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. 2015 May;64(5):1786-93.
doi: 10.2337/db14-1388. Epub 2014 Dec 15.

Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study

Tanja Dujic  1 , Kaixin Zhou  2 , Louise A Donnelly  2 , Roger Tavendale  2 , Colin N A Palmer  2 , Ewan R Pearson  3
Affiliations

Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study

Tanja Dujic et al. Diabetes. 2015 May.

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.

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Figures

Figure 1
Figure 1
Association of the individual drugs/drug classes with metformin intolerance. The analysis was adjusted for age, sex, weight, and co-treatment with other OCT1 inhibitors. TCAs, tricyclic antidepressants; PPIs, proton pump inhibitors; OR, odds ratio; LCL, lower confidence limit; UCL, higher confidence limit.
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