Cardiorenal Outcomes of Sodium–Glucose Cotransporter 2 Inhibitors in Type 2 Diabetes Mellitus With Nephrotic‐Range Proteinuria: A Multi‐Institutional Target Trial Emulation

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) slow kidney disease progression, but their cardiorenal outcomes in type 2 diabetes mellitus (T2DM) with nephrotic-range proteinuria, an extremely high-risk phenotype, are uncertain. MATERIALS AND METHODS: We conducted a retrospective cohort study in the TriNetX network using a new-user, active-comparator target trial emulation design. Adults with T2DM and nephrotic-range proteinuria, defined as UPCR > 3500 mg/g or UACR > 1967 mg/g, who initiated SGLT2i or dipeptidyl peptidase-4 inhibitors (DPP4i) were included. Propensity score matching (1:1) balanced covariates. The primary outcome was major adverse kidney events (MAKE); secondary outcomes were end-stage kidney disease (ESKD) on dialysis, all-cause mortality, cardiovascular events and safety endpoints. RESULTS: After matching, 1051 participants were included per group (mean UPCR 5181-5416 mg/g). SGLT2i users had a lower risk of MAKE than DPP4i users (30.0% vs. 41.2%; HR 0.75, 95% CI 0.65-0.86), lower risk of ESKD (HR 0.73, 95% CI 0.62-0.85) and all-cause mortality (HR 0.71, 95% CI 0.55-0.91). Risks of cardiovascular events and safety outcomes, including genital infection, ketoacidosis, hypoglycaemia and urinary tract infection, showed no clear differences between groups. CONCLUSIONS: Among adults with T2DM and nephrotic-range proteinuria, SGLT2i versus DPP4i was associated with lower long-term risks of ESKD and all-cause mortality and no clear differences in cardiovascular or safety outcomes were observed. These real-world observational findings support a potential kidney-protective role of SGLT2i in this very high-risk group and complement existing randomized trial data, but dedicated randomized trials in patients with nephrotic-range proteinuria remain necessary.