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Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin.

Zimdahl H, Ittrich C, Graefe-Mody U, Boehm BO, Mark M, Woerle HJ, Dugi KA - Diabetologia (2014)

Bottom Line: 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.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).Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles.

View Article: PubMed Central - PubMed

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.

ABSTRACT

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.

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Adjusted mean difference between HbA1c (%) at a given time and HbA1c (%) at baseline (change in HbA1c [%] from baseline) with 95% CIs for the whole cohort of patients from the four clinical trials and the subgroup for which pharmacogenomic data were available. ANCOVA model includes baseline HbA1c as linear covariate and prior oral glucose-lowering therapy (yes/no), treatment, study and treatment-by-study interaction as fixed classification effects. Placebo complete clinical data, n = 728; placebo genotyped subgroup, n = 268; linagliptin complete clinical data, n = 1,876; linagliptin genotyped subgroup, n = 693. Black triangles, placebo complete clinical data; white triangles, placebo genotyped subgroup; black circles, linagliptin complete clinical data; white circles, linagliptin genotyped subgroup. To convert values for HbA1c in DCCT % to mmol/mol, multiply by 10.929 and then subtract 23.50
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Fig2: Adjusted mean difference between HbA1c (%) at a given time and HbA1c (%) at baseline (change in HbA1c [%] from baseline) with 95% CIs for the whole cohort of patients from the four clinical trials and the subgroup for which pharmacogenomic data were available. ANCOVA model includes baseline HbA1c as linear covariate and prior oral glucose-lowering therapy (yes/no), treatment, study and treatment-by-study interaction as fixed classification effects. Placebo complete clinical data, n = 728; placebo genotyped subgroup, n = 268; linagliptin complete clinical data, n = 1,876; linagliptin genotyped subgroup, n = 693. Black triangles, placebo complete clinical data; white triangles, placebo genotyped subgroup; black circles, linagliptin complete clinical data; white circles, linagliptin genotyped subgroup. To convert values for HbA1c in DCCT % to mmol/mol, multiply by 10.929 and then subtract 23.50

Mentions: To determine whether the subgroup for which genomic analysis was performed was representative of the population of patients who participated in all four trials, the clinical response observed for the subgroup was compared with that of the whole patient population (Fig. 2). The clinical responses to treatment with linagliptin or placebo in the subgroups for which pharmacogenomic data were available were essentially identical to those of the corresponding treatment groups in the whole cohort of patients from the four clinical trials—reduction in HbA1c was similar in the two groups treated with linagliptin and HbA1c did not change from baseline in the two groups receiving placebo. These results suggest that the pharmacogenomic subgroups were representative of the entire pooled patient population.Fig. 2


Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin.

Zimdahl H, Ittrich C, Graefe-Mody U, Boehm BO, Mark M, Woerle HJ, Dugi KA - Diabetologia (2014)

Adjusted mean difference between HbA1c (%) at a given time and HbA1c (%) at baseline (change in HbA1c [%] from baseline) with 95% CIs for the whole cohort of patients from the four clinical trials and the subgroup for which pharmacogenomic data were available. ANCOVA model includes baseline HbA1c as linear covariate and prior oral glucose-lowering therapy (yes/no), treatment, study and treatment-by-study interaction as fixed classification effects. Placebo complete clinical data, n = 728; placebo genotyped subgroup, n = 268; linagliptin complete clinical data, n = 1,876; linagliptin genotyped subgroup, n = 693. Black triangles, placebo complete clinical data; white triangles, placebo genotyped subgroup; black circles, linagliptin complete clinical data; white circles, linagliptin genotyped subgroup. To convert values for HbA1c in DCCT % to mmol/mol, multiply by 10.929 and then subtract 23.50
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig2: Adjusted mean difference between HbA1c (%) at a given time and HbA1c (%) at baseline (change in HbA1c [%] from baseline) with 95% CIs for the whole cohort of patients from the four clinical trials and the subgroup for which pharmacogenomic data were available. ANCOVA model includes baseline HbA1c as linear covariate and prior oral glucose-lowering therapy (yes/no), treatment, study and treatment-by-study interaction as fixed classification effects. Placebo complete clinical data, n = 728; placebo genotyped subgroup, n = 268; linagliptin complete clinical data, n = 1,876; linagliptin genotyped subgroup, n = 693. Black triangles, placebo complete clinical data; white triangles, placebo genotyped subgroup; black circles, linagliptin complete clinical data; white circles, linagliptin genotyped subgroup. To convert values for HbA1c in DCCT % to mmol/mol, multiply by 10.929 and then subtract 23.50
Mentions: To determine whether the subgroup for which genomic analysis was performed was representative of the population of patients who participated in all four trials, the clinical response observed for the subgroup was compared with that of the whole patient population (Fig. 2). The clinical responses to treatment with linagliptin or placebo in the subgroups for which pharmacogenomic data were available were essentially identical to those of the corresponding treatment groups in the whole cohort of patients from the four clinical trials—reduction in HbA1c was similar in the two groups treated with linagliptin and HbA1c did not change from baseline in the two groups receiving placebo. These results suggest that the pharmacogenomic subgroups were representative of the entire pooled patient population.Fig. 2

Bottom Line: 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.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).Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles.

View Article: PubMed Central - PubMed

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.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus