Renal Glucose Handling

Abstract

OBJECTIVEIpragliflozin, 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 METHODSGlycosuria 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).RESULTSIpragliflozin 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, r2 = 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.CONCLUSIONSIn 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.

Pharmacokinetics and Pharmacodynamics of the SGLT2 Inhibitor Remogliflozin Etabonate in Subjects with Mild and Moderate Renal Impairment

“…Indeed, renal impairment may deeply impact the pharmacokinetics of these agents and thereby influence choices, dosing, and monitoring of these drugs according to the reduction of glomerular filtration rate (Snyder and Berns, 2004;Cavanaugh, 2007;Haneda and Morikawa, 2009). The situation is even more complex in the elderly population, where renal impairment and polymedication are more common (Ferrannini et al, 2013). Sodium/glucose cotransporters (SGLTs) are expressed in the absorptive epithelia of the gastrointestinal tract (SGLT1) and renal tubules (SGLT1 and SGLT2).…”

Basal glucosuria is ubiquitous in critically ill patients

“…On the contrary, hyperfiltration found during pregnancy is associated with a lowered renal glucose threshold . The renal glucose threshold can also be lowered using specific SGLT2 inhibitors like ipragliflozin, which is used in diabetes treatment …”

Sodium&ndash;glucose cotransporter-2 inhibition and acidosis in patients with type 2 diabetes: a review of US FDA data and possible conclusions

“…Consequently, glycemia is not reduced. Extension of SGLT2 inhibitors to patients with renal dysfunction thus has limited benefit, 12 and if combined with other agents such as metformin, it may potentiate adverse consequences. The combinations of metformin and SGLT2 inhibitor may increase the risk to populations with age-related frailty and/or marginal renal function.…”