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Dawed, A.Y.* ; Zhou, K.* ; van Leeuwen, N.* ; Mahajan, A.* ; Robertson, N.* ; Koivula, R.W.* ; Elders, P.J.M.* ; Rauh, S.P.* ; Jones, A.G.* ; Holl, R.W.* ; Stingl, J.C.* ; Franks, P.W.* ; McCarthy, M.I.* ; 't Hart, L.M.* ; Pearson, E.R.* ; DIRECT Consortium (Thorand, B. ; Adamski, J. ; Grallert, H. ; Haid, M. ; Sharma, S.)

Variation in the plasma membrane monoamine transporter (PMAT, encoded in SLC29A4) and organic cation transporter 1 (OCT1, encoded in SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes: An IMI DIRECT study.

Diabetes Care 42, 1027-1033 (2019)
Publ. Version/Full Text Postprint Research data DOI PMC
Open Access Green
OBJECTIVEGastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects.RESEARCH DESIGN AND METHODSThe study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance.RESULTSWomen (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01).CONCLUSIONSThese results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genetic-variation; Drug; Association; Pharmacokinetics; Accumulation
ISSN (print) / ISBN 0149-5992
e-ISSN 1935-5548
Journal Diabetes Care
Quellenangaben Volume: 42, Issue: 6, Pages: 1027-1033 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, Va.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Molekulare Endokrinologie und Metabolismus (MEM)