MON-300 EFFICACY AND SAFETY OF CANAGLIFLOZIN, A SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR, IN DIABETIC KIDNEY DISEASE: A RANDOMIZED OPEN-LABEL PROSPECTIVE TRIAL

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors are expected to have, renoprotective effects based on the possible mechanism that SGLT2 inhibitors reduce hyperfiltration by blocking proximal tubule sodium reabsorption and activating tubuloglomerular feedback (TGF) and may decrease inflammatory, fibrotic, and hyperplastic response of proximal tubular cells by blocking glucose reabsorption into proximal tubular cells. Although SGLT2 inhibition is associated with an acute reduction in estimated glomerular filtration rate (eGFR) by about 4-6 mL/min per 1.73m2, eGFR typically has a tendency to return to baseline and remains stable thereafter. Furthermore, a 30 to 40% reduction in albuminuria was found. However, the effects of SGLT2 inhibition are unclear with regard to other kidney related biomarkers, such as those associated with tubulointerstitial damage. In the present study, we aimed to examine precisely the renoprotective effects of the SGLT2 inhibitor canagliflozin by measuring albuminuria, tubulointerstitial biomarkers, eGFR, and other metabolic parameters in patients with diabetic kidney disease (DKD) who are treated with renin-angiotensin system (RAS) inhibitors. In this prospective, open-label, parallel-group study, Japanese diabetes patients were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Before randomization, patients received fixed doses of conventional antidiabetic drugs (oral drugs and/or insulin) and RAS inhibitors for 8 weeks; these drugs were continued during the study. A total of 44 patients were randomly assigned to the canagliflozin group (n = 22) or the control group (n = 22). Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory and vital parameters, and adverse events. Both groups included 22 patients in the analysis. Mean change in UACR was -221 g/gCr and 81 mg/gCr in the canagliflozin and control groups, respectively (P=0.004). Percent reduction in UACR was significantly greater in the canagliflozin group than in the control group (-49 ± 26% vs. 24 ± 47 %; P<0.0001). Urinary liver-type fatty acid binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG), and β2-microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in eGFR at the end of the study was 0.7 and -3.4 mL/min/1.73m2 in the canagliflozin and control group, respectively (P=0.024). A significant decrease in body mass index (BMI), systolic, diastolic blood pressure (BP), and mean arterial pressure was observed in the canagliflozin group. In addition, canagliflozin was associated with a significant increase in hemoglobin concentrations and hematocrit levels. Canagliflozin treatment leads to a reduction in albuminuria, urinary L-FABP, NAG, and β2-microglobulin levels in patients with DKD, regardless of simultaneous RAS inhibition. Furthermore, after 52 weeks, canagliflozin, in contrast to the control treatment, significantly reduced HbA1c and was associated with reductions in body weight, BPs, and liver transaminase levels in patients with DKD. The effect of canagliflozin on UACR appeared to be, in large part, beyond the effects on glycemic control. These findings suggest that canagliflozin may be an appropriate treatment option for patients with DKD.