Abstract
Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor. To evaluate the cardiac safety of luseogliflozin, a thorough QT/QTc study was conducted in healthy Japanese subjects. The effects of moxifloxacin on QT prolongation in Japanese subjects were also evaluated. In this double-blind, placebo- and open-label positive-controlled, 4-way crossover study, 28 male and 28 female subjects received a single dose of luseogliflozin 5 mg (therapeutic dose), luseogliflozin 20 mg (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Serial triplicate digital 12-lead electrocardiograms (ECGs) were recorded before and after dosing, and results were analyzed using the Fridericia correction (QTcF) method. Serial blood sampling was performed for pharmacokinetic analyses of luseogliflozin and moxifloxacin to analyze the relationship between QTcF interval and plasma concentration. The upper limits of the two-sided 90% confidence intervals (CIs) for baseline and placebo-adjusted QTcF intervals (ΔΔQTcF) in the 5 mg and 20 mg luseogliflozin groups were less than 10 ms at all time points. No correlation between plasma luseogliflozin concentrations and ΔΔQTcF was observed. In the moxifloxacin group, the lower limits of the two-sided 90% CIs for ΔΔQTcF were greater than 5 ms at all time points. A positive relationship was observed between plasma moxifloxacin concentration and change in ΔΔQTcF. Luseogliflozin was well tolerated at both dose levels. The majority of adverse events were mild in severity, and no serious or life-threatening adverse events occurred. Neither therapeutic (5 mg) nor supratherapeutic (20 mg) doses of luseogliflozin affected QT prolongation in healthy Japanese subjects.
Highlights
Luseogliflozin, a novel 1-thio-D-glucitol derivative, is a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor that is approved for marketing in Japan for the treatment of type 2 diabetes [1]
The upper bound of the 90% two-sided confidence intervals (CIs) for the least squares mean ΔΔQTcF was below the 10 ms threshold at all evaluation time points for both the therapeutic dose (5 mg) and supratherapeutic dose (20 mg) of luseogliflozin
We found that the effect of moxifloxacin on QT/QTc interval was sufficiently high in Japanese healthy subjects
Summary
Luseogliflozin, a novel 1-thio-D-glucitol derivative, is a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor that is approved for marketing in Japan for the treatment of type 2 diabetes [1]. Luseogliflozin inhibits the activity of SGLT2 in the renal proximal tubule and shows hypoglycemic effects based on promotion of urinary glucose excretion in various animal models [2]. The action of luseogliflozin is postulated to normalize hyperglycemia by stimulating excretion of glucose from blood into urine via inhibition of the reabsorption of filtered glucose in the renal proximal tubule. The pharmacological effects of SGLT2 inhibitors are insulin independent, making them an attractive new therapeutic target in type 2 diabetes mellitus [3]. Several SGLT2 inhibitors have already appeared on the market, and others are under the development. Safety and efficacy have been demonstrated in most [4]
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