Variants in pharmacokinetic transporters and glycemic response to metformin: A metgen meta-analysis

T. Dujic; K. Zhou; S. W. Yee; N. van Leeuwen; C. E. de Keyser; M. Javorský; S. Goswami; L. Zaharenko; M. M. H.  Christiansen; Mattijs Out; R. Tavendale; M. Kubo; M. M. Hedderson; A. A. van der Heijden; L. Klimčáková; V. Pirags; A. Kooy; K. Brøsen; J. Klovins; S.  Semiz; I. Tkáč; B. H.  Stricker; C. N. A.  Palmer; L. M. 't Hart; K. M Giacomini; E. R. Pearson

doi:10.1002/cpt.567

Variants in pharmacokinetic transporters and glycemic response to metformin: A metgen meta-analysis

T. Dujic, K. Zhou, S. W. Yee, N. van Leeuwen, C. E. de Keyser, M. Javorský, S. Goswami, L. Zaharenko, M. M. H. Christiansen, Mattijs Out, R. Tavendale, M. Kubo, M. M. Hedderson, A. A. van der Heijden, L. Klimčáková, V. Pirags, A. Kooy, K. Brøsen, J. Klovins, S. SemizI. Tkáč, B. H. Stricker, C. N. A. Palmer, L. M. 't Hart, K. M Giacomini, E. R. Pearson (Lead / Corresponding author)

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Abstract

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporters genes, with inconsistent results. To clarify the significance of these variants in glycaemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (OCT1, OCT2, MATE1, MATE2-K and OCTN1) were analysed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed metformin daily dose. Our results suggest that candidate transporters genes variants have little contribution to variability in glycaemic response to metformin in T2D.

Original language	English
Pages (from-to)	763-772
Number of pages	10
Journal	Clinical Pharmacology & Therapeutics
Volume	101
Issue number	6
Early online date	10 Nov 2016
DOIs	https://doi.org/10.1002/cpt.567
Publication status	Published - Jun 2017

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(c) 2016 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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1 Active

DIRECT: Diabetes Research on Patient Stratification (joint with 25 other partners)
Colhoun, H. (Investigator), Houston, G. (Investigator), Morris, A. (Investigator), Palmer, C. (Investigator) & Pearson, E. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/02/12 → 28/02/27
Project: Research
Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)
Pearson, E. (Investigator)
16/02/15 → 15/08/21
Project: Research

Pearson, Ewan
- Diabetes Endocrinology and Reproductive Biology - Clinical Professor (Teaching and Research) of Diabetic Medicine
Person: Academic

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Dujic, T., Zhou, K., Yee, S. W., van Leeuwen, N., de Keyser, C. E., Javorský, M., Goswami, S., Zaharenko, L., Christiansen, M. M. H., Out, M., Tavendale, R., Kubo, M., Hedderson, M. M., van der Heijden, A. A., Klimčáková, L., Pirags, V., Kooy, A., Brøsen, K., Klovins, J., ... Pearson, E. R. (2017). Variants in pharmacokinetic transporters and glycemic response to metformin: A metgen meta-analysis. Clinical Pharmacology & Therapeutics, 101(6), 763-772. https://doi.org/10.1002/cpt.567

@article{1672c9bfd7c5437680f4ebfd3efabd1d,

title = "Variants in pharmacokinetic transporters and glycemic response to metformin: A metgen meta-analysis",

abstract = "Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporters genes, with inconsistent results. To clarify the significance of these variants in glycaemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (OCT1, OCT2, MATE1, MATE2-K and OCTN1) were analysed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed metformin daily dose. Our results suggest that candidate transporters genes variants have little contribution to variability in glycaemic response to metformin in T2D. ",

author = "T. Dujic and K. Zhou and Yee, {S. W.} and {van Leeuwen}, N. and {de Keyser}, {C. E.} and M. Javorsk{\'y} and S. Goswami and L. Zaharenko and Christiansen, {M. M. H.} and Mattijs Out and R. Tavendale and M. Kubo and Hedderson, {M. M.} and {van der Heijden}, {A. A.} and L. Klim{\v c}{\'a}kov{\'a} and V. Pirags and A. Kooy and K. Br{\o}sen and J. Klovins and S. Semiz and I. Tk{\'a}{\v c} and Stricker, {B. H.} and Palmer, {C. N. A.} and {'t Hart}, {L. M.} and Giacomini, {K. M} and Pearson, {E. R.}",

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doi = "10.1002/cpt.567",

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Dujic, T, Zhou, K, Yee, SW, van Leeuwen, N, de Keyser, CE, Javorský, M, Goswami, S, Zaharenko, L, Christiansen, MMH, Out, M, Tavendale, R, Kubo, M, Hedderson, MM, van der Heijden, AA, Klimčáková, L, Pirags, V, Kooy, A, Brøsen, K, Klovins, J, Semiz, S, Tkáč, I, Stricker, BH, Palmer, CNA, 't Hart, LM, Giacomini, KM & Pearson, ER 2017, 'Variants in pharmacokinetic transporters and glycemic response to metformin: A metgen meta-analysis', Clinical Pharmacology & Therapeutics, vol. 101, no. 6, pp. 763-772. https://doi.org/10.1002/cpt.567

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T1 - Variants in pharmacokinetic transporters and glycemic response to metformin

T2 - A metgen meta-analysis

AU - Dujic, T.

AU - Zhou, K.

AU - Yee, S. W.

AU - van Leeuwen, N.

AU - de Keyser, C. E.

AU - Javorský, M.

AU - Goswami, S.

AU - Zaharenko, L.

AU - Christiansen, M. M. H.

AU - Out, Mattijs

AU - Tavendale, R.

AU - Kubo, M.

AU - Hedderson, M. M.

AU - van der Heijden, A. A.

AU - Klimčáková, L.

AU - Pirags, V.

AU - Kooy, A.

AU - Brøsen, K.

AU - Klovins, J.

AU - Semiz, S.

AU - Tkáč, I.

AU - Stricker, B. H.

AU - Palmer, C. N. A.

AU - 't Hart, L. M.

AU - Giacomini, K. M

AU - Pearson, E. R.

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N2 - Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporters genes, with inconsistent results. To clarify the significance of these variants in glycaemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (OCT1, OCT2, MATE1, MATE2-K and OCTN1) were analysed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed metformin daily dose. Our results suggest that candidate transporters genes variants have little contribution to variability in glycaemic response to metformin in T2D.

AB - Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporters genes, with inconsistent results. To clarify the significance of these variants in glycaemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (OCT1, OCT2, MATE1, MATE2-K and OCTN1) were analysed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed metformin daily dose. Our results suggest that candidate transporters genes variants have little contribution to variability in glycaemic response to metformin in T2D.

U2 - 10.1002/cpt.567

DO - 10.1002/cpt.567

M3 - Article

C2 - 27859023

SN - 0009-9236

VL - 101

SP - 763

EP - 772

JO - Clinical Pharmacology & Therapeutics

JF - Clinical Pharmacology & Therapeutics

IS - 6

ER -

Variants in pharmacokinetic transporters and glycemic response to metformin: A metgen meta-analysis

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DIRECT: Diabetes Research on Patient Stratification (joint with 25 other partners)

Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)

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Pearson, Ewan

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