Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes.

Abstract

AIMS:

Metformin is the most widely used oral anti-diabetes agent and has considerable benefits over other therapies, yet 20-30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter-individual variability is unclear. We have recently shown the association between organic cation transporter 1 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced-function polymorphisms with common metformin-induced gastrointestinal side effects in Type 2 diabetes.

METHODS:

This prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss-of-function variants in the OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced-function alleles with gastrointestinal side effects was analysed using logistic regression.

RESULTS:

Forty-three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 reduced-function alleles was significantly associated with over two-fold higher odds of the common metformin-induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07-5.01, P = 0.034).

CONCLUSIONS:

In conclusion, we showed for the first time the association between OCT1 variants and common metformin-induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter-individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment.

• Authors: T Dujic, A Causevic, T Bego, M Malenica, Z Velija-Asimi, E R Pearson, S Semiz
• Journal: Diabetic medicine : a journal of the British Diabetic Association (Diabet Med) Vol. 33 Issue 4 Pg. 511-4 (Apr 2016) ISSN: 1464-5491 [Electronic] England
• PMID: 26605869 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Diabetes UK.

Chemical References

• Hypoglycemic Agents
• Organic Cation Transporter 1
• Metformin

Topics

• Aged
• Alleles
• Amino Acid Substitution
• Bosnia and Herzegovina
• Cohort Studies
• Diabetes Mellitus, Type 2 (drug therapy)
• Female
• Gastroenteritis (chemically induced, genetics, metabolism, physiopathology)
• Gene Deletion
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Hypoglycemic Agents (adverse effects, therapeutic use)
• Male
• Metformin (adverse effects, therapeutic use)
• Middle Aged
• Organic Cation Transporter 1 (genetics, metabolism)
• Polymorphism, Genetic
• Prospective Studies
• Severity of Illness Index
• Sex Characteristics