Renal glucose handling: impact of chronic kidney disease and sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes

Abstract

Objective: Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, stimulates glycosuria and lowers glycemia in patients with type 2 diabetes (T2DM). The objective of this study was to assess the pharmacodynamics of ipragliflozin in T2DM patients with impaired renal function.

Research design and methods: Glycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 ± 9 years, fasting glucose 133 ± 39 mg/dL, mean ± SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR1 ≥90 mL · min(-1) · 1.73 m(-2)), mild (eGFR2 ≥60 to <90), moderate (eGFR3 ≥30 to <60), or severe reduction in eGFR (eGFR4 ≤15 to <30).

Results: Ipragliflozin significantly increased urinary glucose excretion in each eGFR class (P < 0.0001). However, ipragliflozin-induced glycosuria declined (median [IQR]) across eGFR class (from 46 mg/min [33] in eGFR1 to 8 mg/min [7] in eGFR4, P < 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P < 0.0001 for both, r(2) = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia.

Conclusions: In T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment.

Trial registration: ClinicalTrials.gov NCT01302028.

Figures

Figure 1

Box-plots of postdose glucose excretion rates (left panels) and FGE (right panels) in European (upper panels) and Japanese subjects (lower panels) by eGFR class (eGFR1 through eGFR4 coded by gray intensity). The numbers at the bottom of the boxes are eGFR values (mean ± SD) for the corresponding class. Patient 5004 in the European group had greater excretion than filtration and was therefore excluded from this analysis.

Figure 2

Individual baseline (upper panel) and postdose (lower panel) values of glucose absorption and urinary excretion for European (EU) and Japanese cohorts are plotted against the corresponding values of glucose filtration rate. The line of best fit is y = −0.5 + 1.1x −0.001x2 (r2 = 0.96) for baseline absorption, and y = 7.5 − 0.2x + 0.001x2 (r2 = 0.93) for baseline excretion. The corresponding line of best fit for postdose absorption is y = 3.3 + 0.5x (r2 = 0.65) and the one for postdose excretion is y = −4.9 + 0.5x (r2 = 0.59).

Figure 3

Dependency of postdose glycosuria on eGFR and FPG concentration. Line of best fit and 95% CIs are shown. The model parameter estimates are glycosuria (g/day) = −11 + 0.96 × eGFR (mL · min−1 · 1.73 m−2), and glycosuria (g/day) = −48 + 0.83 × fasting glucose (mg/dL).