Authors: Thomas F. Lüscher, Stefano Taddei, Juan-Carlos Kaski, J. Wouter Jukema, David Kallend, Thomas Münzel, John J.P. Kastelein, John E. Deanfield, on behalf of the dal-VESSEL investigators
Background: At least epidemiologically increased high-density lipoprotein cholesterol (HDL-C) is protective against cardiovascular (CV) disease and is currently being investigated as a novel therapeutic target. HDL-C stimulates nitric oxide (NO), suppresses inflammation and exerts a multitude of protective CV effects. Dalcetrapib is a cholesteryl ester transfer protein (CETP) modulator that increases HDL-C. In a clinical study, torcetrapib, a CETP inhibitor, unexpectedly increased aldosterone, endothelin and blood pressure (BP) as well as CV mortality and morbidity, despite marked increases in HDL-C. In animal studies, torcetrapib was shown to impair endothelial function. We therefore assessed the effects of the novel CETP modulator dalcetrapib on endothelial function, BP and lipids in patients with coronary heart disease (CHD) or CHD risk equivalents (clinical trials.gov NCT00655538).
Methods: In a double-blind, placebo-controlled trial, eligible patients on statin treatment to a stable low-density lipoprotein cholesterol (LDL-C) level, were randomised to dalcetrapib 600 mg qd or placebo for 36 weeks in addition to their existing treatments. The primary efficacy endpoint was change from baseline in percentage flow-mediated dilation (%FMD) of the right brachial artery after 5 minutes of forearm cuff occlusion, at 12 weeks follow up. The primary safety endpoint was 24-hour ambulatory BP (ABPM) at week 4. Secondary endpoints were %FMD change from baseline after 36 weeks of treatment, change in ABPM at 12 and 36 weeks and change in HDL-C, LDL-C and triglyceride levels and safety parameters.
Findings: 476 patients were randomised. Baseline FMD was 4.1 ± 2.2% and 3.98 ± 2.4% in the placebo and dalcetrapib groups respectively and did not change significantly throughout the 36 week study. Data on changes in blood flow are currently being analysed. Data are presented as placebo corrected change from baseline unless otherwise stated. After 4 and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51% and 56% (p<0.001 vs placebo), respectively, while after 12 and 36 weeks of treatment HDL-C increased by 27% and 31% (p<0.001; from 39 ± 7 to 49 ± 10 and 51 ± 13 mg/dl, respectively). Triglycerides decreased by 9% and 14% (p<0.005; from 162 ± 81 to 151 ± 83 and 149 ± 71 mg/dl, respectively), while LDL-C did not change.
At baseline, ABPM averaged 125 ± 12/74 ± 8 mmHg in the placebo group and 127 ± 11/75 ± 7 mmHg in the dalcetrapib group and did not change significantly up to 36 weeks. Biomarkers of inflammation (CRP, ICAM, VCAM, IL-6), oxidative stress (MPO) and coagulation (tPA, PAI-1) did not differ at baseline nor after treatment with either placebo or dalcetrapib. During the whole study, 23 pre-specified positively adjudicated events occurred (11 with dalcetrapib and 12 with placebo; ns)
Interpretation: This is the first successful multicentre trial using FMD to evaluate a novel cardiovascular drug. In patients with or at risk of CHD, dalcetrapib reduced CETP activity and increased HDL-C levels by 30% without affecting NO-dependent endothelial function (FMD) or markers of inflammation and oxidative stress. Dalcetrapib was well tolerated and did not increase ABPM. dal-OUTCOMES (clinical trials.gov NCT00658515) will determine whether dalcetrapib improves outcome in spite of a lack of effect on endothelial function.
This is a phase 2 multi-centre trial evaluating the feasibility of using flow mediated dilatation and assessment of risk markers. Investigators examined a novel compound (dalcetrapib) which reduces cholesterol ester transfer protein (CETP) by approximately 49% and increased HDL cholesterol by approximately 31%.
Using validated techniques to examine flow mediated dilatation in the brachial artery, they examined the effect of dalcetrapib on nitric oxide dependent endothelial function, blood pressure and markers of inflammation and oxidative stress.
Although there were trends suggesting that flow mediated dilatation was less marked after dalcetrapib than placebo, these differences were not significant. Similarly there were no significant differences in blood pressure at 4 weeks, 12 weeks and 36 weeks. There were trends for about 1mm greater blood pressure in those treated with dalcetrapib. The issue of blood pressure with CETP inhibitors is important as torcetrapib was shown to increase blood pressure by approximately 5mmHg (Barter et al N Engl J Med 2007 Nov 22; Vol. 357 (21), pp. 2109-220.
Although the authors conclude that dalcetrapib does not worsen endothelial function nor does it raise blood pressure (as prior cholesterol ester transfer inhibitors have done) caution must be exercised in view of the limited size of this phase 2 study. To put the flow mediated dilatation findings into context, statins produce a dose dependent reduction in LDL and an increase in flow mediated dilatation of approximately 40-60%.
The impact of dalcetrapib on clinical outcomes is currently being tested in a large phase 3 trial.