title: Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study.
abstract: Metformin is the most widely prescribed medication for the treatment of type 2 diabetes (T2D). However, gastrointestinal (GI) side effects develop in ~25% of patients treated with metformin, leading to the discontinuation of therapy in ~5% of cases. We hypothesized that reduced transport of metformin via organic cation transporter 1 (OCT1) could increase metformin concentration in the intestine, leading to increased risk of severe GI side effects and drug discontinuation. We compared the phenotype, carriage of reduced-function OCT1 variants, and concomitant prescribing of drugs known to inhibit OCT1 transport in 251 intolerant and 1,915 fully metformin-tolerant T2D patients. We showed that women and older people were more likely to be intolerant to metformin. Concomitant use of medications, known to inhibit OCT1 activity, was associated with intolerance (odds ratio [OR] 1.63 [95% CI 1.22-2.17], P = 0.001) as was carriage of two reduced-function OCT1 alleles compared with carriage of one or no deficient allele (OR 2.41 [95% CI 1.48-3.93], P < 0.001). Intolerance was over four times more likely to develop (OR 4.13 [95% CI 2.09-8.16], P < 0.001) in individuals with two reduced-function OCT1 alleles who were treated with OCT1 inhibitors. Our results suggest that reduced OCT1 transport is an important determinant of metformin intolerance.
authors.affiliation: Department of Biochemistry & Clinical Analysis, Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: Tanja
authors.initials: T
authors.lastname: Dujic
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, U.K.
authors.forename: Kaixin
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, U.K.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Donnelly
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, U.K.
authors.forename: Roger
authors.initials: R
authors.lastname: Tavendale
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, U.K.
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, U.K. e.z.pearson@dundee.ac.uk.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
mesh_terms: D000368:Aged; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008297:Male; D008687:Metformin / Q000009:adverse effects*; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors
chemical_list: D007004:Hypoglycemic Agents; D027702:Organic Cation Transporter 1; D008687:Metformin