Known drug-drug interactions (DDIs) are responsible for 13 percent of adverse drug events and 4.8 percent of hospital admissions in older adults. Even these high figures may understate the true impact of DDIs because they include only the effects of known interactions. Many clinically important DDIs take years to discover. Given the widespread and growing use of multiple medications by persons with diabetes, there is tremendous potential for DDIs to occur in this population. Of the ten most commonly used second-line antidiabetic agents, five are insulin secretagogues, which, based on known metabolic pathways, may interact with many commonly- prescribed medications. DDIs involving insulin secretagogues can cause serious hypoglycemia, which can be immediately life-threatening and have cause long-term consequences. The broad objective of this project is to produce clinically-actionable knowledge about which drugs interact with insulin secretagogues to cause serious hypoglycemia, as well as the time-course of such interactions and the subgroups most susceptible to these DDIs. We will achieve this objective by taking a translational science approach to DDIs in which we 1) perform high-throughput simulation of potential DDIs based on pharmacologic knowledge;2) perform high-throughput screening of healthcare data;and then 3) confirm (or refute) and elucidate selected high-probability DDIs in an independent population by conducting in-depth pharmacoepidemiologic studies. This project will produce clinically-actionable knowledge about which drugs interact with secretagogues to cause severe hypoglycemia, and generalizable biological knowledge about the drugs and pathways involved in these interactions.

Public Health Relevance

Drug-drug interactions (DDIs) are a major clinical and public health burden. Given that most individuals with type 2 diabetes mellitus take five or more medications, they are at high risk for clinically significant DDIs. Insulin secretagogues are used by many patients with diabetes, and have a high potential to cause serious hypoglycemia, especially in the setting of DDIs. This study will produce clinically-actionable knowledge about which drugs interact with insulin secretagogues to cause serious hypoglycemia, as well as the time-course of such interactions and the subgroups most susceptible to these DDIs.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01DK102694-01
Application #
8748916
Study Section
Health Services Organization and Delivery Study Section (HSOD)
Program Officer
Bremer, Andrew
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Schelleman, H; Han, X; Brensinger, C M et al. (2014) Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins. Br J Clin Pharmacol 78:639-48
Leonard, Charles E; Razzaghi, Hanieh; Freeman, Cristin P et al. (2014) Empiric potassium supplementation and increased survival in users of loop diuretics. PLoS One 9:e102279