The investigational CETP inhibitor dalcetrapib does not increase plaque burden, and even appears to prompt positive vascular effects in patients with or at high risk of coronary heart disease, according to data from the dal-PLAQUE trial published online Sept. 12 in the Lancet.
The trial provides reassuring data after the spectacular failure in 2006 of another cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, raised concerns that HDL cholesterol–raising drugs had proinflammatory or proatherosclerotic effects.
Dalcetrapib was shown to increase HDL cholesterol by 31% without affecting LDL cholesterol or raising blood pressure at 24 months in the recently reported companion dal-VESSEL trial.
The phase IIb exploratory dal-PLAQUE trial used magnetic resonance imaging (MRI) to assess plaque burden and positron emission tomography/computed tomography (PET/CT) measurements of 18F-fluorodeoxyglucose (18F-FDG) uptake to assess inflammation in an index vessel (right carotid artery, left carotid artery, or ascending thoracic aorta), among 130 patients randomized to dalcetrapib 600 mg per day or placebo in addition to standard medication for 24 months.
"No evidence of pro-atherogenic effect of dalcetrapib therapy was recorded in terms of plaque burden compared with placebo as assessed by MRI after 24 months," lead author Dr. Zahi A. Fayad reported (Lancet 2011 Sept. 12 [doi:10.1016/S0140-6736(11)61383-4]).
Notably, the absolute change from baseline in total carotid vessel area by MRI was significant in patients on dalcetrapib, relative to placebo, at –4.01 mm2.
The change in the dalcetrapib group was –2.20 mm2 for wall area and 0.60% for normalized wall index, compared with placebo, both nonsignificant differences. All three of these indices were under the predefined limits of no harm.
The change in wall thickness at 24 months was –0.3 mm. The upper confidence interval for this fourth index was beyond the predefined limit of no harm, but there was less increase with dalcetrapib than with placebo (mean 1.19 mm with dalcetrapib vs. 1.27 mm with placebo), observed Dr. Fayad of Mount Sinai School of Medicine, New York.
In an accompanying editorial, Dr. Erik S.G. Stroes and Dr. Diederick F. van Wijk said that first and foremost, it is encouraging that the dalcetrapib group did not show an increase in total vessel area, "which clearly differs from the progression of common carotid artery thickness after torcetrapib administration." Instead, the opposite occurred, with the progression of vessel wall area, indicating outward remodeling in the course of atherogenesis, decreasing in the dalcetrapib group (Lancet 2011 Sept. 12 [doi:10.1016/S0140-6736(11)61421-9]).
The editorialists suggested that the absence of benefit with dalcetrapib on parameters of the aortic vessel wall might be due to the heterogeneity of antiatherosclerotic effects or the small sample size, and said a similar study with the more potent CETP inhibitor anacetrapib could resolve this issue.
"As we await the final verdict on dalcetrapib in 2013, when the dal-OUTCOME study will provide data on cardiovascular end points in 15,600 patients, the findings of Fayad and colleagues bring us one step higher in the ladder of CETP research, after its free fall since 2006," wrote Dr. Stroes and Dr. Wijk, of the Academic Medical Center, Amsterdam, Netherlands.
The dal-PLAQUE investigators reported that the PET/CT measurements of index vessel most-diseased-segment target-to-background ratio (TBR) did not differ significantly between the dalcetrapib and placebo groups at 6 months (2.56 vs. 2.54).
Analysis of the carotid vessel 18F-FDG-PET/CT data, however, showed a 7.3% reduction in most-diseased-segment TBR in the dalcetrapib group, compared with no change with placebo, Dr. Fayad and his associates reported. Increased HDL cholesterol concentrations appeared to be correlated with decreased TBR. In addition, reductions in TBR at 6 months were noted to be associated with a reduction in the rate of increase in total vessel area by MRI at 24 months.
Notably, systemic inflammation as measured by high-sensitivity C-reactive protein did not decrease in the dalcetrapib group. On the contrary, it rose 33%.
"These findings highlight that the blood and imaging biomarkers of inflammation might provide substantially different information about the vascular inflammatory milieu, the exact nature of which remains incompletely elucidated," wrote the authors of dal-PLAQUE, the first placebo-controlled trial to use noninvasive multimodality imaging as primary end points.
Finally, the editorialists called for additional studies to assess the effect of selective, potent anti-inflammatory drugs on vessel wall inflammation and cardiovascular outcome. As an example, they highlighted the current CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) evaluating canakinumab, an antibody that inhibits the endogenous proinflammatory protein interleukin-1 beta in patients with coronary artery disease.
Hoffmann-La Roche funded the study and preparation of the journal article. Dr. Fayad reports research grants from Roche, GlaxoSmithKline, Merck, VBL Therapeutics, Novartis, Bristol-Myers Squibb, and Via Pharmaceuticals, and honoraria from Roche. His coauthors report financial relationships with several firms, including, in some cases, employment with Hoffmann-La Roche. Dr. Stroes and Dr. Wijk report no conflicts.