Patients with type 2 diabetes mellitus (T2DM) who develop nephrotic-range proteinuria face a markedly elevated risk of kidney failure and death, yet comparative real-world evidence for therapeutic strategies in this subgroup remains limited. A retrospective cohort analysis published in Diabetes, Obesity and Metabolism assessed whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) were associated with improved cardiorenal outcomes compared with dipeptidyl peptidase-4 inhibitors (DPP4i).

Data were derived from the TriNetX database using a new-user, active-comparator framework designed to emulate a target trial. Adults with T2DM and heavy proteinuria were identified using thresholds of urine protein-to-creatinine ratio (UPCR) above 3500 mg/g or urine albumin-to-creatinine ratio (UACR) above 1967 mg/g. After applying 1:1 propensity score matching, 1051 individuals were included in each treatment group, with similar baseline characteristics and mean UPCR values between 5181 and 5416 mg/g.

The primary endpoint was major adverse kidney events (MAKE), while secondary endpoints included end-stage kidney disease (ESKD) requiring dialysis, all-cause mortality, cardiovascular outcomes, and adverse events. Compared with DPP4i, SGLT2i use was associated with a lower incidence of MAKE (30.0% vs 41.2%; hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65-0.86). Risks of ESKD (HR 0.73, 95% CI 0.62-0.85) and all-cause mortality (HR 0.71, 95% CI 0.55-0.91) were also lower. Rates of cardiovascular events and safety outcomes, including genital infections, ketoacidosis, hypoglycemia, and urinary tract infections, were similar across groups.

These findings suggest that SGLT2i use was associated with more favorable kidney and survival outcomes in this high-risk population, although randomized trials in patients with nephrotic-range proteinuria are needed to confirm these observations.