Liao Jianwei, Yang Liyun, Zhou Luping, Zhao Hongbin, Qi Xiao, Cui Yimin, Ouyang Dongsheng
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Central South University, Changsha, China.
Front Pharmacol. 2022 Mar 11;13:755469. doi: 10.3389/fphar.2022.755469. eCollection 2022.
Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the 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 gene variation on LDL-C reduction. 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 gene expression and the reduction of LDL-C. 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%, < 0.01) or GC (-13.02%, < 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%. The g1679C > G SNP in the 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].
海泽麦布是一种新型胆固醇抑制剂，它特异性靶向[具体基因名称未给出]基因。个体间存在显著差异，这表明存在大量疗效不佳者和无反应者。此外，目前关于尼曼-匹克C1样1（NPC1L1）基因对低密度脂蛋白胆固醇（LDL-C）降低的潜在影响的文献并不一致且存在争议。鉴于这些问题，我们进行了一项高质量临床试验，以研究[具体基因名称未给出]基因变异对LDL-C降低的具体特征。这是一项采用析因设计的多中心、随机、双盲、安慰剂对照临床试验。符合条件的患者被随机分配到六种治疗之一：安慰剂、海泽麦布（10或20毫克）、阿托伐他汀，以及阿托伐他汀加上海泽麦布（10或20毫克）。采集空腹血样进行基因分型，并测定LDL-C浓度和靶向药物谷浓度，以研究[具体基因名称未给出]基因表达与LDL-C降低之间的关联。总共最初招募了727人；其中，444人有资格开始试验。我们鉴定出一个单核苷酸多态性（g1679C>G），它对LDL-C水平产生了显著不同的影响。作为单一疗法，在海泽麦布（20毫克）组中，CC基因型携带者的平均LDL-C降低幅度（-23.99%）显著高于GG基因型携带者（-16.45%，P<0.01）或GC基因型携带者（-13.02%，P<0.01）。相比之下，在海泽麦布（20毫克）加阿托伐他汀组中，当与阿托伐他汀联合使用时，GC基因型携带者的LDL-C降低幅度大于非GC基因型携带者（-52.23%对-45.03%）。此外，随着海泽麦布剂量从16.1%增加到65.4%，LDL-C降低>50%的个体比例增加。[具体基因名称未给出]基因中的g1679C>G单核苷酸多态性至关重要，并且对海泽麦布治疗反应产生不同影响。杂合子患者接受单一疗法治疗时疗效不佳，但当海泽麦布与阿托伐他汀联合使用时，在LDL-C降低方面显示出良好反应。为了精确地使用海泽麦布治疗高胆固醇血症，有必要鉴定g1679C>G单核苷酸多态性的基因型患者。我们还强调了识别适合接受依泽替米贝治疗的受试者的潜在必要性。临床试验注册：[https://clinicaltrials.gov/]，标识符[CTR20150351]。
