Effects of fenofibrate and ezetimibe, both as monotherapy and in coadministration, on cholesterol mass within lipoprotein subfractions and low-density lipoprotein peak particle size in patients with mixed hyperlipidemia

Diane L Tribble, Michel Farnier, Geraldine Macdonell, Inna Perevozskaya, Michael J Davies, Barry Gumbiner, Thomas A Musliner
Metabolism: Clinical and Experimental 2008, 57 (6): 796-801
Coadministration of fenofibrate and ezetimibe (FENO + EZE) produced complementary and favorable effects on the major lipids and lipoproteins, low-density lipoprotein cholesterol (LDL-C), triglycerides, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C levels, and was well tolerated in patients with mixed hyperlipidemia. The current analysis evaluates the effects of FENO and EZE, as monotherapies and in coadministration, on lipoprotein subfractions and LDL particle size distributions in these patients. In a 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients with mixed hyperlipidemia were randomized in a 1:3:3:3 ratio to one of 4 treatment groups: placebo, FENO 160 mg/day, EZE 10 mg/day, or FENO 160 mg/day + EZE 10 mg/day. At baseline and study end point, the Vertical Auto Profile II method was used to measure the cholesterol associated with 2 very low-density lipoprotein (VLDL) subfractions (VLDL-C1 + 2 and VLDL-C3), intermediate-density lipoproteins (IDL-C), and 4 LDL subfractions (LDL-C1 through LDL-C4, from most buoyant to most dense), lipoprotein (Lp) (a), and 2 HDL-C subfractions (HDL-C2 and HDL-C3). The LDL particle size was determined using segmented gradient gel electrophoresis. Fenofibrate reduced cholesterol mass within VLDL, IDL, and dense LDL (primarily LDL-C4) subfractions, and increased cholesterol mass within the more buoyant LDL-C2 subfraction, consistent with a shift to a more buoyant LDL peak particle size. Ezetimibe reduced cholesterol mass within all of the apolipoprotein B-containing particles (eg, VLDL-C, IDL-C, and LDL-C) but did not lead to a shift in the LDL particle size distribution profile. Coadministration of FENO and EZE promoted more pronounced reductions in VLDL-C, IDL-C, and LDL-C, and a preferential decrease in dense LDL subfractions. Fenofibrate and FENO + EZE promoted similar increases in HDL-C2 and HDL-C3. Coadministration of FENO + EZE produced complementary and favorable changes in lipoprotein fractions and subfractions, as assessed by the Vertical Auto Profile II method, in patients with mixed hyperlipidemia. These changes reflected the combined effects of FENO in reducing triglycerides-rich lipoproteins and promoting a shift in the LDL particle distribution profile toward larger, more buoyant particles and of EZE in promoting reductions in cholesterol mass across the apolipoprotein B particle spectrum.

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