Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas.
OBJECTIVE
Hypoglycemia is a common adverse effect of sulfonylurea oral hypoglycemic agents. Impaired metabolism of sulfonylureas due to gene polymorphisms in the metabolic enzyme CYP2C9 might lead to hypoglycemia. In the present study we explored the association of the CYP2C9 variant alleles CYP2C9*2 and CYP2C9*3 with the incidence of hypoglycemic events in diabetic patients receiving the sulfonylureas glimepiride and gliclazide.


METHODS
A total of 92 Type 2 diabetes mellitus (T2DM) patients receiving sulfonylurea and reporting drug-associated hypoglycemia, and 84 T2DM patients receiving sulfonylurea and having never experienced hypoglycemia were included in the study. A sample of 283 nondiabetic controls that had been genotyped earlier served as a second control group. CYP2C9*2 and *3 alleles were detected by use of PCR-RFLP analysis.


RESULTS
Frequencies of CYP2C9*1/*3 genotype and CYP2C9*3 allele were significantly lower in T2DM patients than nondiabetic controls (p = 0.003 and p = 0.017, respectively). A total of 11 out of 92 subjects (12%) experiencing hypoglycemia carried the CYP2C9*3 allele, as opposed to only 1 out of 84 subjects (1.2%) free of sulfonylurea-induced hypoglycemia. In a model adjusted for age, BMI, mean daily dose of sulfonylurea, duration of T2DM and renal function, CYP2C9*1/*3 genotype increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 1.687; p = 0.011). However, no differences in CYP2C9*2 allele frequency between the two groups were found.


CONCLUSIONS
The presence of CYP2C9*3 appears to be protective for development of T2DM. Furthermore, in T2DM patients, CYP2C9*3 increases the risk of hypoglycemia when they are treated with sulfonylureas, possibly due to impaired metabolism of these drugs. CYP2C9 genotyping might thus be a useful tool for predicting adverse effects caused by sulfonylureas and help clinicians in safer prescribing of oral hypoglycemic agents. The potential T2DM protective effect of CYP2C9*3 allele requires further investigation.
Ragia
Georgia
G
Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece.
Petridis
Ioannis
I
Tavridou
Anna
A
Christakidis
Dimitrios
D
Manolopoulos
Vangelis G
VG
D000328:Adult; D000368:Aged; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology / Q000235:genetics*; D007004:Hypoglycemic Agents / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D012306:Risk; D013453:Sulfonylurea Compounds / Q000009:adverse effects*
D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases