Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents.
OBJECTIVE
The genetically polymorphic cytochrome P450 (CYP) enzyme CYP2C9 metabolizes most sulphonylurea oral hypoglycaemic agents. The aim of this study was to test the hypothesis that individuals with genotypes predicting low CYP2C9 activity may be at a higher risk of severe drug-associated hypoglycaemia.


METHODS
In a case-control study, 20 diabetic patients admitted to the emergency department with severe hypoglycaemia during sulphonylurea drug treatment were compared with a control group of 337 patients with type 2 diabetes but without a history of severe hypoglycaemia. A large sample of 1988 healthy Caucasian subjects served as a second control group.


RESULTS
The CYP2C9 genotypes *3/*3 and *2/*3 that are predictive of low enzyme activity were more common in the hypoglycaemic group than in the comparison groups (10%vs <2%, respectively: odds ratio 5.2; 95% confidence interval 1.01, 27). Furthermore, the diabetic patient group with severe hypoglycaemia exhibited lower body mass indexes, higher rates of renal failure, were older compared with the diabetic group without severe hypoglycaemia, and were being treated with higher doses of glibenclamide.


CONCLUSIONS
These findings suggest that among other factors, individuals with genetically determined low CYP2C9 activity are at an increased risk of sulphonylurea-associated severe hypoglycaemia. Thus, genotyping might be a tool for the better prediction of adverse effects caused by oral hypoglycaemic agents.
Holstein
A
A
1st Department of Medicine, Klinikum Lippe, Detmold, Germany.
Plaschke
A
A
Ptak
M
M
Egberts
E-H
EH
El-Din
J
J
Brockmöller
J
J
Kirchheiner
J
J
D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D005905:Glyburide / Q000009:adverse effects*; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D013453:Sulfonylurea Compounds / Q000009:adverse effects*
D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D005905:Glyburide