Tribble Diane L, Farnier Michel, Macdonell Geraldine, Perevozskaya Inna, Davies Michael J, Gumbiner Barry, Musliner Thomas A
Merck Research Laboratories, Rahway, NJ 07065, USA.
Metabolism. 2008 Jun;57(6):796-801. doi: 10.1016/j.metabol.2008.01.026.
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.
非诺贝特与依折麦布联合用药（非诺贝特+依折麦布）对主要脂质和脂蛋白、低密度脂蛋白胆固醇（LDL-C）、甘油三酯、高密度脂蛋白胆固醇（HDL-C）和非HDL-C水平产生了互补且有益的作用，并且在混合性高脂血症患者中耐受性良好。本分析评估了非诺贝特和依折麦布作为单一疗法及联合用药时，对这些患者脂蛋白亚组分和LDL颗粒大小分布的影响。在一项为期12周的多中心、随机、双盲、安慰剂对照、平行组研究中，混合性高脂血症患者按1:3:3:3的比例随机分为4个治疗组之一：安慰剂组、非诺贝特160毫克/天组、依折麦布10毫克/天组或非诺贝特160毫克/天+依折麦布10毫克/天组。在基线和研究终点，采用垂直自动谱II法测量与2个极低密度脂蛋白（VLDL）亚组分（VLDL-C1+2和VLDL-C3）、中间密度脂蛋白（IDL-C）、4个LDL亚组分（LDL-C1至LDL-C4，从最漂浮到最致密）、脂蛋白（Lp）（a）以及2个HDL-C亚组分（HDL-C2和HDL-C3）相关的胆固醇。使用分段梯度凝胶电泳测定LDL颗粒大小。非诺贝特降低了VLDL、IDL和致密LDL（主要是LDL-C4）亚组分中的胆固醇质量，并增加了更漂浮的LDL-C2亚组分中的胆固醇质量，这与向更漂浮的LDL峰值颗粒大小转变一致。依折麦布降低了所有含载脂蛋白B颗粒（如VLDL-C、IDL-C和LDL-C）中的胆固醇质量，但未导致LDL颗粒大小分布曲线发生偏移。非诺贝特与依折麦布联合用药促使VLDL-C、IDL-C和LDL-C更显著降低，且致密LDL亚组分优先减少。非诺贝特和非诺贝特+依折麦布促使HDL-C2和HDL-C3有相似程度的升高。采用垂直自动谱II法评估，非诺贝特+依折麦布联合用药在混合性高脂血症患者的脂蛋白组分和亚组分中产生了互补且有益的变化。这些变化反映了非诺贝特在降低富含甘油三酯的脂蛋白以及促使LDL颗粒分布曲线向更大、更漂浮颗粒转变方面的联合作用，以及依折麦布在促使整个载脂蛋白B颗粒谱中的胆固醇质量降低方面的作用。
