Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin
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 aim...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2014
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| Online Access: | https://hdl.handle.net/10356/105881 http://hdl.handle.net/10220/20950 |
| _version_ | 1826110480789274624 |
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| author | Graefe-Mody, Ulrike Boehm, Bernhard O. Mark, Michael Zimdahl, Heike Ittrich, Carina Woerle, Hans-Juergen Dugi, Klaus A. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Graefe-Mody, Ulrike Boehm, Bernhard O. Mark, Michael Zimdahl, Heike Ittrich, Carina Woerle, Hans-Juergen Dugi, Klaus A. |
| author_sort | Graefe-Mody, Ulrike |
| collection | NTU |
| description | 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.
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/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. |
| first_indexed | 2024-10-01T02:35:07Z |
| format | Journal Article |
| id | ntu-10356/105881 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:35:07Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | ntu-10356/1058812022-02-16T16:28:38Z Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin Graefe-Mody, Ulrike Boehm, Bernhard O. Mark, Michael Zimdahl, Heike Ittrich, Carina Woerle, Hans-Juergen Dugi, Klaus A. Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Medicine 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. 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/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. Accepted version 2014-09-22T08:42:11Z 2019-12-06T21:59:54Z 2014-09-22T08:42:11Z 2019-12-06T21:59:54Z 2014 2014 Journal Article Zimdahl, H., Ittrich, C., Graefe-Mody, U., Boehm, B. O., Mark, M., Woerle, H. J., et al. (2014). Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin. Diabetologia, 57(9), 1869-1875. https://hdl.handle.net/10356/105881 http://hdl.handle.net/10220/20950 10.1007/s00125-014-3276-y 24906949 en Diabetologia © 2014 The Authors. This is the author created version of a work that has been peer reviewed and accepted for publication in Diabetologia, published by Springer-Verlag Berlin Heidelberg on behalf of The Authors. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1007/s00125-014-3276-y]. 7 p. application/pdf |
| spellingShingle | DRNTU::Science::Medicine Graefe-Mody, Ulrike Boehm, Bernhard O. Mark, Michael Zimdahl, Heike Ittrich, Carina Woerle, Hans-Juergen Dugi, Klaus A. Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin |
| title | Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin |
| title_full | Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin |
| title_fullStr | Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin |
| title_full_unstemmed | Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin |
| title_short | Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin |
| title_sort | influence of tcf7l2 gene variants on the therapeutic response to the dipeptidylpeptidase 4 inhibitor linagliptin |
| topic | DRNTU::Science::Medicine |
| url | https://hdl.handle.net/10356/105881 http://hdl.handle.net/10220/20950 |
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