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dal-VESSEL: Dalcetrapib increased cholesteryl ester transfer protein activity, raised HDL

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European Society of Cardiology Congress 2011

The experimental compound dalcetrapib increased both cholesteryl esterase transfer protein activity and HDL levels without adverse effects on endothelial function or BP, results from a phase 2b study suggested.

Researchers for the randomized, double blind dal-VESSEL study sought to rule out any adverse effects of dalcetrapib (F. Hoffmann-La Roche) on endothelial function in 476 patients with CHD randomly assigned to either 600 mg dalcetrapib daily (n=232) or placebo (n=234). They used ambulatory BP monitoring to assess BP levels and flow mediated dilatation (FMD) to assess endothelial function. The primary study endpoints were change from baseline of FMD of the right brachial artery after 5 minutes of cuff occlusion at 12 weeks, as well as 24-hour ambulatory BP monitoring measurement at 4 weeks.

According to the results, no significant change in FMD was observed at week 12 and out to 36 weeks. The researchers also reported an increase in HDL levels during the 36-week study period, with a 27.5 ± 1.28% (P<.0001) increase from baseline at 4 weeks in the dalcetrapib group vs. placebo and a 30.7 ± 1.45% increase from baseline in the dalcetrapib group vs. placebo at week 36 (P<.0001). The increase occurred, the presenter said, without affecting LDL or ApoB100 levels.

“Dalcetrapib did not cause endothelial dysfunction, but also did not improve it,” Thomas F. Lüscher, MD, a professor of medicine at University Hospital in Zurich, Switzerland, said in a presentation. “In contrast to torcetrapib, dalcetrapib did not have an effect on ambulatory BP monitoring, providing further reassurance regarding the safety of the compound. The trial also demonstrates the feasibility of using FMD to test the influence of novel CV compounds on the biology of the vessel wall and endothelial function in particular.”

Discussant Keith Fox, MD, of the University and Royal Infirmary of Edinburgh in the United Kingdom, said one take-away from dal-VESSEL was that the primary safety endpoint regarding systolic BP was met. He urged caution, however, on drawing too many conclusions from the trial results without further study.

“Although the authors conclude that dalcetrapib does not worsen endothelial function, nor does it raise BP (as prior cholesterol ester transferase inhibitors have done), caution must be exercised in view of the limited size of this phase 2 study,” Fox said in a statement. “To put the FMD findings into context, statins produce a dose-dependent reduction in LDL and an increase in FMD of approximately 40% to 60%. The impact of dalcetrapib on clinical outcomes is currently being tested in a large phase 3 trial.”

For more information:

• Fox K. Hotline I. Presented at: European Society of Cardiology Congress 2011; Aug. 27-31; Paris.
• Lüscher T. Hotline I. Presented at: European Society of Cardiology Congress 2011; Aug. 27-31; Paris.

Disclosures: Dr. Fox reports no relevant financial disclosures. Dr. Lüscher has received research support from Pfizer, Eli Lily and Merck, and has consulted for CSl, Merck, Pfizer and F. Hoffmann-La Roche.

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