CYP2C9*2 allele increases risk for hypoglycemia in POR*1/*1 type 2 diabetic patients treated with sulfonylureas.

It is previously shown that carriers of the defective allele CYP2C93 that leads to impaired sulfonylurea metabolism are at increased sulfonylurea-induced hypoglycemia risk due to diminished drug metabolism, whereas no effect of CYP2C92 allele was found. Recently, a polymorphism in P450 oxidoreductase (POR) gene, assigned as POR28 allele, was associated with increased CYP2C9 activity. The aim of this study was to assess i) the effect of POR28 allele on sulfonylurea-induced hypoglycemia risk and ii) the association of CYP2C92 allele with hypoglycemia risk in non-carriers of POR28 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). POR28 allele was detected by use of real-time TaqMan PCR. POR28 allele was not associated with sulfonyl-urea-induced hypoglycemia. In POR1/1 patients, CYP2C91/2 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 POR1/1 entered as a selection variable, CYP2C92 allele increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 3.218, p=0.031). In conclusion, our results suggest that POR28 allele is masking the association of CYP2C92 allele with sulfonyl-urea-induced hypoglycemia. Therefore, POR28 allele is an important source of CYP2C9 activity variability and combined with CYP2C9 gene poly-morphisms may explain individual variability in the effect of sulfonylureas.