A genetically supported drug repurposing pipeline for diabetes treatment using electronic health records.

Shuey MM, Lee KM, Keaton J, Khankari NK, Breeyear JH, Walker VM, Miller DR, Heberer KR, Reaven PD, Clarke SL, Lee J, Lynch JA, Vujkovic M, Edwards TL. A genetically supported drug repurposing pipeline for diabetes treatment using electronic health records. EBioMedicine. 2023 Aug 1; 94:104674.

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Abstract:

BACKGROUND: The identification of new uses for existing drug therapies has the potential to identify treatments for comorbid conditions that have the added benefit of glycemic control while also providing a rapid, low-cost approach to drug (re)discovery. METHODS: We developed and tested a genetically-informed drug-repurposing pipeline for diabetes management. This approach mapped genetically-predicted gene expression signals from the largest genome-wide association study for type 2 diabetes mellitus to drug targets using publicly available databases to identify drug-gene pairs. These drug-gene pairs were then validated using a two-step approach: 1) a self-controlled case-series (SCCS) using electronic health records from a discovery and replication population, and 2) Mendelian randomization (MR). FINDINGS: After filtering on sample size, 20 candidate drug-gene pairs were validated and various medications demonstrated evidence of glycemic regulation including two anti-hypertensive classes: angiotensin-converting enzyme inhibitors as well as calcium channel blockers (CCBs). The CCBs demonstrated the strongest evidence of glycemic reduction in both validation approaches (SCCS HbA1c and glucose reduction: -0.11%, p  =  0.01 and -0.85 mg/dL, p  =  0.02, respectively; MR: OR  =  0.84, 95% CI  =  0.81, 0.87, p  =  5.0 x 10-25). INTERPRETATION: Our results support CCBs as a strong candidate medication for blood glucose reduction in addition to cardiovascular disease reduction. Further, these results support the adaptation of this approach for use in future drug-repurposing efforts for other conditions. FUNDING: National Institutes of Health, Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK Medical Research Council, American Heart Association, and Department of Veterans Affairs (VA) Informatics and Computing Infrastructure and VA Cooperative Studies Program.