ( 5 )

Abstract:


The plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Traditional HDL-raising therapies, like fibrates, PPAR-γ agonists, and nicacin, among others, are associated with undesirable side effects, limited efficacy, or have not yet been shown to improve morbidity and mortality on top of statins in clinical outcome trials. A novel pharmacological target for raising circulating HDL-C levels is the cholesterol ester transfer protein (CETP), an enzyme that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. Four pharmacological small-molecule inhibitors of CETP, i.e. torcetrapib (Pfizer), dalcetrapib (JTT-705; Roche), anacetrapib (Merck), and evacetrapib (Eli Lilly) have been developed. Notwithstanding a marked increase in HDL, torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial and raised safety concerns related to the off-target effects of CETP inhibition. Most recently, development of dalcetrapib was abruptly stopped due to a lack of clinically meaningful efficacy. Thus, it will be of utmost importance to demonstrate that the remaining CETP inhibitors in development not only increase HDL-C levels in plasma, but also improve HDL-function in patients with coronary disease or an acute coronary syndrome.

Keywords:

HDL, CETP, clinical outcomes, endothelial function

Affiliation:

Cardiovascular Center, University Hospital, CH-8091 Zurich, Switzerland.



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