The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the dal-ACUTE randomized trial.

Abstract

AIMS:

The effects of cholesteryl ester transfer protein (CETP) inhibition on lipids, inflammation, and markers of high-density lipoprotein (HDL) function, following an acute coronary syndrome (ACS), are unknown.

METHODS AND RESULTS:

The dal-ACUTE study randomized 300 patients (1 : 1) to dalcetrapib 600 mg/day or placebo within 1 week of an ACS. The primary endpoint was per cent change in HDL-cholesterol (HDL-C) after 4 weeks. Secondary endpoints included apolipoprotein levels, markers of HDL function, and inflammation. Dalcetrapib treatment increased HDL-C and apolipoprotein A1 by 33.7 and 11.8%, respectively (both P < 0.001) and total cholesterol efflux by 9.5% (P = 0.003) after 4 weeks, principally via an increase in non-ATP-binding cassette transporter (ABC) A1-mediated efflux, without statistically significant changes in pre-β1-HDL levels. The increase in total efflux with dalcetrapib correlated most strongly with increases in apolipoprotein A1 and HDL-C (r = 0.46 and 0.43, respectively) rather than the increase in pre-β1-HDL (r = 0.32). Baseline and on-treatment ABCA1-mediated efflux correlated most strongly with pre-β1-HDL levels; in contrast, non-ABCA1-mediated efflux correlated better with apolipoprotein A1 and HDL-C levels.

CONCLUSIONS:

High-density lipoprotein raised through CETP inhibition with dalcetrapib improves cholesterol efflux, principally via a non-ABCA1-mediated pathway. While HDL-C was increased by one-third, apolipoprotein A1 and total efflux were increased only by one-tenth, supporting the concept of dissociation between improvements in HDL function and HDL-C levels, which may be of relevance to ongoing trials and the development of therapeutic interventions targeting HDL.

• Authors: Kausik K Ray, Marc Ditmarsch, David Kallend, Eric J Niesor, Gabriela Suchankova, Ruchi Upmanyu, Judith Anzures-Cabrera, Valerie Lehnert, Meike Pauly-Evers, Ingar Holme, Josef Štásek, Maarten W J van Hessen, Peter Jones, dal-ACUTE Investigators
• Journal: European heart journal (Eur Heart J) Vol. 35 Issue 27 Pg. 1792-800 (Jul 14 2014) ISSN: 1522-9645 [Electronic] England
• PMID: 24639426 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: [email protected].

Chemical References

• ABCA1 protein, human
• ATP Binding Cassette Transporter 1
• Amides
• Anticholesteremic Agents
• Apolipoproteins
• Biomarkers
• CETP protein, human
• Cholesterol Ester Transfer Proteins
• Cholesterol, HDL
• Esters
• Lipoproteins
• Sulfhydryl Compounds
• dalcetrapib
• C-Reactive Protein

Topics

• ATP Binding Cassette Transporter 1 (metabolism)
• Acute Coronary Syndrome (drug therapy)
• Amides
• Angina, Unstable (drug therapy)
• Anticholesteremic Agents (administration & dosage)
• Apolipoproteins (metabolism)
• Biomarkers (metabolism)
• C-Reactive Protein (metabolism)
• Cholesterol Ester Transfer Proteins (antagonists & inhibitors)
• Cholesterol, HDL (metabolism)
• Double-Blind Method
• Drug Administration Schedule
• Esters
• Female
• Humans
• Lipid Metabolism (drug effects)
• Lipoproteins (metabolism)
• Male
• Middle Aged
• Myocardial Infarction (drug therapy)
• Sulfhydryl Compounds (administration & dosage)