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. Hougaard Christensen; M. 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. Hougaard Christensen
, M. 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^*

^*Corresponding author for this work

University of Sarajevo
University of Dundee
University of California at San Francisco
Leiden University
Erasmus University Rotterdam
Inspectorate of Health Care
P. J. Safarik University
University Hospital L. Pasteur
Latvian Biomedical Research and Study Centre
University of Southern Denmark
Treant Zorggroep
Bethesda Diabetes Research Centre
RIKEN
Kaiser Permanente
VU University Medical Center Amsterdam
International University of Sarajevo

Research output: Contribution to journal › Article › peer-review

91 Citations (Scopus)

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 transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed 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 a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Original language	English
Pages (from-to)	763-772
Number of pages	10
Journal	Clinical Pharmacology and Therapeutics
Volume	101
Issue number	6
DOIs	https://doi.org/10.1002/cpt.567 https://doi.org/10.1002/cpt.567
Publication status	Published - 1 Jun 2017
Externally published	Yes

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Dujic, T., Zhou, K., Yee, S. W., van Leeuwen, N., de Keyser, C. E., Javorský, M., Goswami, S., Zaharenko, L., Hougaard Christensen, M. M., 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 and Therapeutics, 101(6), 763-772. https://doi.org/10.1002/cpt.567, https://doi.org/10.1002/cpt.567

@article{6869d99d1d5744bc99f305b3d0e93d22,

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 transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed 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 a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic 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 \{Hougaard Christensen\}, \{M. M.\} and M. 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.\}",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors Clinical Pharmacology \& Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics",

year = "2017",

month = jun,

day = "1",

doi = "10.1002/cpt.567",

language = "English",

volume = "101",

pages = "763--772",

journal = "Clinical Pharmacology and Therapeutics",

issn = "0009-9236",

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Dujic, T, Zhou, K, Yee, SW, van Leeuwen, N, de Keyser, CE, Javorský, M, Goswami, S, Zaharenko, L, Hougaard Christensen, MM, 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 and Therapeutics, vol. 101, no. 6, pp. 763-772. https://doi.org/10.1002/cpt.567, https://doi.org/10.1002/cpt.567

TY - JOUR

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 - Hougaard Christensen, M. M.

AU - Out, M.

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.

PY - 2017/6/1

Y1 - 2017/6/1

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 transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed 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 a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic 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 transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed 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 a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

UR - https://www.scopus.com/pages/publications/85012060225

U2 - 10.1002/cpt.567

DO - 10.1002/cpt.567

M3 - Article

C2 - 27859023

AN - SCOPUS:85012060225

SN - 0009-9236

VL - 101

SP - 763

EP - 772

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 6

ER -

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis

Abstract

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