Additive cardioprotection by dapagliflozin and pioglitazone co-therapy in streptozotocin-induced diabetic rats

In diabetes mellitus, inflammation and apoptosis contribute to cardiovascular injury and oxidative damage. Dapagliflozin and Pio, beyond their hypoglycemic effects, mitigate organ damage. This study explored whether their combination provides enhanced protection against cardiac damage in streptozotocin-induced diabetic rats. Wistar rats were divided into control, diabetic (STZ, 55 mg/kg, i.p.), dapagliflozin-treated (10 mg/kg, chow), pioglitazone-treated (12 mg/kg, chow), and combination groups. After six weeks, systolic blood pressure, glucose, and lipids were assessed; subsequently, the left ventricle was excised for real-time quantitative PCR and western blot analyses. Both drugs alleviated STZ-induced weight loss, water intake, and urine output without significant glucose reduction. The monotherapy also effectively modulated oxidative stress, inflammation, and apoptosis. The combination of drugs led to a more favourable lipid profile than the individual drugs. Dapagliflozin + pioglitazone additively upregulated MnSOD, normalized Bcl2 and Bax/Bcl2 ratios, and decreased tumour necrosis factor-α levels in the left ventricle. These effects were associated with improved cardiac damage markers (Myh6/Myh7 ratio) and systolic blood pressure compared to the administration of the drugs alone. Combined dapagliflozin and pioglitazone protect diabetic rat hearts by reducing oxidative stress, inflammation, and apoptosis, independently of glycemic control. This combination therapy offers a promising approach to mitigate cardiovascular complications in diabetes.