The hallmark of type 2 diabetes mellitus (T2DM) is abnormal glucose homeostasis due to hyperglycaemia or insulin resistance. Metabolic abnormalities in T2DM lead to cellular dysfunction and the development of diabetic cardiomyopathy and heart failure. New antihyperglycemic agents, such as glucagon-like peptide-1 receptor agonists and the sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown to attenuate endothelial dysfunction at the cellular level. In addition, they showed cardiovascular safety and cardioprotective effects. How these drugs exert their cardioprotective effects is unknown, although recent studies show that cardiovascular homeostasis occurs through the interplay of the sodium hydrogen exchangers (NHE), specifically NHE1 and NHE3 with SGLT2i. Another theoretical explanation for the SGLT2i cardioprotective effects is through natriuresis by the kidney. This theory highlights the possible involvement of renal NHE transporters in the management of heart failure. This review outlines possible mechanisms predisposing to diabetic cardiomyopathy and discusses the interaction between NHE and SGLT2i in cardiovascular disease.