Potential CYP2C9‐mediated drug–drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide

Abstract

Abstract. Tirkkonen T, Heikkilä P, Huupponen R, Laine K (University of Turku; Turku University Hospital; and StatFinn Ltd; Turku, Finland). Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide. J Intern Med 2010; 268: 359-366.Objectives. 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.Design, setting and subjects. An observational pharmacoepidemiological database study was performed in a university hospital setting with 3884 patients with T2DM.Main outcome measures. 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.

Pharmacokinetics of Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Glimepiride Following Co-administration in Healthy Volunteers: A Randomised, Open-label, Crossover Study

“…As with other sulphonylureas, the use of glimepiride in patients with type 2 diabetes is associated with an increased risk of hypoglycaemia [13]. Glimepiride is extensively metabolised in the liver, mainly by CYP2C9 [14], and concomitant administration of agents that inhibit CYP2C9, such as gemfibrozil and fluconazole, has been shown to increase the risk of hypoglycaemia [15]. Empagliflozin does not inhibit CYP450 enzymes in vitro (unpublished data), so the potential for CYP-mediated drug interactions is unlikely, but cannot be ruled out.…”

Clinically and pharmacologically relevant interactions of antidiabetic drugs

“…Beta blockers can mask the early warning symptoms of hypoglycemia; however, later studies have shown that these effects may be less prominent with newer beta-1 selective drugs [Shorr et al 1997]. As mentioned earlier, many antimicrobials present a high interaction risk with antidiabetics, especially with Sulfonylureas [Tirkkonen et al 2010, Parekh et al 2014. Interactions with antimicrobials are clinically most relevant because adverse effects take place most often whenever a drug is added or removed [Patsalos et al 2003], and antimicrobials are usually taken temporarily.…”

“…Thus, interactions due to CYP2C9 inhibition play a crucial role in the treatment with SUs. A Finnish study revealed that a clinically relevant interaction occurred in about 20% of T2DM patients treated with SUs; 75% of the identified interactions were due to concomitant treatment with trimethoprim, metronidazole, or ketoconazole [Tirkkonen et al 2010].…”

Candida parapsilosis keratitis treated successfully with topical and oral fluconazole

“…We started from a relatively low dose (200 mg daily) of oral FCZ because we already prescribed topical FCZ and due to concerns of a possible drug interaction between FCZ and glimepiride, an antidiabetic medication that was used in this patient 2223. The stroma infiltration soon subsided and the epithelium healed in 8 days.…”