Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects

Abstract

Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending-dose (SAD; 2.5-500 mg) and multiple-ascending-dose (MAD; 2.5-100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose-proportional plasma concentrations with a half-life of approximately 17 h. The amount of glucosuria was also dose-dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5-100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of approximately 20-50 mg provided close-to-maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose-dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once-daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.

Lack of Pharmacokinetic Interactions Between Dapagliflozin and Simvastatin, Valsartan, Warfarin, or Digoxin

“…Dapagliflozin is a first-in-class oral, selective, reversible inhibitor of SGLT2 in development for the treatment of T2DM [9]. Studies in healthy and diabetic rats have demonstrated that dapagliflozin improves glucose homeostasis [10], and dosedependent urinary glucose excretion is induced by dapagliflozin in humans [11,12]. Clinical studies have also demonstrated the efficacy of dapagliflozin in the treatment of T2DM [12][13][14][15][16][17].…”

SGLT-2 Inhibitors in Development for Type 2 Diabetes Treatment

“…Single and multiple ascending dose (SAD and MAD) studies with dapagliflozin in healthy people and those with T2D confirmed a pharmacokinetic profile consistent with once-daily dosing [12,13]. The half-life is around 17 hours with dosedependent concentrations.…”

New in the Treatment of Type 2 Diabetes

“…Однако ажиотаж вокруг появления дапаглифлозина заметно поубавился, когда в июле 2011 г. экспертный комитет FDA отклонил раз-решение дапаглифлозина к применению, аргументируя свое решение опасениями по поводу риска злокачественных об-разований мочевого пузыря и молочной железы. Несмотря на предосторожность FDA, в ноябре 2012 г. дапаглифлозин получил одобрение Еврокомиссии [34].…”