1. Academic Validation
  2. Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins

Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins

  • Br J Clin Pharmacol. 2014 Sep;78(3):639-48. doi: 10.1111/bcp.12353.
H Schelleman 1 X Han C M Brensinger S K Quinney W B Bilker D A Flockhart L Li Sean Hennessy
Affiliations

Affiliation

  • 1 Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Abstract

Aims: To examine whether initiation of fibrates or statins in sulfonylurea users is associated with hypoglycaemia, and examine in vitro inhibition of Cytochrome P450 (CYP) enzymes by statins, fenofibrate and glipizide.

Methods: We used healthcare data to conduct nested case-control studies of serious hypoglycaemia (i.e. resulting in hospital admission or emergency department treatment) in persons taking glipizide or glyburide, and calculated adjusted overall and time-stratified odds ratios (ORs) and 95% confidence intervals (CIs). We also characterized the in vitro inhibition of CYP enzymes by statins, fenofibrate and glipizide using fluorometric CYP450 inhibition assays, and estimated area under the concentration-time curve ratios (AUCRs) for the drug pairs.

Results: We found elevated adjusted overall ORs for glyburide-fenofibrate (OR 1.84, 95% CI 1.37, 2.47) and glyburide-gemfibrozil (OR 1.57, 95% CI 1.25, 1.96). The apparent risk did decline over time as might be expected from a pharmacokinetic mechanism. Fenofibrate was a potent in vitro inhibitor of CYP2C19 (IC50 = 0.2 μm) and CYP2B6 (IC50 = 0.7 μm) and a moderate inhibitor of CYP2C9 (IC50 = 9.7 μm). The predicted CYP-based AUCRs for fenofibrate-glyburide and gemfibrozil-glyburide interactions were only 1.09 and 1.04, suggesting that CYP inhibition is unlikely to explain such an interaction.

Conclusions: Use of fenofibrate or gemfibrozil together with glyburide was associated with elevated overall risks of serious hypoglycaemia. CYP inhibition seems unlikely to explain this observation. We speculate that a pharmacodynamic effect of fibrates (e.g. activate peroxisome proliferator-activator receptor alpha) may contribute to these apparent interactions.

Keywords

cytochrome P-450 enzyme; drug-drug interactions; fibric acids; hypoglycaemia; statins; sulfonylurea compounds.

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