Abstract
Background
Ipragliflozin (ASP1941) is a selective sodium glucose cotransporter 2 inhibitor in
clinical development for the treatment of patients with type 2 diabetes mellitus (T2DM).
Objectives
The primary objective was to evaluate the safety profile and tolerability of ipragliflozin
as a glucose-lowering agent in combination with stable metformin therapy in patients
with T2DM. A secondary objective was to evaluate the effect of ipragliflozin on the
pharmacokinetic (PK) properties of metformin.
Methods
Thirty-six patients with T2DM stable on metformin therapy (850, 1000, or 1500 mg bid)
were randomized in a double-blind manner to receive ipragliflozin (300 mg qd; n =
18) or matching placebo (n = 18) for 14 days. Safety profiles, including monitoring
of hypoglycemic events, treatment-emergent adverse events (TEAEs), laboratory measurements,
and vital signs were assessed throughout the study. The PK properties of metformin
and ipragliflozin were determined in plasma. The geometric mean ratio and its 90%
CI for the maximum plasma concentration and AUC0–10 were calculated for metformin + ipragliflozin (day 14) versus metformin alone (day
−1). Pharmacodynamic properties were assessed by measurement of urinary glucose excretion
over 24 hours (UGE0–24).
Results
All the TEAEs, except 1, were mild. Fifteen TEAEs were observed in the ipragliflozin
group (7 of 18 patients [38.9%]), and 19 TEAEs were observed in the placebo group
in (8 of 18 patients [44.4%]). Treatment-related TEAEs were reported by 3 of 18 patients
(16.7%) receiving metformin + ipragliflozin and by 5 of 18 patients (27.8%) receiving
metformin + placebo. No hypoglycemic events (blood glucose level <54 mg/L [to convert
to millimoles per liter, multiply by 0.0555]) were observed. The geometric mean ratios
for Cmax and AUC0–10 of metformin + ipragliflozin versus metformin alone were 1.11 (90% CI, 1.03–1.19)
and 1.18 (90% CI, 1.08–1.28), respectively. After ipragliflozin treatment, UGE0–24 on day 14 (74.9 g) was significantly higher than that in the placebo group (3.6 g)
and at baseline (3.3 g).
Conclusions
Combination treatment for 14 days with ipragliflozin and metformin was well tolerated
in patients withT2DM without hypoglycemia. The addition of ipragliflozin (300 mg qd)
to metformin therapy did not result in a clinically relevant change in the PK properties
of metformin. ClinicalTrials.gov identifier: NCT01302145.
Key words
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Article info
Publication history
Published online: July 16, 2012
Accepted:
June 26,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
