Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) effects on cardiac ischemia/reperfusion (I/R) injury are unclear. Unlike SGLT2-i, dipeptidyl peptidase 4 inhibitors (DPP4-i) have shown effective cardioprotection in cardiac I/R injury. We aimed to investigate whether SGLT2-i reduces myocardial dysfunction and myocardial injury to a greater extent than DPP4-i in obese insulin-resistant rats with/without cardiac I/R injury. The high-fat (HF) diet-induced obese insulin-resistant rats were divided into 4 groups and received the following treatments for 28 days: vehicle (HFV); vildagliptin at a dosage of 3 mg/kg/day (HFVil); dapagliflozin at a dosage of 1 mg/kg/day (HFDa) and combination drugs (HFDaVil). At the end, I/R injury was induced by a 30-min left anterior descending coronary occlusion and 120-min reperfusion. Dapagliflozin showed a greater efficacy than vildagliptin in improving the metabolic impairments, low frequency/high frequency (LF/HF) ratio, systolic blood pressure and left ventricular (LV) function in comparison to HFV rats. In cardiac I/R injury, dapagliflozin had a greater efficacy than vildagiptin in decreasing mitochondrial DRP1, cleaved caspase 3, LV dysfunction and infarct size in comparison to HFV rats. However, the combined therapy showed the greatest efficacy in attenuating LV dysfunction, mitochondrial DRP1 and infarct size in comparison to HFV rats. In conclusion, dapagliflozin has a more pronounced effect than vildagliptin in obese insulin-resistant rats for the improvement of LV function. In rats with cardiac I/R injury, although dapagliflozin had a greater efficacy on cardioprotection than vildagliptin, the combined therapy exerted the highest cardioprotective effects potentially by reducing mitochondrial fission.

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Long-term high-fat diet (HFD) consumption causes cardiac dysfunction. Although calorie restriction (CR) has been shown to be useful in obesity, we hypothesized that combined CR with dipeptidyl peptidase-4 (DPP-4) inhibitor provides greater efficacy than monotherapy in attenuating cardiac dysfunction and metabolic impairment in HFD-induced obese-insulin resistant rats. Thirty male Wistar rats were divided into 2 groups to be fed on either a normal diet (ND, n = 6) or a HFD (n = 24) for 12 weeks. Then, HFD rats were divided into 4 subgroups (n = 6/subgroup) to receive just the vehicle, CR diet (60% of mean energy intake and changed to ND), vildagliptin (3 mg/kg/day) or combined CR and vildagliptin for 4 weeks. Metabolic parameters, heart rate variability (HRV), cardiac mitochondrial function, left ventricular (LV) and fibroblast growth factor (FGF) 21 signaling pathway were determined. Rats on a HFD developed insulin and FGF21 resistance, oxidative stress, cardiac mitochondrial dysfunction and impaired LV function. Rats on CR alone showed both decreased body weight and visceral fat accumulation, whereas vildagliptin did not alter these parameters. Rats in CR, vildagliptin and CR plus vildagliptin subgroups had improved insulin sensitivity and oxidative stress. However, vildagliptin improved heart rate variability (HRV), cardiac mitochondrial function and LV function better than the CR. Chronic HFD consumption leads to obese-insulin resistance and FGF21 resistance. Although CR is effective in improving metabolic regulation, vildagliptin provides greater efficacy in preventing cardiac dysfunction by improving anti-apoptosis and FGF21 signaling pathways and attenuating cardiac mitochondrial dysfunction in obese-insulin-resistant rats.