Table8_The NPC1L1 Gene Exerts a Notable Impact on the Reduction of Low-Density Lipoprotein Cholesterol in Response to Hyzetimibe: A Factorial-Designed Clinical Trial.DOC

Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of NPC1L1 gene variation on LDL-C reduction.Methods: This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the NPC1L1 gene expression and the reduction of LDL-C.Results: In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (−23.99%) than either the GG (−16.45%, p < 0.01) or GC (−13.02%, p < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. −45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%.Conclusion: The g1679C > G SNP in the NPC1L1 gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe.Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351]

背景：Hyzetimibe是一种新型胆固醇抑制剂，特异性靶向NPC1L1基因。显著的个体间变异性表明存在大量对治疗反应不良和非反应个体。此外，关于Niemann-Pick C1样1（NPC1L1）基因对低密度脂蛋白胆固醇（LDL-C）降低的潜在影响，现有文献存在不一致和争议。鉴于这些担忧，我们进行了一项高质量的临床试验，以研究NPC1L1基因变异对LDL-C降低的特定特征。方法：这是一项多中心、随机、双盲、安慰剂对照、析因设计的临床试验。合格的受试者被随机分配到六种治疗之一：安慰剂、Hyzetimibe（10或20毫克）、阿托伐他汀以及阿托伐他汀加Hyzetimibe（10或20毫克）。收集空腹血样并进行基因分型，测定LDL-C浓度和目标药物谷浓度，以研究NPC1L1基因表达与LDL-C降低之间的关联。结果：总共招募了727名个体；其中，444名符合条件开始试验。我们确定了一个SNP（g1679C > G），对LDL-C水平产生显著不同的影响。作为单药治疗，CC等位基因携带者在Hyzetimibe（20毫克）组中平均LDL-C降低幅度显著高于GG（−16.45%，p < 0.01）或GC（−13.02%，p < 0.01）等位基因携带者。相反，当与阿托伐他汀合用时，GC等位基因携带者在Hyzetimibe（20毫克）加阿托伐他汀组中的LDL-C降低幅度大于非GC等位基因携带者（-52.23% vs. −45.03%）。此外，LDL-C降低超过50%的个体比例随着Hyzetimibe剂量从16.1%增加到65.4%。结论：NPC1L1基因中的g1679C > G SNP至关重要，对Hyzetimibe治疗的反应产生差异性的影响。杂合子患者在单药治疗中表现出较差的治疗效果，但在Hyzetimibe与阿托伐他汀合用时显示出良好的LDL-C降低效果。为了以精确的方式使用Hyzetimibe治疗高胆固醇血症，有必要识别g1679C > G SNP的基因型患者。我们还强调，有必要识别适合接受Ezetimibe治疗的适当受试者。临床试验注册：[https://clinicaltrials.gov/]，标识符[CTR20150351]