AHA 2012: dal-ACUTE: CETP inhibition improves HDL functionality

The dal-ACUTE study showed that treatment with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib modestly raised HDL cholesterol plasma levels and improved HDL cholesterol efflux capacity in patients with recent acute coronary syndromes (ACS). The study was reported at the American Heart Association Scientific Sessions today.

Abstract 16388/2003. Ray K, Ditmarsch M, Kallend D et al. Efficacy and Safety of Early Dalcetrapib Treatment on Lipid Profile and Markers of HDL Functionality in Patients Hospitalized for an Acute Coronary Syndrome - The dal-ACUTE Study.

HDL cholesterol concentration is an independent coronary risk factor. Additionally, in the ACS setting, the functionality of HDL particles may be impaired, placing patients at risk of recurrent events. Studies have reported that these HDL exhibit attenuated endothelial repair capacity, and anti-inflammatory and anti-oxidative activity, compared with HDL from healthy individuals.1 Consequently, treatments that improve HDL cholesterol plasma levels and/or enhance HDL functionality may offer therapeutic potential.

The dal-ACUTE study randomized 300 patients within 1 week (average 3.9 days) of hospitalization for ACS to treatment with dalcetrapib 600 mg/day or placebo for 20 weeks. Most patients (75%) had not previously received a statin. After 4 weeks, HDL cholesterol levels in the dalcetrapib group were increased by 33.7% compared with placebo, with a corresponding 11.8% increase in apolipoprotein (apo)A-I (p<0.0001 for both analyses). Total cholesterol efflux was also significantly improved with dalcetrapib compared with placebo (least squares mean change 9.5%, 95% CI 3.17, 16.18, p=0.003). The increase in efflux capacity with dalcetrapib was associated to a greater extent (by 2-fold) with apoA-I levels than HDL-C levels. There was no difference in low-density lipoprotein cholesterol or apoB levels between the two groups at this time. Dalcetrapib was generally well tolerated.

HDL Forum comment: Professor Kausik K. Ray, Professor of Cardiovascular Disease Prevention, St George’s University of London, UK

Dal-ACUTE adds to experimental evidence2 that CETP inhibition does not produce ‘dysfunctional’ HDL. In ACS patients the atheroprotective activity of HDL has been shown to be impaired. Treating these patients with the CETP inhibitor improved the ability of HDL to efflux cholesterol from the plaque, likely to improve the stability of the plaque. In short, the ‘take home’ message of this study is that raising HDL cholesterol levels via CETP inhibition improved the functionality of HDL in ACS patients. However, as shown by dal-OUTCOMES,3 the magnitude of these changes is insufficient to translate to improved cardiovascular outcomes.

References

1. Besler C, Heinrich K, Rohrer L, et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 2011;121:2693-708.

2. Yvan-Charvet L, Matsuura F, Wang N et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol 2007;27:1132-8.

3. Schwartz GC, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. New Engl J Med 2012; Published online November 5, 2012.

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