SummaryBackgroundThe 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.MethodsWe 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).FindingsAfter 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).InterpretationOur 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.Funding10.13039/100000002National Institutes of Health,10.13039/501100000265Medical Research CouncilIntegrative Epidemiology Unit at the10.13039/501100000883University of Bristol,10.13039/501100000265UK Medical Research Council,10.13039/100000968American Heart Association, and10.13039/100000738Department of Veterans Affairs(VA) Informatics and Computing Infrastructure and VA Cooperative Studies Program.