Elsevier

The Lancet

Volume 378, Issue 9802, 29 October–4 November 2011, Pages 1547-1559
The Lancet

Articles
Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial

https://doi.org/10.1016/S0140-6736(11)61383-4Get rights and content

Summary

Background

Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.

Methods

In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 18F-fluorodeoxyglucose (18F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473.

Findings

189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7·3 [90% CI −13·5 to −0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups.

Interpretation

Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed.

Funding

F Hoffmann-La Roche Ltd.

Introduction

The improvement of cardiovascular outcomes in patients with, or at high risk of, atherosclerotic disease is needed, despite significant reductions in events achieved with low-density lipoprotein cholesterol (LDL-C)–lowering therapies, particularly statins.1, 2, 3 One potential approach to reduce atherosclerotic plaque burden is to raise high-density lipoprotein cholesterol (HDL-C),4, 5 for which epidemiological studies have consistently shown an inverse relation with risk of coronary artery disease.6, 7 Even in statin-treated patients, low HDL-C plasma concentrations are an independent risk factor for cardiovascular events,8, 9 whereas higher levels of HDL-C are associated with reduced plaque progression10 and reduced frequency of cardiovascular events.11

Drugs that act on cholesteryl ester transfer protein (CETP) can result in substantial increases in serum HDL-C. A previously investigated CETP inhibitor, torcetrapib, effectively increased HDL-C, but was associated with an increase in mortality,12 subsequently thought to be due to compound-specific off-target effects, such as increases in blood pressure and vascular inflammation.13 Dalcetrapib is a novel modulator of CETP activity that increases HDL-C.14, 15, 16 To date, its tolerability has been reassuring with no evidence of clinically relevant increases in blood pressure.15, 16, 17 Preclinical experiments in rabbits showed a decrease in atherosclerosis with dalcetrapib;18 however, the direct clinical effects of dalcetrapib on atherosclerosis are unknown.

MRI and PET/CT are promising techniques for assessment of vascular morphology and vascular inflammation, respectively, and for quantification of the effects of drug interventions on plaque stability and burden.19, 20, 21, 22 By directly measuring the effect on the vessel wall of cumulative cardiovascular risk factors combined,23, 24 these non-invasive imaging techniques can serve as valuable biomarkers.25 A multimodality approach with these two techniques to assess dalcetrapib's effects was therefore used in dal-PLAQUE—MRI to measure established classic variables of plaque morphology, and assess the progression or regression of atherosclerosis, and PET/CT measurement of 18F-fluorodeoxyglucose (18F-FDG) uptake to identify plaque inflammation. This 24-month dal-PLAQUE trial is the longest placebo-controlled active-drug MRI study until now, as well as the first to use non-invasive multimodality imaging for primary endpoints. The primary aim of the study was to show, with a dual-imaging approach, whether dalcetrapib causes an increase in atherosclerotic plaque progression or vascular inflammation compared with placebo.

Section snippets

Study design

This phase 2b double-blind, randomised, placebo-controlled study was investigator initiated with the final study protocol designed in collaboration with the sponsor (F Hoffmann-La Roche Ltd). This study was done at 11 centres in Canada and the USA, in compliance with the principles of the Declaration of Helsinki and according to Good Clinical Practice guidelines. The protocol was reviewed and approved by the institutional review board of every centre. All participants provided written informed

Results

Of 189 patients screened, 130 were randomly assigned to either placebo or dalcetrapib 600 mg/day (figure 1). Baseline demographics including risk factors of atherosclerotic disease and coronary heart disease were generally balanced between the two groups (table 1). More patients had coronary heart disease in the dalcetrapib group whereas more had peripheral arterial disease in the placebo group. Despite a slight imbalance in statin use, LDL-C concentrations were well matched in both groups at

Discussion

The primary endpoints for dal-PLAQUE showed dalcetrapib did not increase plaque progression over 24 months or inflammation in the vessel wall over 6 months compared with placebo. For the coprimary PET/CT and MRI endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. These data suggest dalcetrapib might be associated with favourable vascular changes. After 24 months, total vessel area increased less with

References (64)

  • N Tahara et al.

    Simvastatin attenuates plaque inflammation—evaluation by fluorodeoxyglucose positron emission tomography

    J Am Coll Cardiol

    (2006)
  • KA Rye et al.

    The metabolism and anti-atherogenic properties of HDL

    J Lipid Res

    (2009)
  • JD Curb et al.

    A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly

    J Lipid Res

    (2004)
  • PJ Barter et al.

    Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease

    J Am Coll Cardiol

    (2006)
  • B Paulmier et al.

    Arterial wall uptake of fluorodeoxyglucose on PET imaging in stable cancer disease patients indicates higher risk for cardiovascular events

    J Nucl Cardiol

    (2008)
  • HR Underhill et al.

    Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial

    Am Heart J

    (2008)
  • N Tahara et al.

    Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome

    J Am Coll Cardiol

    (2007)
  • CC Tellis et al.

    The role of lipoprotein-associated phospholipase A2 inatherosclerosis may depend on its lipoprotein carrier in plasma

    Biochim Biophys Acta

    (2009)
  • GG Schwartz et al.

    Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome

    Am Heart J

    (2009)
  • Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival study (4S)

    Lancet

    (1994)
  • CP Cannon et al.

    Intensive versus moderate lipid lowering with statins after acute coronary syndromes

    N Engl J Med

    (2004)
  • C Baigent et al.

    Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials

    Lancet

    (2010)
  • MJ Chapman et al.

    Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors

    Eur Heart J

    (2010)
  • MJ Chapman et al.

    Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

    Eur Heart J

    (2011)
  • WE Boden

    High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High-Density Lipoprotein Intervention Trial

    Am J Cardiol

    (2000)
  • H Jafri et al.

    Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk

    Ann Intern Med

    (2010)
  • SH Johnsen et al.

    Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis the Tromsø study

    Circulation

    (2005)
  • L Wei et al.

    Impact on cardiovascular events of increasing high density lipoprotein cholesterol with and without lipid lowering drugs

    Heart

    (2006)
  • PJ Barter et al.

    Effects of torcetrapib in patients at high risk for coronary events

    N Engl J Med

    (2007)
  • DJ Rader

    Illuminating HDL—is it still a viable therapeutic target?

    N Engl J Med

    (2007)
  • EA Stein et al.

    Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial

    Eur Heart J

    (2010)
  • ESG Stroes et al.

    Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats

    Br J Pharmacol

    (2009)
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