SGLT-2i use and risk of mortality and heart failure in kidney transplant recipients with type 2 diabetes.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduce heart failure hospitalization and all-cause mortality among individuals with type 2 diabetes, suggesting potential benefits for kidney transplant recipients (KTRs). KTRs, however, often have longer diabetes duration, more end-organ damage, and higher cardiovascular risk than typical trial populations. Post-transplant immunosuppression may increase the risk of infections associated with SGLT-2i. We examined the real-world effectiveness and safety of SGLT-2i among KTRs with type 2 diabetes, compared with dipeptidyl peptidase-4 inhibitors (DPP-4i).
Methods: Using Epic Cosmos, a national electronic health records dataset covering >300 million patients across 1,981 U.S. hospitals, we identified 6,384 KTRs (aged ≥ 18) with type 2 diabetes at the time of transplant (01/2013-08/2025). Post-transplant use of SGLT-2i and DPP-4i was captured from pharmacy dispensing data. The study was designed to emulate a target trial comparing post-transplant use of SGLT-2i versus DPP-4i on mortality and heart failure among KTRs. Associations were quantified using Cox models with inverse probability of treatment weighting to adjust for baseline confounders. We also examined safety outcomes, including urinary tract infections [UTI], acute kidney injury [AKI], mycotic genital infection, bone fractures, and diabetic ketoacidosis, as well as negative control outcomes (burn and tinnitus) to evaluate for residual confounding.
Results: Compared with DPP-4i users, SGLT-2i users were younger (57.7 vs. 59.4 years), less likely to be female (32.9% vs. 38.2%), and had a higher proportion of Black patients (37.6% vs. 36.7%). After adjustment, SGLT-2i use was associated with a 41% lower risk of mortality (adjusted hazard ratio [aHR]=0.59, 95% confidence interval [CI]: 0.50-0.70) and a 21% lower risk of heart failure (aHR=0.79, 95%CI: 0.63-0.99). SGLT-2i use was also associated with 16% lower risk of UTI (aHR=0.84, 95%CI:0.73-0.98), 22% lower risk of AKI (aHR=0.78, 95%CI:0.66-0.91), and 19% lower risk of bone fractures (aHR=0.81, 95%CI:0.69-0.94). No significant associations were observed for mycotic genital infection, diabetic ketoacidosis, or negative control outcomes (burn and tinnitus).  
Conclusion: Among KTRs with type 2 diabetes, SGLT-2i use was associated with lower risks of mortality and heart failure compared with DPP-4i, as well as lower risks of safety outcomes including UTI, AKI, and bone fractures. These findings suggest that SGLT-2i may offer clinically meaningful cardiovascular and renal benefits in this high-risk population, supporting broader use in post-kidney transplant management.