Effect of sodium-glucose cotransporter 2 inhibitor on proximal tubular function and injury in patients with type 2 diabetes: a randomized controlled trial

Abstract

Background: Intensive glucose control reduces the risk for microvascular complications in type 2 diabetes (T2DM). Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to exert renoprotection beyond glycemic control, although their effects on the organs are not well known. There are limited data on SGLT2 inhibitors for the biomarkers of kidney injury in type 2 diabetes mellitus (T2DM) patients.

Objective: Our objective was to demonstrate the effect of SGLT2 inhibitors on proximal tubular injury and function in patients with T2DM.

Methods: T2DM patients with persistent glycated hemoglobin (HbA1c) levels >7% were randomly assigned to either dapagliflozin 10 mg/day (n = 28) or standard treatment (n = 29) for 12 weeks. Proximal tubular injury biomarkers, including urine kidney injury molecule-1:creatinine ratio (UKIM1CR), urine cystatin C:creatinine ratio (UCCR), urine albumin:creatinine ratio (UACR), fractional excretion of phosphate (FEPO₄) and fractional excretion of uric acid (FEUA) were measured at baseline and study end.

Results: Baseline characteristics were comparable between treatment groups. After 12 weeks, dapagliflozin-treated versus standard-treated patients showed reductions in HbA1c (-0.75 ± 0.21 versus -0.70 ± 0.25%; P = 0.882). There were significant between-group differences in the reduction in UACR {-23.3 [95% confidence interval (CI) -44.4 to -2.2] versus +19.9 (-4.0-43.8) mg/g Cr; P = 0.010} and UKIM1CR [-26.7 (95% CI -232.9-179.5) versus +422.2 (46.7-797.7) ng/g Cr; P = 0.047], but no significant difference in changes in UCCR between the two groups. There was no significant change in glomerular filtration rate, serum phosphate level, FEUA and FEPO₄ in the dapagliflozin group. No serious renal-related adverse events were observed in either group.

Conclusions: This study indicates that dapagliflozin in T2DM patients can decrease the levels of urinary proximal tubular injury biomarkers, thus highlighting its renoprotective effect. SGLT2 inhibitors could prove useful in treating T2DM by protecting against renal tubular injury and may lead to reduced long-term renal outcomes.

Keywords: cystatin C; dapagliflozin; kidney injury molecule-1; sodium-glucose cotransporter 2 inhibitor; type 2 diabetes.

FIGURE 1.

Flowchart of the study.

FIGURE 2.

Mean and percentage changes in UACR and UKIM1CR after 12 weeks of treatment. There were no significant changes in mean UACR and UKIM1CR from baseline in both control and dapagliflozin treatment groups, but significantly increased UKIM1CR in the control treatment group. There were significant between-group differences in the mean changes in (A) UACR and (B) KIM1CR (P < 0.05). There was (C) a significant between-group difference in the percentage changes of UACR (P = 0.036) but (D) no significant between-group difference in the percentage changes of UKIM1CR (P = 0.128).