Electrophysiological Effects of the Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitor Dapagliflozin on Human Cardiac Potassium Channels.

The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be caused in part by previously unrecognized effects on atrial repolarizing potassium (K + ) channels. This study was designed to assess direct pharmacological effects of dapagliflozin on cloned ion channels K v 11.1, K v 1.5, K v 4.3, K ir 2.1, K 2P 2.1, K 2P 3.1, and K 2P 17.1, contributing to I Kur , I to , I Kr , I K1 , and I K2P K + currents. Human channels coded by KCNH2 , KCNA5 , KCND3 , KCNJ2 , KCNK2 , KCNK3 , and KCNK17 were heterologously expressed in Xenopus laevis oocytes, and currents were recorded using the voltage clamp technique. Dapagliflozin (100 µM) reduced K v 11.1 and K v 1.5 currents, whereas K ir 2.1, K 2P 2.1, and K 2P 17.1 currents were enhanced. The drug did not significantly affect peak current amplitudes of K v 4.3 or K 2P 3.1 K + channels. Biophysical characterization did not reveal significant effects of dapagliflozin on current-voltage relationships of study channels. In conclusion, dapagliflozin exhibits direct functional interactions with human atrial K + channels underlying I Kur , I Kr , I K1 , and I K2P currents. Substantial activation of K 2P 2.1 and K 2P 17.1 currents could contribute to the beneficial antiarrhythmic outcome associated with the drug. Indirect or chronic effects remain to be investigated in vivo.