Abstract 15216: Modulation of CETP Activity by Dalcetrapib Increases Pre-β-HDL and Associated Parameters of HDL Functionality: Preclinical and Clinical Evidence
Introduction: Dalcetrapib is a cholesteryl ester transfer protein modulator (CETPm) that increases HDL-C, preserves CETP-induced pre-β-HDL formation, and promotes ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from macrophages in vitro. We evaluated the effect of dalcetrapib on pre-β-HDL formation in vivo, and on phytosterols; as potential biomarkers of basolateral intestinal ABCA1-mediated pre-β-HDL lipidation.
Methods: Plasma pre-β1-HDL was measured in a subgroup of patients treated with dalcetrapib 600 mg/day (n=34) or placebo (n=26) from the dal-PLAQUE study (NC21153). Plasma non-cholesterol sterol biomarker levels were measured in 22 healthy subjects given dalcetrapib 600 mg/day for 7 days (WP20019) and in hamsters given dalcetrapib 300 mg/kg/day for 21 days.
Results: In study NC21153 at 3 and 12 months versus placebo, dalcetrapib increased HDL-C by 36.2% and 35.1% in the pre-β-HDL measured subgroup and by 31.4% and 27.6% in the total cohort, LDL-C decreased by 3.9% and 6.8%. For patients with low baseline pre-β1-HDL (<100 μ g/mL, dalcetrapib n=26, placebo n=13), pre-β1-HDL was increased by dalcetrapib at 3 months (19.4%) and 12 months (26.4%) and unchanged for baseline pre-β-HDL >100 μ g/mL (dalcetrapib n=8, placebo n=13). In healthy subjects dalcetrapib increased HDL-C by 27% (p<0.0001). In spite of a decrease in LDL-C by 16% (p<0.0001), plasma campesterol and β-sitosterol cholesterol ratios (markers of cholesterol absorption) increased by 27% (p=0.001) and 32% (p<0.001), respectively without notable change in lathosterol or desmosterol cholesterol ratio. In hamsters, dalcetrapib increased plasma campesterol and β-sitosterol cholesterol ratios by 54% (p=0.04) and 64% (p=0.0002), respectively; no increase was seen in lathosterol or desmosterol cholesterol ratio.
Conclusions: Dalcetrapib consistently raises HDL-C by ∼30% in the clinical setting while maintaining pre-β-HDL formation. Dalcetrapib increased plasma campesterol and β-sitosterol both in healthy subjects - as observed in previous studies in subjects with high HDL-C - and hamsters, suggesting that sterol markers of cholesterol absorption may also be markers of intestinal pre-β-HDL lipidation by enterocyte basolateral ABCA1.
- © 2011 by American Heart Association, Inc.