Biomedical Informatics Approaches to Identifying Drug–Drug Interactions: Application to Insulin Secretagogues

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Drug–drug interactions with insulin secretagogues are associated with increased risk of serious hypoglycemia in patients with type 2 diabetes. We aimed to systematically screen for drugs that interact with the five most commonly used secretagogues—glipizide, glyburide, glimepiride, repaglinide, and nateglinide—to cause serious hypoglycemia.


We screened 400 drugs frequently coprescribed with the secretagogues as candidate interacting precipitants. We first predicted the drug–drug interaction potential based on the pharmacokinetics of each secretagogue–precipitant pair. We then performed pharmacoepidemiologic screening for each secretagogue of interest, and for metformin as a negative control, using an administrative claims database and the self-controlled case series design. The overall rate ratios (RRs) and those for four predefined risk periods were estimated using Poisson regression. The RRs were adjusted for multiple estimation using semi-Bayes method, and then adjusted for metformin results to distinguish native effects of the precipitant from a drug–drug interaction.


We predicted 34 pharmacokinetic drug–drug interactions with the secretagogues, nine moderate and 25 weak. There were 140 and 61 secretagogue–precipitant pairs associated with increased rates of serious hypoglycemia before and after the metformin adjustment, respectively. The results from pharmacokinetic prediction correlated poorly with those from pharmacoepidemiologic screening.


The self-controlled case series design has the potential to be widely applicable to screening for drug–drug interactions that lead to adverse outcomes identifiable in healthcare databases. Coupling pharmacokinetic prediction with pharmacoepidemiologic screening did not notably improve the ability to identify drug–drug interactions in this case.

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