Vildagliptin (LAF237 dihydrate;NVP-LAF 237 dihydrate) is a dipeptidyl peptidase 4 (DPP4) inhibitor that delays the degradation of glucagon-like peptide-1 (GLP-1). Treatment of obese diabetic mice with 1 mg/kg/day Vildagliptin or with 10 mg/kg/day valsartan for 8 weeks increases pancreatic islet β-cell density and stimulates islet β-cell proliferation while preventing apoptosis and islet fibrosis and decreasing superoxide production and nitrotyrosine formation. The combination of both compounds significantly magnifies the beneficial effect of either monotherapy. Valsartan or Vildagliptin pretreatment significantly increases plasma GLP-1 expression, reduces apoptosis of endothelial cells isolated from diabetic mice aorta. The expression of NADPH oxidase subunits also significantly decreases resulting in decreased superoxide production and ICAM-1 (fold change: valsartan : 7.5±0.7, P<0.05; LAF237: 10.2±1.7, P<0.05), VCAM-1 (fold change: valsartan : 5.2±1.2, P<0.05; LAF237: 4.8±0.6, P<0.05), and MCP-1 (fold change: valsartan: 3.2±0.6, LAF237: 4.7±0.8; P<0.05) expression. Moreover, the combination treatment with valsartan and Vildagliptin results in a more significant increase of GLP-1 expression. The decrease of the vascular oxidative stress and inflammation reaction is also higher than monotherapy with valsartan or Vildagliptin. Daily oral administration of Vildagliptin (5 mg/kg) alone or in combination with Pioglitazone (20 mg/kg) for 7 weeks significantly reduces blood glucose levels and HbA1c. It increases serum insulin levels and decreases serum glucagon. It also shows a strong anti-oxidant activity.