Comparison of the Effects of Empagliflozin and Sotagliflozin on a Zebrafish Diabetic Heart Failure with Reduced Ejection Fraction Model

Abstract

Abstract The sodium-glucose co-transporter 2 (SGLT2) inhibitor, empagliflozin (EMPA), and dual SGLT1/2 inhibitor, sotagliflozin (SOTA) are emerging as heart failure (HF) medications beyond their glucose-lowering-effects in diabetes mellitus (DM). However, the precise mechanism underlying this cardioprotective effect has not yet been elucidated. Here, we evaluated the effects of EMPA and SOTA in a DM combined with HF with reduced ejection fraction (DM-HFrEF) zebrafish model. The myocardial contractile functions and motility were evaluated by MicroZebraLab and DanioVision, respectively. The structural binding and modulating effect of the two medications on sodium-hydrogen exchanger 1 (NHE1) was evaluated in silico and in vitro. DM-HFrEF zebrafish showed impaired cardiac contractility and decreased motility and survival, all of which were improved by 5 µM EMPA or SOTA treatment. However, the 25 µM SOTA treatment group had worse survival rates and less motility preservation than the EMPA treatment group with the same concentration, and an epicardial edema and uninflated swim bladder were observed. We evaluated the structural binding and modulation effect of the two medications on NHE1 both in silico and in vitro. The SOTA, EMPA and cariporide (CARI) showed a similar structural binding affinity to NHE1. In addition, EMPA, SOTA, and CARI effectively reduced intracellular H+, Na+ and Ca2+ changes through the inhibition of NHE1 activity. These findings suggest that both EMPA and SOTA exert cardioprotective effect in DM-HFrEF zebrafish model through the inhibition of NHE1 activity. In addition, despite the similar cardioprotective effects of both drugs, SOTA may be less effective than EMPA at high concentrations.