Dalcetrapib Shows Promise by Safely Raising HDL
PARIS, France—The experimental agent dalcetrapib appears to raise high-density lipoprotein (HDL) cholesterol levels by inhibiting cholesterol ester transfer protein (CETP) activity without adversely affecting blood pressure or endothelial function, according to phase II trial data presented Sunday, August 28 at the European Society of Cardiology Congress 2011.
For the dal-VESSEL trial, Thomas F. Lüscher, MD, of University Hospital (Zurich, Switzerland), and colleagues enrolled 476 patients at 19 European centers who suffered from or were at risk for CHD plus had HDL levels below 50 mg/dL. Patients were randomized to receive 600-mg dalcetrapib (R. Hoffman-La Roche, Basel, Switzerland) or placebo for 36 weeks.
Baseline characteristics were similar between the 2 groups. Total cholesterol levels were 3.945 ± 0.665 mmol/L in dalcetrapib patients and 3.802 ± 0.563 mmol/L in placebo patients, while HDL cholesterol levels were 1.013 ± 0.190 mmol/L and 0.995 ± 0.185 mmol/L, respectively.
The study's primary endpoint of changes in brachial flow-mediated dilation, an indicator of endothelial dysfunction, appeared unaffected by dalcetrapib from baseline to 12 weeks. In addition, the drug did not worsen 24-hour ambulatory blood-pressure monitoring, the primary safety endpoint, assessed at 4 weeks.
Dalcetrapib reduced CETP activity by 49% and elevated HDL levels by 31%. Yet it did not affect low density lipoprotein cholesterol. Dr. Lüscher also expressed uncertainty as to why the change in HDL did not translate into better endothelial function.
Drug Safer Than Previous Contender
According to discussant Keith A. A. Fox, MD, of the University of Edinburgh (Edinburgh, Scotland), researchers were eager to find a CETP inhibitor that showed efficacy without dangerous side effects, because a previous agent, torcetrapib, reached phase III trials before being dropped because of an increase in deaths. The older drug had adverse effects on endothelial function and blood pressure, Dr. Lüscher noted.
Now dalcetrapib will be tested in a larger trial of 14,000 patients, Dr. Lüscher reported, with results expected by around 2013. In an interview with TCTMD, he explained how dalcetrapib might improve endothelial function. The drug inhibits CETP, thus increasing HDL.
“Endothelial cells in the vessel wall produce nitric oxide and dilate the vessel walls, and HDL has been shown to increase nitric oxide. But if the endothelial cells are dysfunctional, the release of nitric oxide is impaired,” he commented. “Endothelial dysfunction is the earliest phase of arteriosclerosis.”
However, dal-VESSEL found no change in vasodilation. “Maybe the HDL change was not good enough, or HDL in patients with coronary disease wasn’t improved,” Dr. Lüscher said, adding that only diseased patients were included in the trial. “Follow-up was only for 6 months, and although the patients were at high risk in the long run, in 6 months, the event rate was not very high.”
Lüscher TF. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: The dal-VESSEL randomized clinical trial. Presented at: European Society of Cardiology Congress; August 28, 2011; Paris, France.
- The dal-VESSEL study was sponsored by F. Hoffmann-La Roche.
- Dr. Lüscher reports receiving research grants from Eli Lilly, Merck, and Pfizer and receiving consulting or lecture fees from CSL, F. Hoffmann-La Roche, Merck, and Pfizer.