Background: Diabetes is associated with both micro- and macrovascular complications. Aim of the study: The aim of the present study is to evaluate the prophylactic effect of Sitagliptin, Pioglitazone and Dapagliflozine on Isoprenaline (ISO) induced myocardial infarction in type II diabetic rats, regarding these parameters: lipid profile, blood glucose, kidney function, troponin, MDA, tumor necrosis factor-α, HR, ST elevation and histopathological changes of myocardium. Methods: Rats were classified into: Group I: control normal group. Group II: was not treated diabetic (diseased group). Group III: was treated with sitagliptin. Group IV: was treated with pioglitazone. Group V: was treated with dapagliflozine. Treated groups received drugs for 4 weeks. Results: Treated groups showed significant improvement in all parameters and improvement of the histopathology of the myocardium. A significant improvement in the parameters was seen in the treated groups at the end of the 4^th week. Conclusion: Our study revealed that dapagliflozine produced more improvement in blood glucose level, and there was no significant difference between it and pioglitazone in improving lipid profile. Pioglitazone was superior in decreasing creatinine level, serum troponin, HR, ST elevation, MDA, TNFα and histopathological changes of myocardium. There was no significant difference between the three drugs regarding to their effect on blood urea. So our drugs ,mainly pioglitazone may have a prophylactic effect against MI in diabetic rats, this may be due to their antioxidant and anti-inflammatory effect through reduction of MDA and TNF α respectively, glycemic control and improvement of dyslipidemia.