Liraglutide combined with dapagliflozin treatment improves myocardial disease and endothelial dysfunction in T2DM mice

Background Diabetic cardiomyopathy (DCM) and endothelial dysfunction are major drivers of cardiovascular morbidity in type 2 diabetes (T2DM). The present study investigates whether combined therapy with liraglutide (LIRA) and dapagliflozin (DAPA) provides synergistic cardioprotection and vascular improvement in a murine model of T2DM. Methods A murine model of T2DM was established by high-fat diet feeding followed by low-dose streptozotocin injection. Diabetic mice were treated for 4 weeks with LIRA, DAPA, or their combination. Echocardiographic analysis was performed to assess cardiac systolic function and structural parameters. Systemic metabolic parameters, cardiac injury biomarkers, histopathology, oxidative stress markers, and inflammation were assessed. Key signaling pathways were evaluated by Western blot and qPCR. Results Compared with monotherapies, combined LIRA and DAPA treatment produced superior metabolic improvements, including attenuated weight loss and enhanced glucose tolerance. The combination also more effectively reduced markers of myocardial injury (CK-MB, LDH), diminished cardiac fibrosis, and preserved aortic architecture while inhibiting endothelial apoptosis. Mechanistically, co-administration synergistically activated both the antioxidative NRF2/HO-1 pathway and the vasoprotective AMPK/PKA-eNOS axis, leading to a more comprehensive suppression of oxidative stress, inflammation, and apoptosis in cardiac and vascular tissues. Conclusion The combined use of LIRA and DAPA exerts synergistic cardioprotective and vasoprotective effects in a preclinical model of T2DM-induced DCM. This synergistic effect may be mediated by the coordinated activation of the NRF2/HO-1 and AMPK/PKA-eNOS signaling pathways, leading to the attenuation of the key pathological drivers of diabetic cardiovascular injury. These findings provide a mechanistic rationale for the clinical exploration of GLP-1RA and SGLT2i combination therapy in DCM.