Abstract 18661: Endothelial Effects of High-Density Lipoprotein (HDL) Remain Impaired Following Dalcetrapib Treatment in Patients with Coronary Artery Disease or Risk Equivalent
Introduction: As low HDL-Cholesterol levels are associated with an increased cardiovascular risk at least in epidemiology, raising HDL-Cholesterol is being examined as a potentially important therapeutic strategy. However, vascular effects of HDL have recently been found to be highly heterogeneous and benefits may be lost, at least partially, in patients with coronary artery disease (CAD). We therefore studied in patients with CAD or CAD-risk equivalent the effect of the CETP inhibitor dalcetrapib as compared to placebo on HDL function.
Methods: HDL was isolated by sequential ultracentrifugation from patients randomized to treatment with dalcetrapib (600 mg/day; n=25) or placebo (n=25) at baseline, 12 and 36 weeks, and from healthy subjects. The effect of HDL on endothelial nitric oxide (NO) production was measured by ESR spectroscopy and on endothelial pro-inflammatory and pro-apoptotic activation determined by VCAM-1 and active caspase-3 expression assays, respectively.
Results: There was no significant improvement in the capacity of HDL to stimulate endothelial NO production following dalcetrapib treatment or placebo in patients with CAD or risk equivalents, that remained impaired as compared to HDL-Healthy. HDL isolated from the dalcetrapib group showed an increase in the capacity to reduce endothelial VCAM-1 activation (9.0±6.3% at 12 weeks, 9.7±6.7% at 36 weeks, vs. 5.3±4.5% at baseline; p<0.05); but remained significantly impaired (HDL-Healthy: 15.2±6.5%; p<0.05). There was also an increase of the capacity of this HDL to reduce active endothelial caspase-3 expression (12.1±8.7% at 36 weeks vs. 6.9±9.9% at baseline; p<0.05); however, these endothelial anti-apoptotic capacities remained largely impaired as compared to healthy subjects (18.9±6.6%; p<0.05).
Conclusions: Despite a significant increase in HDL-C levels (+31% at 36 weeks), dalcetrapib treatment did not restore the potential anti-atherosclerotic properties of HDL on the endothelium as found in the healthy controls. This finding may contribute, at least in part, to the lack of benefit on endothelial function seen in dal-VESSEL trial and demonstrates the importance of measuring not just HDL-C plasma levels but also its vascular impact when assessing novel treatments.
- © 2012 by American Heart Association, Inc.