Effects of sodium-glucose cotransporter 2 inhibitors on the kidneys: a pharmacovigilance study and genetic causal analysis

Abstract Objective The benefits of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD) or heart failure are well established. However, real-world reports suggest potential acute kidney injury (AKI), conflicting with trial evidence. This study aimed to systematically evaluate the renal safety profile of SGLT2 inhibitors, providing evidence-based support for individualized therapy. Methods Signals of renal adverse events associated with SGLT2 inhibitors were assessed using disproportionality analysis of real-world data from the Food and Drug Administration’s Adverse Event Reporting System. Causal inference was performed with genome-wide association study data through two-sample Mendelian randomization to investigate the potential causal relationships between SGLT2 inhibitor use and renal function indicators. Results Acute kidney injury, renal failure, and renal impairment were the most frequently reported adverse events, with significant and consistent signals indicating positive association between renal injury possibility and SGLT2 inhibitors. In contrast, CKD and end-stage renal disease exhibited negative signals, suggesting lower risk on long-term renal disease. MR analyses demonstrated significant causal associations between SGLT2 inhibitors and multiple renal function parameters, including estimated glomerular filtration rate (eGFR), kidney injury molecule-1 (KIM-1), blood urea nitrogen (BUN) and urinary albumin excretion (UAE). Conclusion This pharmacovigilance study reveals the renal effects of SGLT2 inhibitors, highlighting their relationship with renal injury risk, as well as chronic renal disease. Meanwhile, provides genetic evidence for associations between SGLT2 inhibition and renal function biomarkers. The findings provide evidence to explain early renal function changes during therapy and may facilitate timely identification of renal injury related to SGLT2 inhibitors.