Ameliorative Effect of Empagliflozin and Linagliptin on Cisplatin-Induced Nephrotoxicity and Cardiotoxicity by Reducing Oxidative Stress

Introduction: Cisplatin (CP) is a chemotherapeutic agent limited by its toxic effects on the heart and kidneys, resulting in nephrotoxicity and cardiotoxicity. This study investigated the protective effects of the antidiabetic drugs linagliptin (LINA) and empagliflozin (EMPA), alone and in combination, on cisplatin-induced heart and kidney damage in non-diabetic rats. Methods: Forty-nine rats were randomized into seven groups (n=7 each): control (saline; 10 mL/kg), cisplatin (CP; 10 mg/kg), empagliflozin (EMPA; 10 mg/kg), linagliptin (LINA; 3 mg/kg), and treatment groups (CP+EMPA, CP+LINA, and CP+EMPA+LINA). EMPA and LINA were administered orally for 10 days; CP was administered intraperitoneally on days 1 and 6 after treatment with EMPA, LINA, or both. Renal and cardiac injury biomarkers were measured in the blood. Hearts and kidney tissues from animals were extracted to assess reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations, as well as the activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). Results: The CP-treated group showed elevated renal, cardiac, and oxidative stress markers. Conversely, the activities of SOD, GPX, and CAT were reduced in the CP-treated groups compared to the control. EMPA, LINA, or combination reduced creatinine, BUN, LDH, CK-MB, troponin I, and ROS levels. LINA showed weaker antioxidant effects in the heart than in the kidney or EMPA. Conclusion: Our findings suggest that LINA may have a weaker antioxidant effect in the heart than in the kidney or EMPA. Administration of the combinations (LINA+EMPA) affects MDA levels in CP-treated animals, with a significant reduction in the heart and kidney. Individual treatments do not significantly alter MDA levels. However, combined treatment significantly improves SOD, GPX, and CAT activities in the heart and kidney, indicating a superior protective effect, suggesting potential to mitigate CP-induced toxicity.