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

Abstract

ObjectivesThe identification of novel uses for existing drug therapies has the potential to provide a rapid, low-cost approach to drug (re)discovery. In the current study we developed and tested a genetically-informed drug-repurposing pipeline for diabetes management. DesignWe 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). SettingThe SCCS experiments were completed using two EHRs: the Million Veterans Program (USA) as the discovery and the Vanderbilt University Medical Center (Tennessee, USA) as the replication. ResultsAfter 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=5.0x10-25). ConclusionsOur 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. Summary BoxesO_ST_ABSSection 1: What is already known on this topicC_ST_ABSMedications with genetic support are significantly more likely to make it through clinical trials. Section 2: What this study addsOur results identified two anti-hypertensive medication classes, calcium channel blockers and angiotensin-converting enzyme inhibitors, as genetically supported drug-repurposing targets that demonstrated glycemic measurement reduction in real-world clinical populations. These results suggest patients with diabetes or pre-diabetes could benefit from preferential use of these medication classes when they present with comorbid hypertension or other cardiovascular conditions. Finally, this study demonstrates a successful implementation of a novel genetically-supported drug-repurposing pipeline for diabetes treatment that can be readily adapted and applied to other diseases and as such it has the potential to identify/prioritize drug repurposing targets for these other conditions.