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

H. Schelleman, X. Han, C. M. Brensinger, Sara Quinney, W. B. Bilker, D. A. Flockhart, L. Li, Sean Hennessy

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)639-648
Number of pages10
JournalBritish Journal of Clinical Pharmacology
Volume78
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Fibric Acids
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Drug Evaluation
Fenofibrate
Drug Interactions
Glyburide
Cytochrome P-450 Enzyme System
Glipizide
Gemfibrozil
Odds Ratio
Hypoglycemia
Inhibitory Concentration 50
Confidence Intervals
Peroxisome Proliferators
Emergency Treatment
Hospital Departments
In Vitro Techniques
Case-Control Studies
Hospital Emergency Service
Pharmacokinetics

Keywords

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

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins. / Schelleman, H.; Han, X.; Brensinger, C. M.; Quinney, Sara; Bilker, W. B.; Flockhart, D. A.; Li, L.; Hennessy, Sean.

In: British Journal of Clinical Pharmacology, Vol. 78, No. 3, 2014, p. 639-648.

Research output: Contribution to journalArticle

Schelleman, H. ; Han, X. ; Brensinger, C. M. ; Quinney, Sara ; Bilker, W. B. ; Flockhart, D. A. ; Li, L. ; Hennessy, Sean. / Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins. In: British Journal of Clinical Pharmacology. 2014 ; Vol. 78, No. 3. pp. 639-648.
@article{dc3119459d6248608d349d10016bd5f8,
title = "Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins",
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",
author = "H. Schelleman and X. Han and Brensinger, {C. M.} and Sara Quinney and Bilker, {W. B.} and Flockhart, {D. A.} and L. Li and Sean Hennessy",
year = "2014",
doi = "10.1111/bcp.12353",
language = "English",
volume = "78",
pages = "639--648",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins

AU - Schelleman, H.

AU - Han, X.

AU - Brensinger, C. M.

AU - Quinney, Sara

AU - Bilker, W. B.

AU - Flockhart, D. A.

AU - Li, L.

AU - Hennessy, Sean

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - cytochrome P-450 enzyme

KW - drug-drug interactions

KW - fibric acids

KW - hypoglycaemia

KW - statins

KW - sulfonylurea compounds

UR - http://www.scopus.com/inward/record.url?scp=84906519682&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906519682&partnerID=8YFLogxK

U2 - 10.1111/bcp.12353

DO - 10.1111/bcp.12353

M3 - Article

VL - 78

SP - 639

EP - 648

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 3

ER -