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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Area Under Curve
  • Case-Control Studies
  • Cytochrome P-450 Enzyme Inhibitors / adverse effects
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Drug Interactions
  • Female
  • Fibric Acids / adverse effects*
  • Fibric Acids / pharmacology
  • Glipizide / adverse effects
  • Glipizide / pharmacology
  • Glyburide / adverse effects
  • Glyburide / pharmacology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hypoglycemia / epidemiology
  • Hypoglycemia / etiology*
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology
  • Male
  • Middle Aged
  • Pharmacoepidemiology
  • Sulfonylurea Compounds / adverse effects*
  • Sulfonylurea Compounds / pharmacology
  • Young Adult


  • Cytochrome P-450 Enzyme Inhibitors
  • Fibric Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • Glyburide
  • Glipizide