Endocrine Abstracts

Empagliflozin is a potent, highly selective sodium glucose cotransporter-2 inhibitor in development for treatment of type 2 diabetes mellitus. This randomized, placebo-controlled, double-blind study assessed the effects of empagliflozin on the QT interval. Thirty healthy subjects (14/16 female/male; mean [range] age 34.5 [18–52] years) received single doses of 25 mg (within therapeutic range) and 200 mg (supratherapeutic) empagliflozin and 400 mg moxifloxacin as positive control. A new 5-period crossover, ‘double-placebo period’ design was utilized that reduced the sample size (from 40 to 30 subjects) and the total number of treatment periods compared with the classical 4-period TQT-design. Triplicate 12-lead 10-s-ECGs were recorded at baseline and selected time points over 24 h after dosing. Placebo-corrected mean change from baseline (MCfB) in population heart rate (HR)-corrected QT interval (QTcN) 1–4 h after dosing (primary endpoint) was 0.6 (90% CI: −0.7, 1.9) ms and −0.2 (−1.4, 0.9) ms for 25 and 200 mg empagliflozin, respectively – below the ICH E14 non-inferiority margin of 10 ms. Maximum placebo-corrected MCfB in QTcN between 0.5–24 hours after dosing were 2.2 (−0.3, 4.7) ms and 1.6 (−0.4, 3.5) ms for 25 and 200 mg empagliflozin, respectively. 90% CIs for placebo-corrected MCfB in HR 1–4 h after dosing were within −1.8 and 0.8 beats per min for both doses, indicating no relevant empagliflozin-related changes. Assay sensitivity was confirmed by placebo-corrected MCfB in QTcN 2–4 h post dose of 12.4 (10.7, 14.1) ms with moxifloxacin. Empagliflozin tolerability was rated ‘good’ for all subjects. Adverse events (AEs) were reported for 23.3% of subjects receiving empagliflozin and 27.6% receiving placebo. The most frequent AE was nasopharyngitis (4 subjects on empagliflozin, 5 on placebo). In conclusion, single doses of empagliflozin 25 and 200 mg were not associated with QTcN prolongation or changes in HR, and were well tolerated.

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Funding: This work was supported, however funding details unavailable.