Liraglutide and Dapagliflozin combination synergistically improves diabetic cardiomyopathy and endothelial dysfunction in T2DM mice

Type 2 Diabetes Mellitus (T2DM) is a leading cause of cardiovascular morbidity, with diabetic cardiomyopathy (DCM) and endothelial dysfunction being critical drivers. DCM involves structural and functional changes in the heart, independent of coronary artery disease, while endothelial dysfunction impairs vascular health, contributing to complications like myocardial infarction. Current T2DM treatments often target glycemic control but may not fully address the complex interplay of oxidative stress and inflammation underlying these cardiovascular pathologies. Liraglutide, a GLP-1 receptor agonist, and dapagliflozin, an SGLT2 inhibitor, have shown individual cardioprotective benefits. This study explores their combined synergistic potential to offer more comprehensive protection against T2DM-induced myocardial and vascular damage.

A T2DM murine model was established using a high-fat diet followed by low-dose streptozotocin injection. Diabetic mice were then treated for 4 weeks with Liraglutide (LIRA), Dapagliflozin (DAPA), or their combination. Cardiac systolic function and structural parameters were assessed via echocardiography. Systemic metabolic parameters, cardiac injury biomarkers (CK-MB, LDH), histopathology, oxidative stress markers, and inflammation were evaluated. Key signaling pathways, including NRF2/HO-1 and AMPK/PKA-eNOS, were investigated using Western blot and qPCR to elucidate the underlying mechanisms of action.

Combined Liraglutide and Dapagliflozin treatment demonstrated superior metabolic improvements compared to monotherapies, including attenuated weight loss and enhanced glucose tolerance. The combination also more effectively reduced markers of myocardial injury, specifically CK-MB and LDH, and significantly diminished cardiac fibrosis. Furthermore, co-administration preserved aortic architecture and inhibited endothelial apoptosis, indicating robust vascular protection. This comprehensive protection extended to both cardiac and vascular tissues.

Mechanistically, the co-administration synergistically activated both the antioxidative NRF2/HO-1 pathway and the vasoprotective AMPK/PKA-eNOS axis.

This coordinated activation led to a more comprehensive suppression of oxidative stress, inflammation, and apoptosis across both cardiac and vascular tissues, highlighting a powerful synergistic effect beyond individual drug actions.