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High-Throughput Safety Signal Detection for Sodium-Glucose Cotransporter-2 Inhibitors in Type 2 Diabetes

Dai, H.; Lee, Y. A.; Bian, J.; Guo, J.

2025-11-27 epidemiology
10.1101/2025.11.25.25341015 medRxiv
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ObjectiveTo systematically identify potential safety signals associated with sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes (T2D) using a high-throughput target trial emulation pipeline applied to real-world data. MethodsWe utilized electronic health record (EHR) data from the OneFlorida+ Data Trust (2012-2023). Using a retrospective new-user cohort design, we compared SGLT2i initiators to initiators of other second-line glucose-lowering drugs (GLDs). We evaluated risk across all ICD-10-CM 4-digit diagnosis codes. A semi-Bayesian shrinkage method was employed to adjust hazard ratios (HR) and p-values to account for multiple testing and stabilize estimates for rare outcomes. ResultsThe analysis identified several statistically significant safety signals. Validating our method, we observed known adverse events such as candidiasis of the vulva and vagina (HR=1.64) and other urogenital fungal infections. We also detected potential signals for conditions such as viral conjunctivitis and melanocytic nevi. ConclusionThis high-throughput screening effectively identified both known and potential new safety signals for SGLT2i. The use of semi-Bayesian shrinkage provides a robust framework for post-marketing surveillance in large healthcare databases.

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