title: Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach/Riss, Germany, heike.zimdahl-gelling@boehringer-ingelheim.com.
authors.forename: Heike
authors.initials: H
authors.lastname: Zimdahl
authors.forename: Carina
authors.initials: C
authors.lastname: Ittrich
authors.forename: Ulrike
authors.initials: U
authors.lastname: Graefe-Mody
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Dugi
mesh_terms: D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D000069476:Linagliptin; D011687:Purines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D000069476:Linagliptin