Add-On Spironolactone for Persistent Proteinuria After Sodium-Glucose Cotransporter 2 Inhibitor Therapy in Patients With Diabetic Kidney Disease: A Retrospective Observational Study

BACKGROUND: Despite the widespread use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), many patients with diabetic kidney disease continue to exhibit persistent proteinuria, highlighting an unmet clinical need for effective add-on therapies. Non-steroidal mineralocorticoid receptor antagonists (MRA) such as finerenone have recently shown benefits; however, the role of classical steroidal agents like spironolactone in this setting remains unclear. METHODS: We retrospectively analyzed 29 stable patients with type 2 diabetes mellitus (T2DM) treated at Jinnouchi Hospital who exhibited persistent proteinuria (urinary protein-to-creatinine ratio (UPCR): A2-A3; >0.15 g/g creatinine) despite more than six months of SGLT2i therapy and subsequently received add-on spironolactone for 12 months. Clinical parameters, including UPCR and estimated glomerular filtration rate (eGFR), were assessed 12 months before and at three, six, and 12 months after initiation of spironolactone therapy. We evaluated the effects of spironolactone on changes in proteinuria and the annual rate of eGFR decline. RESULTS: The baseline UPCR (median and interquartile range (IQR)) was 0.70 (0.40-1.27) g/g creatinine, and eGFR (mean ± standard deviation) was 49.1±16.9 mL/min/1.73 m². UPCR significantly decreased to 0.15 (0.12-0.30) g/g creatinine at 12 months after spironolactone initiation (p<0.001). Although an initial decline in eGFR was observed within three months (initial eGFR dip; -9.3%), the annual rate of eGFR decline (median (IQR)) improved from -2.2 (-7.0 to -0.9) to 1.3 (-1.5 to 3.3) mL/min/1.73 m²/year during months 3-12 after spironolactone therapy (p=0.001). CONCLUSION: Add-on spironolactone therapy may provide additional renoprotective effects in patients with T2DM and persistent proteinuria despite SGLT2i treatment. Although spironolactone is an older and inexpensive steroidal MRA, it may still represent a clinically meaningful therapeutic option in the contemporary SGLT2i era.