Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study

Background To assess the effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) for type 2 diabetes on kidney outcomes stratified by patient baseline estimated glomerular filtration rate (eGFR) levels (i.e., eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 mL/min/1.73 m2). Methods Patients from three large healthcare delivery systems in Taiwan who had initiated SGLT-2is or other glucose-lowering drugs (oGLDs) between May 2016 and December 2017 were included. Main outcomes were the times to 30%, 40%, and 50% eGFR reduction after treatment initiation. One-to-one propensity score matching in the overall study cohort and in each eGFR subgroup between SGLT-2i and oGLD users was applied to ensure between-group comparability in baseline characteristics. Results There were 13,666 matched pairs of SGLT-2is and oGLD users in the overall cohort. While a sustained eGFR decline was revealed in oGLD-treated patients (mean values [standard errors] from 85.61 [0.43] to 82.49 [0.44] mL/min/1.73 m2 during the 12 months after treatment initiation), the mean eGFR values of SGLT-2i users decreased in the first 3 months (85.68 [0.37] to 79.71 [0.41] mL/min/1.73 m2) but then improved and sustained until the end of follow-up. There were 2300, 5705, and 5509 matched SGLT-2i and oGLD users in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. Using SGLT-2is versus oGLDs was significantly associated with slower eGFR declines; hazard ratios (HRs) were 0.51 (95% CI 0.37–0.69), 0.51 (0.37–0.70), and 0.47 (0.31–0.71) for 40% eGFR reduction in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. The renoprotective effect of SGLT-2is versus oGLDs was confirmed in the outcomes of 30% and 50% eGFR reduction across the three eGFR subgroups. Conclusions This study supports the renoprotective benefit of real-world SGLT-2i use irrespective of patient baseline kidney function.

A Non-purine Xanthine Oxidoreductase Inhibitor Reduces Albuminuria in Patients with DKD: A Randomized Controlled Trial

Background: Diabetic kidney disease (DKD) is characterized by albuminuria and reduced renal function. Whether or not xanthine oxidoreductase inhibitors (XORIs) have a renoprotective effect in DKD patients with type 2 diabetes remains controversial. We conducted a proof-of-concept study to investigate the renal effects of a novel XORI, TMX-049, in patients with DKD and type 2 diabetes. Methods: This is a multicenter, 12-week, randomized, double-blind, placebo-controlled phase 2a trial conducted at 49 centers across the United States between April 2018 and June 2019. In total, 130 patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 200−3000 mg/g, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, and serum uric acid (sUA) 4−10 mg/dL were randomized 1:1:1 to TMX-049 200 mg (n=44) or 40 mg (n=44), or placebo (n=42). The primary endpoint was change in log-transformed UACR at Week 12 from baseline. The secondary endpoints included changes in UACR, eGFR, and sUA from baseline. Results: The least square mean differences for changes in log-transformed UACR from baseline to Week 12 compared to placebo were −0.43 (95% confidence interval [CI], −0.82-−0.04, P=0.03) for TMX-049 200 mg and −0.05 (95% CI, −0.44-0.34, P=0.8) for 40 mg; a 35% reduction in UACR was observed with TMX-049 200 mg (ratio versus placebo, 0.65; 95% CI, 0.44-0.96) but not 40 mg (0.95; 95% CI, 0.64-1.41). Throughout the treatment period, marked reductions in sUA levels but no changes in eGFR were observed with both TMX-049 doses. TMX-049 was generally well-tolerated, although 2 patients with TMX-049 200 mg developed gout. Conclusions: TMX-049 200 mg reduced albuminuria at 12 weeks in patients with DKD and type 2 diabetes. TMX-049 may exert a renoprotective effect independent of its sUA-lowering effect.