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.

Eur Heart J. 2012 Feb 16

Abstract

Aims High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538).

Methods and results Patients 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 min of cuff occlusion at 12 weeks and the 24 h 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 HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. 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), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg 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-PLA(2) mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo).

Conclusion The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function.

Background

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.

Editorial comments

The authors concluded that dalcetrapib did not have any adverse effects on endothelial function or arterial blood pressure. With respect to the well known favourable effects of HDL on endothelial function as measured by endothelium-dependent vasodilator response as well as other aspects of endothelial function, the results were expected to be somewhat greater [1].
The trial does not provide a mechanistic insight as to why dalcetrapib failed to improve endothelial function despite a significant increase in HDL-C levels. Inclusion of patients with baseline normal HDL-C levels may have made it difficult to show an improvement, but subgroup analysis in low HDL-C patients also failed to show any improvement in endothelial function.
CETP modulation by dalcetrapib might generate HDL that is functionally inactive, at least as far as endothelial function is concerned, thus questioning the controversy about CETP as a legitimate therapeutic target for atherosclerosis [2].
Brachial artery reactivity is only a surrogate of vascular health. Interventions improving it may not necessarily improve clinical outcomes; lack of improvement in brachial artery reactivity may not necessarily preclude clinical benefit. The recently reported results of dalcetrapib on imaging evidence of atherosclerosis in the dal-PLAQUE trial are somewhat encouraging [3].
Despite negative (endothelial function, inflammatory markers) or marginally positive effects on surrogate endpoints (plaque), only large-scale event-based clinical trials can ultimately evaluate whether CETP inhibition with specific inhibitors that do not share the off-target toxic effects of torcetrapib is going to be a therapeutic advance. The results of the dal-OUTCOMES trial will become available in 2013 and hopefully give more information on the role of CETP in atherosclerosis. Surrogate markers do not take into account other known or unknown biological vascular or non-vascular effects that ultimately influence net clinical outcomes. Let’s wait for outcomes!

References

1. Chyu KY, Peter A, Shah PK. Progress in HDL-based therapies for atherosclerosis. Curr Atheroscler Rep 2011;13:405–412
2. Shah PK. The yin and yang of cholesteryl ester transfer protein in cardiovascular disease. Circulation 2009;120:2408–2410.
3. Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, Fuster V, Ballantyne CM, Stein EA, Tardif JC, Rudd JH, Farkouh ME, Tawakol A; dal-PLAQUE Investigators. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomized clinical trial. Lancet 2011;378:1547–1559