Effects of SGLT2 inhibitors on the atrial rhythm: Sotagliflozin modifies the activity of NaV1.5

Background/Introduction Due to their cardioprotective properties, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have become a cornerstone in heart failure therapy. Beyond metabolic and hemodynamic effects, emerging evidence suggests that SGLT2i may exert direct antiarrhythmic effects, as subanalyses of large clinical trials have shown reduced incidence of atrial arrhythmias in patients treated with dapagliflozin. However, the underlying antiarrhythmic mode of action remains a subject of ongoing research. Sotagliflozin, a dual SGLT1/2 inhibitor, represents an intriguing candidate to explore these effects. Purpose Here, we aim to characterize the electrophysiological effects of sotagliflozin on cardiac ion channels and identify potential mechanisms underlying the antiarrhythmic properties. Methods Two-electrode voltage clamp recordings were performed on Xenopus laevis oocytes heterologously expressing ten cardiac ion channels. Sotagliflozin effects on NaV1.5 were compared with those of known Nav-inhibitors ajmaline and lidocaine. Site-directed mutagenesis of NaV1.5 was used to assess amino acid residues critical for drug binding. In silico docking simulations were conducted to support experimental findings. Results Sotagliflozin showed a dose-dependent inhibitory effect on the peak current amplitude of heterologously expressed NaV1.5, with an inhibition of 56.0±9.4% (p = 0.0096; n = 4) at 250 µmol/L. Comparing the effect of sotagliflozin, ajmaline and lidocaine, each at 100 µmol/L, we observed that ajmaline inhibited NaV1.5 by 65.3±2.5% (p = 0.0015; n = 3), lidocaine by 31.0±2.4% (p < 0.0001; n = 7) and sotagliflozin by 21.0±2.3% (p < 0.0001; n = 10). Analyzing the impact of these drugs on the activation of NaV1.5 with Boltzmann's equation, we observed that sotagliflozin at 100 µmol/L led to a depolarizing shift of the potential of half-maximal activation V1/2 (Control: V1/2 = -43.4±0.4 mV; Sotagliflozin: V1/2 = -39.3±0.5 mV; p < 0.0001; n = 10). This effect was even stronger at 250 µmol/L (Control: V1/2 = -42.5±1.4 mV; Sotagliflozin: V1/2 = -32.8±0.5 mV; p < 0.0001; n = 4). Replacement of specific amino acids within the NaV1.5 channel pore altered the response to sotagliflozin, with the F1760A mutation markedly attenuating current inhibition compared to wild type. This finding indicates a direct interaction of sotagliflozin with the NaV1.5 binding site, consistent with results from in silico docking analysis. Conclusion Sotagliflozin interacts with NaV1.5 channels through a direct pore-binding mechanism, leading to a peak current inhibition and altered activation kinetics. These findings identify NaV1.5 as a molecular target of sotagliflozin and indicate a potential mechanism contributing to the antiarrhythmic effects observed in clinical studies.