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

Tanja Dujic, Kaixin Zhou, Sook Wah Yee, Nienke van Leeuwen, Catherine E de Keyser, Martin Javorský, Srijib Goswami, Linda Zaharenko, Mette Marie H Christensen, Mattijs Out, Roger Tavendale, Michiaki Kubo, Monique M Hedderson, Amber A van der Heijden, Lucia Klimčáková, Valdis Pirags, Adriaan Kooy, Kim Brøsen, Janis Klovins, Sabina SemizIvan Tkáč, Bruno H Stricker, Colin N A Palmer, Leen M 't Hart, Kathleen M Giacomini, Ewan R Pearson

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftClinical Pharmacology & Therapeutics
Vol/bind101
Udgave nummer6
Sider (fra-til)763-772
ISSN0009-9236
DOI
StatusUdgivet - 2017

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Dujic, T., Zhou, K., Yee, S. W., van Leeuwen, N., de Keyser, C. E., Javorský, M., Goswami, S., Zaharenko, L., Christensen, 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