Ose Leiv, Reyes Robert, Johnson-Levonas Amy O, Sapre Aditi, Tribble Diane L, Musliner Thomas
Lipid Clinic, Medical Department, Rikshospitalet, Oslo, Norway.
Clin Ther. 2007 Nov;29(11):2419-32. doi: 10.1016/j.clinthera.2007.10.004.
Cholesterol-rich lipoproteins, including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), are known to promote atherosclerosis. Ezetimibe/simvastatin (E/S) is an efficacious lipid-lowering treatment that inhibits both the intestinal absorption and biosynthesis of cholesterol.
The aim of the current analysis was to compare the effects of ezetimibe and simvastatin monotherapy and E/S treatment on lipoprotein subfractions and LDL particle size in patients with primary hypercholesterolemia.
This was an exploratory (hypothesis generating) analysis of archived plasma samples drawn from patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study. After a washout and diet/placebo run-in, patients with hypercholesterolemia (LDL-C, > or =145- < or =250 mg/dL; triglycerides, < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: E/S (10/10, 10/20, 10/40, or 10/80 mg), simvastatin monotherapy (10, 20, 40, or 80 mg), ezetimibe monotherapy (10 mg), or placebo. A subset of patients had lipid subfraction measurements taken at baseline (week 0) and postrandomization (week 12). Plasma samples were used to quantify cholesterol associated with VLDL subfractions (VLDLI+2 and VLDL3), IDL, and 4 LDL subfractions (LDL1-4) via the Vertical Auto Profile II method. LDL-C particle size was determined using segmented gradient gel electrophoresis. The primary end point was median percent change in subfraction cholesterol for E/S versus ezetimibe or simvastatin monotherapy, pooled across doses.
Of the 1528 patients randomized in the original study, 1397 (91%) had lipid subfraction measurements taken. E/S was associated with significant reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe, simvastatin, and placebo. E/S resulted in near-additive reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe and simvastatin monotherapy. Of the subfractions examined, with regard to E/S, the greatest reductions were observed in IDL-C and LDL-C1, LDL-C2, and LDL-C3. When compared with placebo, ezetimibe, simvastatin, and E/S did not shift the distribution of LDL particles toward a larger, more buoyant LDL subclass pattern.
E/S was more effective than ezetimibe and simvastatin monotherapy in reducing atherogenic lipoprotein subfractions in these patients with primary hypercholesterolemia.
富含胆固醇的脂蛋白，包括低密度脂蛋白胆固醇（LDL-C）、中间密度脂蛋白胆固醇（IDL-C）和极低密度脂蛋白胆固醇（VLDL-C），已知可促进动脉粥样硬化。依折麦布/辛伐他汀（E/S）是一种有效的降脂治疗药物，可抑制胆固醇的肠道吸收和生物合成。
本分析旨在比较依折麦布和辛伐他汀单药治疗以及E/S治疗对原发性高胆固醇血症患者脂蛋白亚组分和LDL颗粒大小的影响。
这是一项对多中心、随机、双盲、安慰剂对照、平行组研究中患者的存档血浆样本进行的探索性（假设生成）分析。在洗脱期和饮食/安慰剂导入期后，高胆固醇血症患者（LDL-C≥145～≤250mg/dL；甘油三酯≤350mg/dL）被随机分为10种每日治疗方案中的1种，治疗12周：E/S（10/10、10/20、10/40或10/80mg）、辛伐他汀单药治疗（10、20、40或80mg）、依折麦布单药治疗（10mg）或安慰剂。一部分患者在基线（第0周）和随机分组后（第12周）进行了脂质亚组分测量。通过垂直自动轮廓II法使用血浆样本定量与VLDL亚组分（VLDLI+2和VLDL3）、IDL以及4种LDL亚组分（LDL1-4）相关的胆固醇。使用分段梯度凝胶电泳测定LDL-C颗粒大小。主要终点是E/S与依折麦布或辛伐他汀单药治疗相比，各剂量合并后的亚组分胆固醇中位数变化百分比。
在原研究中随机分组的1528例患者中，1397例（91%）进行了脂质亚组分测量。与依折麦布、辛伐他汀和安慰剂相比，E/S可显著降低VLDL-CI+2、VLDL-C3、IDL-C、LDL-C1、LDL-C2和LDL-C3。与依折麦布和辛伐他汀单药治疗相比，E/S可使VLDL-CI+2、VLDL-C3、IDL-C、LDL-C1、LDL-C2和LDL-C3近乎相加性降低。在所检查的亚组分中，就E/S而言，IDL-C以及LDL-C1、LDL-C2和LDL-C3的降低最为显著。与安慰剂相比，依折麦布、辛伐他汀和E/S均未使LDL颗粒分布向更大、更具浮力的LDL亚类模式转变。
在这些原发性高胆固醇血症患者中，E/S在降低致动脉粥样硬化脂蛋白亚组分方面比依折麦布和辛伐他汀单药治疗更有效。
