Aims/hypothesis Empagliflozin (EMPA), an inhibitor of the renal sodium–glucose cotransporter (SGLT) 2, reduces the risk of cardiovascular death in patients with type 2 diabetes. The underlying mechanism of this effect is unknown. Elevated cardiac cytoplasmic Na + (Na + c ) and Ca 2+ (Ca 2+ c ) concentrations and decreased mitochondrial Ca 2+ concentration (Ca 2+ m ) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify Na + c , Ca 2+ c and Ca 2+ m in cardiomyocytes. Methods Na + c, Ca 2+ c , Ca 2+ m and Na + /H + exchanger (NHE) activity were measured fluorometrically in isolated ventricular myocytes from rabbits and rats. Results An increase in extracellular glucose, from 5.5 mmol/l to 11 mmol/l, resulted in increased Na + c and Ca 2+ c levels. EMPA treatment directly inhibited NHE flux, caused a reduction in Na + c and Ca 2+ c and increased Ca 2+ m . After pretreatment with the NHE inhibitor, Cariporide, these effects of EMPA were strongly reduced. EMPA also affected Na + c and NHE flux in the absence of extracellular glucose. Conclusions/interpretation The glucose lowering kidney-targeted agent, EMPA, demonstrates direct cardiac effects by lowering myocardial Na + c and Ca 2+ c and enhancing Ca 2+ m , through impairment of myocardial NHE flux, independent of SGLT2 activity.