Abstract 19187: Dalcetrapib Does Not Prevent CETP-Induced Pre-β1-HDL Formation in Human Plasma in vitro and in Treated Patients
OBJECTIVES: Pre-β-HDL is thought to represent a marker of the atheroprotective effect of high-density lipoprotein (HDL). Thus the effect on pre-β-HDL of drugs modulating cholesteryl ester transfer protein (CETP) which plays a significant role in HDL remodeling should be investigated during their development. Dalcetrapib was tested in vitro and in vivo for its potential for interference with pre-β-HDL formation using a selective pre-β1-HDL ELISA.
Results: Incubation of human plasma for 21h at 37°C raised the level of pre-β-HDL to 41.3±0.8 μg/mL (53%). In the presence of dalcetrapib 0.1, 1, and 3 μM, pre-β1-HDL formation remained unchanged but was significantly increased to 48.8±0.6 μg/mL at 10 μM (P<0.004). On the contrary, torcetrapib (0.1, 1, 3, and 10 μM) dose-dependently decreased levels of pre-β1-HDL (18.7±0.9 μg/mL at 0.1 μM; P<0.0001). The addition of wild-type recombinant CETP (wt-rhCETP; final CETP concentration: 4.38 μg/mL) increased basal pre-β1-HDL by 80% to 66.20 μg/mL, which was further increased by 3 μM dalcetrapib (21%; P<0.05). Under these conditions, torcetrapib 0.1, 1, and 3 μM decreased CETP-induced pre-β1-HDL by 46.9, 74.0, and 78.5%, respectively (P<0.0001). Dose dependency was studied for CETP 1.25 μg/mL or added wt-rhCETP (final concentration 4.38, 7.5, 13.75, and 26.25 μg/mL) dalcetrapib, or torcetrapib 0.1, 1, 3, and 10 μM. A significant increase in pre-β1-HDL formation was seen for dalcetrapib (P<0.001, 0.007, 0.029, and 0.001 at 0.1, 1, 3, and 10 μM, respectively). Torcetrapib decreased pre-β1-HDL formation even at the lowest concentration of 0.1 μM (P<0.004) and at 1, 3, and 10 μM (each P<0.001). In a subgroup of 12 patients who received 900 mg of dalcetrapib, where HDL-cholesterol increased by 33% (P<0.001) and CETP activity decreased by 54% (P<0.0001), pre-β1-HDL remained unchanged (87.4±9.2 μg/mL baseline, 99.5±16.6 μg/mL at 3 months; NS).
Conclusions: Contrary to torcetrapib, dalcetrapib in vitro does not impair the formation of pre-β1-HDL induced by endogenous or added wt-rhCETP. In patients treated with 900 mg dalcetrapib per day for 3 months, in the presence of significant CETP inhibition, pre-β1-HDL was maintained, suggesting no detrimental effect of dalcetrapib on the potential atheroprotective effect of CETP.
- © 2010 by American Heart Association, Inc.