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Vascular Effects and Safety of Dalcetrapib in Patients With or at Risk of Coronary Heart Disease: The dal-VESSEL Randomized Clinical Trial
Study Questions:
What are the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD)?
Methods:
Patients in the dal-VESSEL trial with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 minutes of cuff occlusion at 12 weeks and the 24-hour ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in high-density lipoprotein cholesterol (HDL-C), LDL-C, triglycerides, cholesterol transport protein (CETP) activity, as well as standard safety parameters.
Results:
Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively, and did not change significantly from placebo after 12 and 36 weeks (p = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all p < 0.0001), whereas at weeks 4, 12, and 36, HDL-C increased by 25, 27, and 31% (placebo corrected, all p < 0.0001). LDL-C levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8 mm Hg in the placebo and 128 ± 11/75 ± 7 mm Hg in the dalcetrapib group (p = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA2 mass levels, which increased by 17% (placebo corrected). Overall, seven patients given dalcetrapib and eight patients given placebo experienced at least one prespecified adjudicated event (11 events with dalcetrapib and 12 events with placebo).
Conclusions:
The authors concluded that this trial establishes the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD.
Perspective:
This study reports that in contrast to torcetrapib, dalcetrapib does not worsen endothelial function, nor does it raise blood pressure, as found with torcetrapib. This, together with other safety data, suggests that the large ongoing clinical program investigating the effects of dalcetrapib should be continued, particularly to examine the longer-term effects of these agents on atherosclerosis plaque measures and clinical outcomes. The ongoing dal-PLAQUE and dal-OUTCOMES trials will help us understand the impact of agents that act on CETP on both atherosclerosis evolution and cardiovascular events and their potential therapeutic role.
Keywords: Inflammation, Atherosclerosis, Brachial Artery, Sulfhydryl Compounds, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Dilatation, Coronary Disease, Oxidative Stress, Blood Pressure, Lipoproteins, LDL, Cholesterol, Biomarkers, Lipoproteins, HDL
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