Effect of SGLT2 Inhibition (SGLT2i) on Blood and Urinary Biomarkers of Cardiovascular and Kidney Disease in Patients with Advanced Diabetic Kidney Disease (DKD)

Background: Serum magnesium (SMg) level is associated with accelerated decline in estimated glomerular filtration rate (eGFR) and adverse cardiovascular (CV) outcomes in people with DKD. SGLT2i improve kidney and CV outcomes and increase SMg levels. We hypothesized that SGLT2i increases SMg in part by increasing serum Klotho level, which may in turn contribute to the beneficial effects of SGLT2i in DKD. Methods: We conducted a 12-week prospective observational study among 33 adult patients with DKD stages 3b-4 prescribed empagliflozin (N=29) or dapagliflozin (N=4)10 mg once daily in routine clinical practice. Blood and 24-hour urine samples were collected prior to and at 6 and 12 weeks after initiating SGLT2i treatment. The primary outcome was the change in serum Klotho level from baseline to 12 weeks. Secondary outcomes included serum creatinine (Scr), urine albumin/creatinine (UACR), serum magnesium, fractional excretion of Mg (FEMg), urine 8-isoprostane/cr, and urine neutrophil gelatinase-associated lipocalin (NGAL). Linear mixed-effects models and the non-parametric Friedman test were used to assess the primary and secondary outcomes. Results: Thirty-two patients completed the study. Age 57 + 9 (14 women, 19 men), 67% (2/3 Hispanic) White, 33% Black. Baseline mean + SD: eGFR 32 + 7 ml/min/1.73m2, UACR 2389 + 1880 mg/g, SMg 1.9 + 0.3 mg/dl. Serum creatinine increased by 0.4 mg/dl (95% CI: 0.26 to 0.54; p < 0.001) and UACR decreased by 479 mg/g (95% CI: -917 to -40; p = 0.033) at 12 weeks. Serum Klotho did not change at 6 or 12 weeks. SMg increased at 6 (0.16 mg/dL; 95% CI: 0.07 to 0.25; p = 0.001) and 12 weeks (0.17 mg/dL; 95% CI: 0.08 to 0.27; p < 0.001), FEMg increased to 1.5% at 6 (95% CI: 0.46 to 2.46; p = 0.005) and 1.6% at 12 weeks (95% CI: 0.62 to 2.64; p = 0.002). Urine 8-isoporostane (p = 0.073) and NGAL (p = 0.024) decreased over time (Figure). Conclusion: Twelve week treatment with SGLT2i did not increase serum klotho levels but did increase SMg and FEMg suggesting increased gut Mg absorption. SGLT2i treatment decreased levels of urinary biomarkers of oxidative stress and kidney injury. Funding: Private Foundation Support