Comparison of the Risk for Proteinuria Among SGLT2 Inhibitors in Patients with Diabetes Without Current Urinary Protein

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) differ in pharmacological properties, including their selectivity for SGLT2 over SGLT1. We hypothesize that these differences may contribute to variations in the effect of SGLT2is on the risk of developing proteinuria in patients with diabetes without current proteinuria. Methods: We analyzed patients with diabetes who were newly prescribed SGLT2is between April 2014 and March 2023 using a large real-world dataset. Using a target trial emulation framework with inverse probability of treatment weighting, we compared the new onset of proteinuria among different SGLT2is—specifically dapagliflozin and empagliflozin versus canagliflozin, which has the lowest selectivity for SGLT2 over SGLT1. We evaluatet the outcome using the Kaplan-Meier method and Cox regression analysis. Results: In 3,011 patients (819 with canagliflozin; 999 with dapagliflozin; 1,193 with empagliflozin) with diabetes (mean age: 66.6–68.2 years; men: 58–63%; mean estimated glomerular filtration rate: 74.9–75.8 mL/min/1.73m2; mean hemoglobin A1c level: 7.69–7.84%), the incidence rates of proteinuria (per 1,000 person-years) were 33.1 for canagliflozin, 34.1 for dapagliflozin, and 22.1 for empagliflozin. During the mean follow-up duration ranged from 762 to 809 days, cumulative incidence and HRs for new onset of proteinuria were lower in empagliflozin new-users (hazard ratio 0.66, 95% confidence interval 0.50–0.88) than in those of canagliflozin (Figure1). Conclusion: Empagliflozin, which exhibits the highest selectivity for SGLT2 over SGLT1, showed a lower risk of new-onset proteinuria in patients with diabetes without proteinuria when compared to canagliflozin. Funding: Commercial Support - Kowa Co., Ltd., Bayer Yakuhin Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo Company Ltd., and Baxter International Inc., Government Support – Non-U.S.