Sodium-glucose cotransporter-2 inhibitors, severe sepsis, and infection-related outcomes in patients with chronic kidney disease and type 2 diabetes

Background: Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are vulnerable to infections. While sodium-glucose cotransporter-2 (SGLT-2) inhibitors provide established cardiorenal benefits, their effects on infection remain unclear. This study aimed to evaluate the association between SGLT-2 inhibitors and the risks of severe sepsis, infection-related complications, and mortality in this population. Methods: We conducted a real-world, active-comparator, new-user cohort study using the U.S. Collaborative Network of TriNetX. Adults with CKD and T2D who initiated SGLT-2 inhibitors or DPP-4 inhibitors between 2018 and 2024 were included. Propensity score matching was applied to balance baseline characteristics. The primary outcome was severe sepsis; secondary outcomes included septic shock, mortality, hospitalization, pneumonia, urinary tract infection (UTI), and genital infection. Results: After matching, 25,049 patients were included in each group. During 1 year of follow-up, SGLT-2 inhibitor use was associated with a lower risk of severe sepsis than DPP-4 inhibitor use (2.7% vs. 3.3%; HR, 0.81; 95% CI, 0.73-0.90). Risks of septic shock (HR, 0.83), mortality (HR, 0.72), hospitalization (HR, 0.90), pneumonia (HR, 0.77), and UTI (HR, 0.72) were reduced, whereas the risk of genital infection (HR, 1.93) was higher. No significant differences were observed in diabetic ketoacidosis or acidosis. Conclusion: Among patients with CKD and T2D, SGLT-2 inhibitor initiation was associated with lower risks of severe sepsis, infection-related outcomes, hospitalization, and mortality compared with DPP-4 inhibitor initiation, despite a higher risk of genital infection. These findings support SGLT-2 inhibitors as a core therapy with potential benefits extending beyond cardiorenal protection in this high-risk population.