Cuchel Marina, Bloedon LeAnne T, Szapary Philippe O, Kolansky Daniel M, Wolfe Megan L, Sarkis Antoine, Millar John S, Ikewaki Katsunori, Siegelman Evan S, Gregg Richard E, Rader Daniel J
University of Pennsylvania School of Medicine, Philadelphia, USA.
N Engl J Med. 2007 Jan 11;356(2):148-56. doi: 10.1056/NEJMoa061189.
Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients.
We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia. All lipid-lowering therapies were suspended 4 weeks before treatment. The patients received BMS-201038 at four different doses (0.03, 0.1, 0.3, and 1.0 mg per kilogram of body weight per day), each for 4 weeks, and returned for a final visit after a 4-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for fat content were performed throughout the study.
All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day. Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P<0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%.
Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.
纯合子家族性高胆固醇血症患者的胆固醇水平显著升高，对药物治疗反应不佳，且过早发生心血管疾病的风险极高。抑制微粒体甘油三酯转移蛋白可能有效降低这些患者的胆固醇水平。
我们进行了一项剂量递增研究，以检查微粒体甘油三酯转移蛋白抑制剂BMS-201038对6例纯合子家族性高胆固醇血症患者的安全性、耐受性及血脂水平的影响。在治疗前4周停用所有降脂治疗。患者接受四种不同剂量（每日每千克体重0.03、0.1、0.3和1.0毫克）的BMS-201038治疗，每种剂量治疗4周，在4周的药物洗脱期后进行最后一次访视。在整个研究过程中进行血脂水平分析、安全性实验室分析以及肝脏脂肪含量的磁共振成像检查。
所有患者均耐受滴定至最高剂量，即每日每千克体重1.0毫克。此剂量治疗使低密度脂蛋白（LDL）胆固醇水平较基线降低50.9%，载脂蛋白B水平降低55.6%（两项比较P均<0.001）。动力学研究显示载脂蛋白B的生成显著减少。最严重的不良事件是肝转氨酶水平升高和肝脂肪蓄积，在最高剂量时发生率从不到10%至超过40%不等。
BMS-201038抑制微粒体甘油三酯转移蛋白可降低纯合子家族性高胆固醇血症患者的LDL胆固醇水平，原因是载脂蛋白B生成减少。然而，该治疗与肝转氨酶水平升高和肝脂肪蓄积有关。
