FENOFIBRATE REDUCES PLASMA CHOLESTERYL ESTER TRANSFER FROM HDL TO VLDL AND NORMALIZES THE ATHEROGENIC, DENSE LDL PROFILE IN COMBINED HYPERLIPIDEMIA

The effect of fenofibrate on plasma cholesteryl eater transfer protein (CETP) activity in relation to the quantitative and qualitative featu res of apoB- and apoA-I-containing lipoprotein subspecies was investig ated in nine patients presenting with combined hyperlipidemia. Fenofib rate (200 mg/d for 8 weeks) induced significant reductions in plasma c holesterol (-16%; P<.01), triglyceride (-44%;P<.007), VLDL cholesterol (-52%; P=.01), LDL cholesterol (-14%; <.001), and apoB (-15%; P<.009) levels and increased HDL cholesterol (19%; P=.0001) and apoA-I (12%; P=.003) levels. An exogenous cholesteryl ester transfer (CET) assay re vealed a marked decrease (-26%; P<.002) in total plasma CETP-dependent CET activity after fenofibrate treatment. Concomitant with the pronou nced reduction in VLDL levels (37%; P<.005), the rate of CET from HDL to VLDL was significantly reduced by 38% (P=.0001), whereas no modific ation in the rate of cholesteryl ester exchange between HDL and LDL oc curred after fenofibrate therapy. Combined hyperlipidemia is character ized by an asymmetrical LDL profile in which small, dense LDL subspeci es (LDL-4 and LDL-5, d=1.039 to 1.063 g/mL) predominate. Fenofibrate q uantitatively normalized the atherogenic LDL profile by reducing level s of dense LDL subspecies (-21%) and by inducing an elevation (26%; P< .(5) in LDL subspecies of intermediate density (LDL-3, d=1.029 to 1.03 9 g/mL), which possess optimal binding affinity for the cellular LDL r eceptor. However, no marked qualitative modifications in the chemical composition or size of LDL particles were observed after drug treatmen t. Interestingly, the HDL cholesterol concentration was increased by f enofibrate therapy, whereas no significant change was detected in tota l plasma HDL mass. In contrast, the HDL subspecies pattern was modifie d as the result of an increase in the total mass (11.7%) of HDL(2a), H DL(3a), and HDL(3b) (n=1.091 to 1.156 g/mL) at the expense of reductio ns in the total mass (-23%) of HDL1, (d=1.063 to 1.091 g/mL) and HDL(3 c) (d=1.156 to 1.179 g/mL). Such changes are consistent with a drug-in duced reduction in CETP activity. In conclusion, the overall mechanism involved in the fenofibrate-induced modulation of the atherogenic den se LDL profile in combined hyperlipidemia primarily involves reduction in CET from HDL to VLDL together with normalization of the intravascu lar transformation of VLDL precursors to receptor-active LDLs of inter mediate density.