Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Divergent safety profile of the SGLT2 inhibitors dapagliflozin and empagliflozin in a whole-heart model
C. Ellermann1, J. Uphoff1, J. Wolfes1, H. Könemann1, B. Rath1, P. Leitz1, L. Eckardt1, G. Frommeyer1
1Klinik für Kardiologie II - Rhythmologie, Universitätsklinikum Münster, Münster;

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. Therefore, purpose of this study was to characterize the safety profile of the SGLT2 inhibitors dapagliflozin and empagliflozin in a sensitive whole-heart model. 

 

Methods and results: 
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. 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.


https://dgk.org/kongress_programme/jt2022/aP463.html