Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, approved for the treatment of diabetes mellitus, have gained attention for their cardioprotective effect. The exact mechanism by which SGLT-2 inhibitors exert their cardioprotective effect remains unclear. Recent studies have suggested that empagliflozin (EMPA), an SGLT inhibitor, exerts its cardioprotective effect by inhibiting the Na ⁺ /H ⁺ exchanger (NHE); a group of membrane proteins that regulate intracellular pH and cell volume. Increased activity and expression of NHE isoform 1 (NHE1), the predominant isoform expressed in the heart, leads to cardiac hypertrophy. Our research group investigates the indirect mechanisms by which SGLT inhibitors exert their cardioprotective effect and have demonstrated that angiotensin II (ANG)-induced hypertrophy of H9c2 cardiomyoblasts is accompanied with increased SGLT-1 and NHE1 protein expression; an effect which is reversed in the presence of EMPA. In addition, we demonstrated that dapagliflozin improved survival of transgenic mice expressing cardiac-specific NHE1.