Novel HDL-Raising Drug Appears Safe

Thomas Lüscher, MD, of the University Hospital in Zurich, reported at the European Society of Cardiology meeting that, through 36 weeks of treatment, dalcetrapib did not raise blood pressure or affect endothelial function compared with placebo in patients with or at risk for coronary heart disease.

Although Lüscher said that it was disappointing that the drug did not improve endothelial function, he said the results support proceeding with the phase III dal-OUTCOME trial, which aims to enroll 15,600 patients with acute coronary syndromes. Lüscher said the first outcomes data might be available in early 2013.

The first CETP inhibitor developed was torcetrapib, which raised HDL cholesterol by about 70% and decreased LDL cholesterol by about 25% in the ILLUMINATE trial. The trial was stopped early, however, because of a significant increase in cardiovascular events and mortality.

Subsequent analyses suggested that the negative effects were related to the torcetrapib molecule itself and not CETP inhibition, opening the door for the development of new CETP inhibitors, including anacetrapib and dalcetrapib.

The DEFINE trial reported last year at the American Heart Association meeting showed that anacetrapib dramatically raised HDL cholesterol and lowered LDL cholesterol without the safety concerns of torcetrapib. That study did not assess clinical outcomes.

Lüscher and his colleagues randomized 476 patients (mean age 62) with or at risk for coronary heart disease who had an HDL cholesterol level of 50 mg/dL or less at baseline to 36 weeks of treatment with either 600 mg dalcetrapib or placebo. More than 90% of patients in both groups were taking statins.

The researchers measured flow-mediated dilation of the brachial artery -- a measure of endothelial function -- at weeks 12 and 36 and 24-hour ambulatory blood pressure at weeks four, 12, and 36.

At baseline, lipid levels were relatively low, according to Lüscher. Total cholesterol was about 147 mg/dL, HDL cholesterol was about 38.6 mg/dL, LDL cholesterol was about 81 mg/dL, and triglycerides were about 151 mg/dL.

Through 36 weeks, dalcetrapib increased HDL cholesterol by about 31%, with no change in the placebo group (P<0.0001). Much of the bump occurred in the first four weeks of treatment. Apolipoprotein A1, which is associated with HDL cholesterol, also increased.

There was, however, no change in LDL cholesterol or in apolipoprotein B100, which is associated with LDL cholesterol.

Flow-mediated dilation was not impaired or improved during the study, and there was no significant change in blood pressure. That is in contrast to torcetrapib, which raised both systolic and diastolic pressure.

Rates of adverse events -- 68% with placebo and 72% with dalcetrapib -- were similar. Serious adverse events occurred in 6% and 5%, respectively. One patient died in the placebo group from coronary heart disease.

In comments following Lüscher's presentation, Keith Fox, MBChB, of the University of Edinburgh in Scotland, noted that, although systolic blood pressure was not significantly different between placebo and dalcetrapib, the average was numerically higher in the dalcetrapib group (128 versus 125 mm Hg, P=0.337).

"One must be cautious because this is a limited size trial and I would argue that it's only when the large phase III trial is completed that we will know for sure whether these apparent modest changes in blood pressure, for example, are real, and whether they have an adverse effect on outcomes," said Fox, who is the president of the British Cardiovascular Society.

Lüscher T, et al "Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease -- the dal-VESSEL randomized clinical trial" ESC 2011; Abstract 411