Metformin and Dapagliflozin Attenuate Doxorubicin-Induced Acute Cardiotoxicity in Wistar Rats: An Electrocardiographic, Biochemical, and Histopathological Approach

Abstract

Doxorubicin is a widely used anticancer drug whose efficacy is limited due to its cardiotoxicity. There is no ideal cardioprotection available against doxorubicin-induced cardiotoxicity. This study aimed to investigate the anticipated cardioprotective potential of metformin and dapagliflozin against doxorubicin-induced acute cardiotoxicity in Wistar rats. At the beginning of the experiment, cardiac screening of experimental animals was done by recording an electrocardiogram (ECG) before allocating them into the groups. Thereafter, a total of thirty healthy adult Wistar rats (150–200 g) were randomly divided into five groups (n = 6) and treated for eight days as follows: group I (normal control), group II (doxorubicin control), group III (metformin 250 mg/kg/day), group IV (metformin 180 mg/kg/day), and group V (dapagliflozin 0.9 mg/kg/day). On the 7th day of the treatment phase, doxorubicin 20 mg/kg was administered intraperitoneal to groups II, III, IV, and V. On the 9th day (immediately after 48 h of doxorubicin administration), blood was collected from anesthetized animals for glucose, lipid profile, CK-MB & AST estimation, and ECG was recorded. Later, animals were sacrificed, and the heart was dissected for histopathological examination. We found that compared to normal control rats, CK-MB, AST, and glucose were significantly increased in doxorubicin control rats. There was a significant reversal of doxorubicin-induced hyperglycemia in the rats treated with metformin 250 mg/kg compared to doxorubicin control rats. Both metformin (180 mg/kg and 250 mg/kg) and dapagliflozin (0.9 mg/kg) significantly altered doxorubicin-induced ECG changes and reduced the levels of cardiac injury biomarkers CK-MB and AST compared to doxorubicin control rats. Metformin and dapagliflozin protected the cellular architecture of the myocardium from doxorubicin-induced myocardial injury. Current study revealed that both metformin and dapagliflozin at the FDA-recommended antidiabetic doses mitigated doxorubicin-induced acute cardiotoxicity in Wistar rats. The obtained data have opened the perspective to perform chronic studies and then to clinical studies to precisely consider metformin and dapagliflozin as potential chemoprotection in the combination of chemotherapy with doxorubicin to limit its cardiotoxicity, especially in patients with comorbid conditions like type II diabetes mellitus.

The Cardioprotective and Anticancer Effects of SGLT2 Inhibitors

“…Dapagliflozin also exhibited substantial cardioprotective effects against DOX cardiotoxicity. 44 , 45 , 46 , 47 , 48 , 50 , 51 , 52 , 53 Dapagliflozin improved ejection fraction and fractional shortening, 44 , 46 , 47 , 48 , 50 , 52 , 53 mitigated DOX-induced hemodynamic declines (+dP/dt and −dP/dt), and reduced LV internal dimensions at end-diastole and end-systole. 44 , 50 Additionally, it successfully reversed DOX-induced electrocardiographic changes.…”

“…Subsequent to landmark studies demonstrating the cardioprotective effects of SGLT2 inhibitors in HF, numerous in vivo ( Table 2 ) and in vitro ( Table 3 ) studies, starting in 2019, have underscored the cardioprotective roles of SGLT2 inhibitors in mitigating cardiotoxicity induced by various cancer treatments, including DOX, 17 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 sunitinib, 20 trastuzumab, 21 cisplatin, 19 ipilmumab, 54 , 55 ponatinib, 56 and carfilzomib. 57 DOX has received particular attention because of its status as the most cardiotoxic cancer treatment and its widespread use.…”

“… 57 DOX has received particular attention because of its status as the most cardiotoxic cancer treatment and its widespread use. 32 Researchers have investigated several models of DOX cardiotoxicity, including acute 39 , 42 , 43 , 48 , 51 and chronic 17 , 39 , 41 , 46 , 47 , 48 cardiotoxicity, cardiorenal syndrome, 40 and conditions involving diabetic 44 and nondiabetic rodents. Empagliflozin 17 , 20 , 21 , 39 , 40 , 41 , 42 , 43 , 49 , 55 , 56 and dapagliflozin 44 , 45 , 46 , 48 , 50 , 51 , 52 , 53 , 54 , 56 have emerged as the most commonly used SGLT2 inhibitors, followed by canagliflozin.…”

“… 32 Researchers have investigated several models of DOX cardiotoxicity, including acute 39 , 42 , 43 , 48 , 51 and chronic 17 , 39 , 41 , 46 , 47 , 48 cardiotoxicity, cardiorenal syndrome, 40 and conditions involving diabetic 44 and nondiabetic rodents. Empagliflozin 17 , 20 , 21 , 39 , 40 , 41 , 42 , 43 , 49 , 55 , 56 and dapagliflozin 44 , 45 , 46 , 48 , 50 , 51 , 52 , 53 , 54 , 56 have emerged as the most commonly used SGLT2 inhibitors, followed by canagliflozin. 19 , 57 Notably, no in vivo studies have reported the protective effects of canagliflozin against DOX, with only 1 in vivo study reporting the cardioprotective effects of canagliflozin against cisplatin 19 and an in vitro study demonstrating its efficacy against carfilzomib.…”

“… Hu et al (2023) 50 Male C57BL/6 mice DOX (5 mg/kg, once a week for 4 wk, i.p.) DAPA (1.5 mg/kg/d for 4 wk, oral gavage) ↓ LVIDd and LVIDs, ↑ EF and FS ↓ Remodeling ↓ NLRP3 inflammasome ↓ Inflammatory markers (IL-6, IL-1β, and IL-18) Satyam et al (2023) 51 Female Wistar rats DOX (20 mg/kg, single dose, i.p.) DAPA (0.9 mg/kg/d for 8 d, oral gavage) Reversed DOX ECG changes ↓ CK-MB, AST Quagliariello et al (2023) 52 Female C57BL/6 mice DOX (2.17 mg/kg for 10 d, i.p.)…”