Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide.
OBJECTIVE
Sulphonylureas are widely used in the treatment of type 2 diabetes mellitus (T2DM). Based on laboratory findings, we determined the clinical significance of potential CYP2C9-mediated drug-drug interactions in hospitalized patients receiving glibenclamide, glimepiride or glipizide, all of which are metabolized by CYP2C9, together with a CYP2C9 inhibitor.


METHODS
An observational pharmaco-epidemiological database study was performed in a university hospital setting with 3884 patients with T2DM.


METHODS
Efficacy and safety of sulphonylurea therapy during the potential interaction (sulphonylurea treatment with a CYP2C9 inhibitor) vs. control periods (sulphonylurea treatment without a CYP2C9 inhibitor) were estimated using laboratory parameters.


RESULTS
Almost 20% of patients were exposed to a potential drug-drug interaction with a CYP2C9 inhibitor during sulphonylurea treatment. More than 75% of the potential interactions occurred with trimethoprim, metronidazole and fluconazole. When all sulphonylureas were pooled and adjusted for age, gender, ward and sulphonylurea dose, mean and maximum fasting plasma glucose concentrations as well as maximum values of glycosylated haemoglobin were significantly lower during the interaction periods compared with control periods, whereas mean and minimum activities of alanine amino transferase and gamma-glutamyl transferase were higher. The minimum fasting plasma glucose values were more often below the target range in patients with potential interactions. The sulphonylurea dose did not differ significantly between patients who were or were not concomitantly treated with a potentially interacting drug.


CONCLUSIONS
Concomitant use of a CYP2C9 inhibitor results in exaggerated pharmacodynamic effects of sulphonylureas and increases the risk of hypoglycaemia in T2DM patients receiving glibenclamide, glimepiride or glipizide.
Tirkkonen
T
T
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Finland. tuire.tirkkonen@utu.fi
Heikkilä
P
P
Huupponen
R
R
Laine
K
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000502:physiology*; D065729:Cytochrome P-450 CYP2C9; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004347:Drug Interactions; D005260:Female; D005913:Glipizide / Q000627:therapeutic use; D005905:Glyburide / Q000627:therapeutic use; D006760:Hospitalization; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D055815:Young Adult
D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D005905:Glyburide; D005913:Glipizide