Divergent electrophysiologic safety profile of dapagliflozin and empagliflozin in a whole-heart model. (3rd October 2022) - Frommeyer, G
Abstract: Background: The SGLT2-inhibitors dapagliflozin and empagliflozin have emerged as standard therapy for the treatment of heart failure with reduced ejection fraction. However, experimental data on the electrophysiologic safety is sparse. Purpose: Aim of this study was to characterize the safety profile of the SGLT2 inhibitors dapagliflozin and empagliflozin in a sensitive whole-heart model. Methods: 26 rabbit hearts of New Zealand white rabbits were excised and mounted to a Langendorff-apparatus. Hearts were divided up into two groups. The first group (n=12) was perfused with dapagliflozin in ascending concentrations (3, 5 and 10 μM). Further 14 hearts were treated with empagliflozin (1, 3 and 5 μM). Ventricular vulnerability was assessed by a predefined pacing protocol consisting of premature extra stimuli and burst stimulation. Results: Dapagliflozin led to a significant reduction of the QT interval (3 μM: −27 ms, p<0.01; 5 μM: −47 ms, p<0.01; 10 μM: - 42 ms, p<0.01), action potential duration (APD90; 3 μM: −21 ms, p<0.01; 5 μM: −37 ms, p<0.01; 10 μM: −24 ms, p<0.01) and effective refractory periods (ERP; 3 μM: −34 ms, p<0.01.; 5 μM: −49 ms, p<0.01; 10 μM: −52 ms, p<0.01). Spatial dispersion of repolarization was not increased after dapagliflozin treatment (3 μM: −4 ms, p=ns; 5 μM: −4 ms, p<0.05; 10 μM: −8 ms, p=ns). Empagliflozin also led to a pronounced abbreviation of cardiac repolarization duration (QT: 1 μM: −28 ms, p<0.01.; 3 μM: −47 ms, p<0.01; 5 μM: −69 ms, p<0.01; APD90: 1 μM: −27 ms, p<0.01; 3 μM: −46 ms, p<0.01; 5 μM: −51 ms, p<0.01) and ERP (1 μM: −28 ms, p<0.05; 3 μM: −40 ms, p<0.01; 5 μM: −56 ms, p<0.01). In contrast to dapagliflozin, empagliflozin amplified spatial dispersion of repolarization (1 μM: −3 ms, p=ns.; 3 μM: +4 ms, p<0.05; 5 μM: +9 ms, p=ns). Dapagliflozin infusion did not provoke more ventricular arrhythmias (VA) compared to baseline conditions (baseline: 2 episodes; 3 μM: 6 episodes, p=ns.; 5 μM: 11 episodes, p=ns; 10 μM: 18 episodes, p=ns). In contrast, empagliflozin treatment significantly increased the occurrence of VA (baseline: 4 episodes; 1 μM: 12 episodes, p<0.05.; 3 μM: 8 episodes, p=ns; 5 μM: 29 episodes, p<0.05). Of note, none of the drugs provoked arrhythmias of the torsade de pointes type after lowering the potassium concentration. Conclusion: The SGLT2 inhibitors dapagliflozin and empagliflozin shorten cardiac repolarization and effective refractory periods. While spatial dispersion remains stable after administration of dapagliflozin, empagliflozin amplifies spatial dispersion of repolarization. As a result, significantly more ventricular arrhythmias were inducible after empagliflozin treatment. Funding Acknowledgement: Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Hans and Gertie Fischer-Foundation (to C.E.)