Zimdahl Heike, Ittrich Carina, Graefe-Mody Ulrike, Boehm Bernhard O, Mark Michael, Woerle Hans-Juergen, Dugi Klaus A
Drug Metabolism and Pharmacokinetics, Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach/Riss, Germany,
Diabetologia. 2014 Sep;57(9):1869-75. doi: 10.1007/s00125-014-3276-y. Epub 2014 Jun 7.
AIMS/HYPOTHESIS: Individuals carrying variants of the transcription factor 7-like 2 gene (TCF7L2) are at increased risk for type 2 diabetes. These metabolic genetic risk factors have been linked to diminished pancreatic islet-cell responsiveness to incretins, thus pharmacological interventions aimed at amplifying endogenous incretin biology may be affected. However, clinical evidence from randomised controlled trials so far is lacking. We investigated the influence of TCF7L2 risk alleles on the response to treatment with the dipeptidylpeptidase-4 (DPP-4) inhibitor linagliptin from four 24 week, phase III, placebo-controlled trials.
Pharmacogenomic samples and clinical data were available from 961 patients with type 2 diabetes. Whole-blood DNA samples were genotyped for TCF7L2 single-nucleotide polymorphisms in conjunction with assessments of 24 week changes in HbA1c.
Linagliptin lowered HbA1c meaningfully in all three genotypes of rs7903146 (non-risk variant carriers CC [n = 356]: -0.82% [-9.0 mmol/mol], p < 0.0001; heterozygous CT [n = 264]: -0.77% [-8.4 mmol/mol], p < 0.0001; homozygous risk variant carriers TT [n = 73]: -0.57% [-6.2 mmol/mol], p < 0.0006). No significant treatment differences were seen between CC and CT patients, although HbA1c response was reduced in TT compared with CC patients (0.26% [2.8 mmol/mol], p = 0.0182).
CONCLUSIONS/INTERPRETATION: Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles. However, differences in treatment response were observed, indicating that diabetes susceptibility genes may be an important contributor to the inter-individual variability of treatment response.
目的/假设：携带转录因子7样2基因（TCF7L2）变异的个体患2型糖尿病的风险增加。这些代谢遗传风险因素与胰岛细胞对肠促胰岛素的反应性降低有关，因此旨在增强内源性肠促胰岛素生物学效应的药物干预可能会受到影响。然而，目前尚缺乏来自随机对照试验的临床证据。我们从四项为期24周的III期安慰剂对照试验中，研究了TCF7L2风险等位基因对二肽基肽酶-4（DPP-4）抑制剂利格列汀治疗反应的影响。
可获得961例2型糖尿病患者的药物基因组样本和临床数据。对全血DNA样本进行TCF7L2单核苷酸多态性基因分型，并评估糖化血红蛋白（HbA1c）24周的变化。
在rs7903146的所有三种基因型中，利格列汀均能显著降低HbA1c（非风险变异携带者CC [n = 356]：-0.82% [-9.0 mmol/mol]，p < 0.0001；杂合子CT [n = 264]：-0.77% [-8.4 mmol/mol]，p < 0.0001；纯合风险变异携带者TT [n = 73]：-0.57% [-6.2 mmol/mol]，p < 0.0006）。CC和CT患者之间未观察到显著的治疗差异，尽管与CC患者相比，TT患者的HbA1c反应有所降低（约0.26% [约2.8 mmol/mol]，p = 0.0182）。
结论/解读：无论有无TCF7L2基因糖尿病风险等位基因，利格列汀均能显著改善2型糖尿病患者的高血糖。然而，观察到治疗反应存在差异，这表明糖尿病易感基因可能是治疗反应个体间差异的重要因素。
