Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are highly vulnerable to infections, which contribute substantially to morbidity and mortality. While sodium-glucose co-transporter-2 (SGLT-2) inhibitors provide established cardiorenal benefits, their effects on infection-related outcomes in patients with CKD and T2D remain unclear. This study aimed to evaluate whether baseline SGLT-2 inhibitors use is associated with reduced risk of severe sepsis, infection-related complications, and mortality in patients with CKD and T2D.

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 demographics, comorbidities, and medications. The primary outcome was severe sepsis; secondary outcomes included septic shock, all-cause mortality, hospitalization, pneumonia, urinary tract infection, and genital infection.

After matching, 25,049 users of SGLT-2 inhibitor and 25,049 users of DPP-4 inhibitor were analyzed. SGLT-2 inhibitor use was associated with a lower risk of severe sepsis (HR, 0.81), septic shock (HR, 0.83), all-cause mortality (HR, 0.72), hospitalization, pneumonia, and urinary tract infection, but a higher risk of genital infection.

Among patients with CKD and T2D, use of SGLT-2 inhibitors was associated with lower risks of severe sepsis, infection-related complications, and mortality compared with DPP-4 inhibitors, despite a modest increase in genital infections. These findings suggest that the benefits of SGLT-2 inhibitors extend beyond established cardiorenal protection and support its role as a core therapeutic option in high-risk patient with CKD and T2D.