Effect of administration and withdrawal of the sodium-glucose cotransporter 2 inhibitor, tofogliflozin, on renal protection in individuals with type 2 diabetes mellitus and diabetic nephropathy: A multicenter, single-arm study (RESTORE-nephropathy study)

Abstract

Aims/introduction: The mechanisms of the renoprotective effects of sodium-glucose cotransporter 2 inhibitors are unknown. This study aimed to explore the effect and mechanism of tofogliflozin on urinary albumin by administration, withdrawal, and re-administration.

Materials and methods: Individuals with type 2 diabetes mellitus and stage 2 or 3 diabetic nephropathy were enrolled. Tofogliflozin was administered for 24 weeks, withdrawn for 12 weeks (withdrawal period), and re-administered for 24 weeks. The primary endpoint was the change in urinary albumin/creatinine ratio (UACR). The secondary endpoints included hemoglobin A1c (HbA1c), hepatic biomarkers, lipid profiles, physical examinations, and blood counts.

Results: A total of 47 individuals were enrolled. UACR significantly decreased throughout the observation period. It also significantly decreased, increased, and again decreased during the period of the 1st administration, withdrawal, and re-administration, respectively. HbA1c, body weight, waist circumference, and systolic blood pressure also showed the same tendency. Aspartate aminotransferase and alanine aminotransferase significantly decreased throughout the observation period, but did not increase during the withdrawal period.

Conclusions: Urinary albumin improved during the administration of tofogliflozin and worsened during its withdrawal, suggesting the reversibility of its renoprotective effect. The administration of tofogliflozin should be continued to avoid the reversal of glycemic control, renoprotective effects, and other beneficial effects.

Keywords: Diabetic nephropathy; Drug withdrawal; Renal protection; Tofogliflozin; Urinary albumin.

Figure 1

Study flow chart showing patient enrollment and analysis.

Figure 2

Change in renal biomarkers. Data are presented as means ± standard errors. *, **, and ***Represent P < 0.05, P < 0.01, and P < 0.001, respectively, for intragroup comparisons. For the intragroup comparison of urinary albumin (a), the MMRM was performed with an unstructured covariance structure, with time and value at baseline as fixed effects, and participants as random effects. If the calculation results did not converge, compound symmetry was used. For the intragroup comparisons of serum creatinine (b), BUN (c), and eGFR (d), one‐sample t tests were performed. BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; MMRM, mixed effect model for repeated measures.

Figure 3

Change in clinical laboratory tests. Data are presented as means ± standard errors. *, **, and ***Represent P < 0.05, P < 0.01, and P < 0.001, respectively, for intragroup comparisons. For the intragroup comparisons, one‐sample t tests were performed. ALT, alanine aminotransferase; AST, aspartate aminotransferase; HbA1c, hemoglobin A1c; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; TC, total cholesterol.

Figure 4

Change in physical examinations. Data are presented as means ± standard errors. *, **, and ***Represent P < 0.05, P < 0.01, and P < 0.001, respectively, for intragroup comparisons. For the intragroup comparisons, one‐sample t tests were performed.