Adjunct Therapy with Ipragliflozin Exerts Limited Effects on Kidney Protection in Type 1 Diabetes: A Retrospective Study Conducted at 25 Centers in Japan (IPRA-CKD)

Abstract

Background/Objectives: While sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated additional non-glycemic benefits for renal protection in individuals with type 2 diabetes, less evidence is available for those with type 1 diabetes (T1D). To determine whether the adjunctive use of the SGLT2 inhibitor ipragliflozin confers kidney protection in individuals with T1D, we retrospectively analyzed data from a real-world cohort examined at 25 centers in Japan. Methods: We enrolled 359 subjects aged 20-74 years with T1D (IPRA group: 159 ipragliflozin users; control [CTRL] group: 200 non-users). The primary outcome was changes in the estimated glomerular filtration rate (eGFR) from baseline to 24 months after the initiation of ipragliflozin. The secondary outcomes were all other changes, including the urinary albumin-creatinine ratio (UACR) and urinary protein-creatinine ratio (UPCR). Results: The IPRA group's eGFR decline slopes were 0.79 mL/min/1.73 m²/year milder than the CTRL group's after propensity score matching, but this difference was not significant. The subjects complicated by chronic kidney disease (CKD) defined as UACR ≥ 30 mg/g and/or UPCR ≥ 0.5 g/g and/or eGFR < 60 mL/min/1.73 m² showed changes in UPCR (g/g) from baseline to 24 months that were significantly lower in the IPRA group (-0.27 ± 1.63) versus the CTRL group (0.18 ± 0.36) (p = 0.016). No significant increase in adverse events (including severe hypoglycemia and hospitalization due to ketosis/ketoacidosis or cardiovascular diseases) was observed in the IPRA group. Conclusions: Adjunctive treatment with ipragliflozin exerted potential renal benefits by decreasing proteinuria in T1D subjects with CKD. Further investigations are required to determine whether its additional benefits exceed the increased risk of ketoacidosis.

Keywords: SGLT2 inhibitor; chronic kidney disease; ipragliflozin; renal outcome; type 1 diabetes.

Figure 1

Subjects prior to (A–I) and after propensity score matching (J–R) in the IPRA group (red) and the CTRL group (blue). All line graphs and bar graphs indicate the means ± SDs. The mean changes in the eGFR over the period before and after the index date were calculated using Wilcoxon’s rank sum test (A,J) but were not significantly different. The annual rates of eGFR changes from baseline (the index date) to 24 months, those from baseline to 6 months, and those from 6 to 24 months after the index date are shown in (B–D,K–M). Changes in the UACR, UPCR, HbA1c, body weight, and total daily insulin dosage from baseline to 24 months after the index date are shown in (E–I,N–R). eGFR: estimated glomerular filtration rate; HbA1c: glycated hemoglobin; UACR: urinary albumin-to-creatinine ratio; UPCR: urinary protein-to-creatine ratio.

Figure 2

The annual rates of eGFR change from baseline to 24 months and those from 6 to 24 months after the index date and the changes in the UACR (mg/g) and UPCR (g/g) over the 24 months were determined in the subgroups based on baseline eGFR values (mL/min/1.73 m²) ≥ 90 (A), 60–89 (B), 45–59 (C), or <45 (D) and baseline BMI (kg/m²) <25 (E), 25–29 (F), or ≥30 (G) at the index date between the IPRA (red bars) and CTRL (blue bars) groups. All graphs indicate the means ± SDs. BMI: body mass index; eGFR: estimated glomerular filtration rate; UACR: urinary albumin-to-creatinine ratio; UPCR: urinary protein-to-creatine ratio.

Figure 3

The annual rates of change in the eGFR from baseline to 24 months and those from 6 to 24 months after the index date and changes in the UACR (mg/g) and UPCR (g/g) over the 24 months were determined in the subgroups based on the presence/absence of CKD (A,B), subgroups with or without a rapid decline in the eGFR (>3 mL/min/1.73 m²/year) over the 12-month period before the index date (C,D), and subgroups with or without RAS inhibitor use (E,F) in the IPRA (red bars) and CTRL (blue bars) groups. All graphs indicate the means ± SDs. * indicates a significant p-value between the IPRA and CTRL groups. CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; RAS: renin–angiotensin system; UACR: urinary albumin-to-creatinine ratio; UPCR: urinary protein-to-creatine ratio.