Mitigating Doxorubicin- and Cisplatin-Induced Cardio-Metabolic Disruptions: The Differential Pharmacological Modulatory Role of Metformin, Dapagliflozin, and a Fixed-Dose Combination on Metabolic Profile in Wistar Rats

The therapeutic efficacy of antineoplastic agents like doxorubicin (DOX) and cisplatin (CIS) is often limited by their significant cardiotoxic and metabolic side effects. This study investigated the protective effects of oral pretreatment with metformin (MET), dapagliflozin (DAP), a MET-DAP fixed-dose combination, and silymarin (SLM) on the cardiometabolic profile of rats intoxicated with a combination of these chemotherapeutic drugs. Male Wistar rats (weight: 130-190 g; age: 10-12 weeks) were pretreated for 14 consecutive days with either 200 mg/kg/day MET, 10 mg/kg/day DAP, a MET-DAP combination (100 mg/kg/day MET and 5 mg/kg/day DAP), or 20 mg/kg/day SLM. From day 4 to day 14, DOX (2.5 mg/kg) and CIS (1.5 mg/kg) were administered on alternate days. The cardiometabolic profile was assessed by measuring body weight, fasting blood glucose, serum lipid profile, and cardiovascular risk indices. The DOX/CIS-intoxicated group exhibited significant reductions in body weight and detrimental alterations in fasting blood glucose and lipid parameters, indicative of severe cardiometabolic dysfunction. Oral pretreatment with MET, DAP, MET-DAP, and SLM effectively counteracted these negative effects, leading to a significant (p≤0.05, p≤0.001, and p≤0.0001) preservation of body weight and normalization of the measured cardiometabolic parameters. These findings suggest that these oral agents possess significant pharmacological activity in mitigating DOX/CIS’ adverse cardiometabolic effects. Thus, highlighted the promising adjunctive therapy of MET-DAP combination in improving patient outcomes during chemotherapy.