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


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.
Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy. ferranni@ifc.cnr.it
Ele
E
Ferrannini
Stephan A
SA
Veltkamp
Ronald A
RA
Smulders
Takeshi
T
Kadokura
D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005919:Glomerular Filtration Rate; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006029:Glycosuria / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000493:pharmacokinetics* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D005960:Glucosides; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C572941:ipragliflozin; D005947:Glucose