Explore the Causal Effect of SGLT2 Inhibition on Venous Thromboembolism Events: A Drug-Target Mendelian Randomization Study With Pharmacovigilance Analysis

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used antidiabetic agents with established cardiorenal benefits, yet their genetic causal association with venous thromboembolism (VTE) remains uncertain. Methods We employed a multifaceted approach to investigate the causal relationship between SGLT2 inhibition and VTE, as well as deep vein thrombosis (DVT) and pulmonary embolism (PE). Drug-target Mendelian randomization (MR) and summary-data-based MR (SMR) analyses were conducted using genetic variants proxying SGLT2 inhibition, derived from SLC5A2 expression quantitative trait loci and glycemic traits. Positive control analyses confirmed validity using type 2 diabetes outcomes. Meta-analyses were performed across multiple independent genome-wide association study datasets. Complementary pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System (FAERS) to assess disproportionality of SGLT2 inhibitor-related VTE reports. Results Genetically proxied SGLT2 inhibition was significantly associated with reduced risk of type 2 diabetes (P < 0.05), validating its robustness. Most MR analyses showed no consistent causal association with VTE, DVT, or PE across datasets, and meta-analyses yielded non-significant pooled estimates (all P > 0.05). SMR analyses revealed no association between SLC5A2 expression and VTE-related outcomes (all P_SMR > 0.05). FAERS disproportionality analysis also identified no safety signals for PE (reporting odds ratio [ROR] = 0.51; 95% CI: 0.42–0.64) or DVT (ROR = 0.54; 95% CI: 0.45–0.64). Conclusions This integrative study provides consistent evidence that SGLT2 inhibition is not causally associated with VTE, DVT, or PE, supporting its thrombotic safety. However, generalizability to non-European populations requires future validation in diverse cohorts.