## 4 Discussion  
In the present study, we compared the beneficial effects of metformin, glipizide, and their combination in diabetic rats and found that: (i) the treatment with the combination of metformin and glipizide was more potent than single therapy in improving glycemic control and attenuating oxidative stress, (ii) metformin was non-inferior to glipizide in improving glycemic control and attenuating oxidative stress; (iii) glipizide exhibited a more powerful effect against atherogenic dyslipidemia than metformin (only by increasing HDL levels but most notably by lowering LDL); and (iv) neither drug significantly affected creatinine levels or renal function, and metformin decreased urea levels further than glipizide or the combination, indicating that both drugs were safe at the prearranged doses. The study flowchart (Figure 7) represents all divided groups in the methodology. The rats were anesthetized and sacrificed after three months, and blood samples were collected from the medial annulus of the eye and a heart puncture. The HbA1C percent was determined using whole blood, while the lipid profile, renal function tests and oxidative stress biomarkers were determined using serum lipid peroxide, nitric oxide and total antioxidant capacity. Figure 6: The correlation coefficient between studied oxidative stress markers and FBG and cholesterol in all studied rats; (**A**) Total cholesterol vs NO, (**B**) Total cholesterol vs LPO, (**C**) Total cholesterol vs TAC, (**D**) Total FBG vs LPO, (**E**) FBG vs NO, and (**F**) FBG vs TAC. Data expressed as correlation coefficient (r) values and \(p\) < 0.001 indicates the significant difference between studied parameters. Lipid peroxidation represents oxidative lipid degradation. Meanwhile, oxidative stress plays a significant role in DM. One of the common treatments for type 2 diabetes is the combination of metformin and glipizide; however, the therapeutic benefits of this combination on oxidative stress, lipid profile and renal functions have not been thoroughly investigated. The antioxidant indices, including LPO, NO and TAC, were measured in this study. It is clear from the current study results that the parameters mentioned above were comparable in all studied populations. When comparing diabetic patients receiving combined therapy to those receiving metformin or glipizide monotherapy, the results were more efficient for the diabetic rats. Nowadays, oxidative stress in diabetes is considered the basis for the pathogenesis of all diabetes-related complications [51]. Glycemic control, lipoprotein profile and hepatoreal function in diabetic patients are all adversely affected by increased free radical production. The findings of this study showed that the administration of a combination of metformin and glipizide significantly improved oxidative stress status in patients with type 2 diabetes. The synergistic interaction between both drugs with different targets and mechanisms of action leads to an increase in the antioxidant capacity, insulin secretion and glucose uptake. This synergistic interaction results in control of oxidative stress damage effects, the lipid profile and glycemic status. The conclusive evidence of such a combination prevents the vascular complications of hyperglycemia (Figure 8). Figure 7: Scheme summarizes all the experimental groups, treatment and administration. A lipid profile assay is a blood analysis that checks fatty lipids and fatty substances in the body used as energy sources. Lipids include cholesterol, triglycerides, HDL, LDL, VLDL and AIP. Lipid profile evaluation is a significant tool in aiding the diagnosis and prognosis of DM [52]. This agrees with previous studies, including on the combinations of metformin and gliclazide (same class) [53; 54].