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Exp Clin Endocrinol Diabetes 2014; 122(01): 60-63
DOI: 10.1055/s-0033-1361097
Short Communication
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

CYP2C9*2 Allele Increases Risk for Hypoglycemia in POR*1/*1 Type 2 Diabetic Patients Treated with Sulfonylureas

G. Ragia
1   Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
,
A. Tavridou
1   Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
2   Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
,
L. Elens
3   Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium
4   Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, The Netherlands
,
R. H. N. Van Schaik
4   Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, The Netherlands
,
V. G. Manolopoulos
1   Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
2   Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
› Author Affiliations
Further Information

Publication History

received 07 September 2013
first decision 24 October 2013

accepted 06 November 2013

Publication Date:
24 January 2014 (online)

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Abstract

It is previously shown that carriers of the defective allele CYP2C9*3 that leads to impaired sulfonylurea metabolism are at increased sulfonylurea-induced hypoglycemia risk due to diminished drug metabolism, whereas no effect of CYP2C9*2 allele was found. Recently, a polymorphism in P450 oxidoreductase (POR) gene, assigned as POR*28 allele, was associated with increased CYP2C9 activity. The aim of this study was to assess i) the effect of POR*28 allele on sulfonylurea-induced hypoglycemia risk and ii) the association of CYP2C9*2 allele with hypoglycemia risk in non-carriers of POR*28 allele. The study group consisted of 176 patients with diagnosed type 2 diabetes mellitus (T2DM) treated with sulfonylureas, of whom 92 patients had experienced at least one drug-associated hypoglycemic event (cases), while 84 had never experienced a hypoglycemic event (controls). POR*28 allele was detected by use of real-time TaqMan PCR. POR*28 allele was not associated with sulfonyl­urea-induced hypoglycemia. In POR*1/*1 patients, CYP2C9*1/*2 genotype was more common in cases than in controls (32.7 vs. 14.3%, p=0.041). In a model adjusted for age, BMI, duration of T2DM and renal function, and POR*1/*1 entered as a selection variable, CYP2C9*2 allele increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 3.218, p=0.031). In conclusion, our results suggest that POR*28 allele is masking the association of CYP2C9*2 allele with sulfonyl­urea-induced hypoglycemia. Therefore, POR*28 allele is an important source of CYP2C9 activity variability and combined with CYP2C9 gene poly­morphisms may explain individual variability in the effect of sulfonylureas.

Keywords

sulfonylurea - hypoglycemia - pharmacogenetics - POR*28 - CYP2C9*2
 

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