Dual SGLT1/2 inhibition with sotagliflozin improves cardiac function and metabolism in type 2 diabetic mice

Sotagliflozin (SOTA), a dual sodium-glucose cotransporter (SGLT)1/2 inhibitor, improves cardiovascular outcomes in patients with diabetes and heart failure, yet the metabolic mechanisms underlying these benefits remain incompletely defined. As a model of type 2 diabetes, db/db mice were treated with SOTA (5 mg/kg/day) in drinking water for 4 weeks. Cardiac metabolism was assessed using LC-MS/MS, cardiac function by echocardiography, and susceptibility to ischemia/reperfusion injury in Langendorff-perfused hearts. Systemic metabolism was characterised by plasma biochemical profiling and ¹H NMR spectroscopy of peripheral tissues. db/db mice exhibited obesity, hyperglycaemia, hyperinsulinaemia, and diastolic dysfunction, alongside perturbed cardiac and systemic metabolism. SOTA treatment improved hyperglycaemia, ventricular function and cardiac metabolomic profile without correcting obesity or insulin resistance. In the heart, SOTA partially restored glycolytic intermediates and improved bioenergetics, whereas systemic metabolic abnormalities largely persisted. These findings suggest dual SGLT1/2 inhibition induces selective cardiac metabolic remodelling in diabetic cardiomyopathy independent of global metabolic correction.