Diabetes mellitus (DM) is defined as a chronic and metabolic disorder. It was approximated about 77 million Indians suffer from DM and it will be increased to 134 million by 2045. Diabetic mellitus can be treated by close control of glucose level which is main aim and target in management of this condition. Management of DM can be done by non-pharmacological and pharmacological approaches. The aim of this study is to compare the safety, efficacy and cost effectiveness of Glipizide-Metformin and Glimepiride-Metformin combination therapy in type 2 diabetes mellitus. In current research by use of prospective method in the cardiology department of Kongunad Multi-speciality Hospital, Coimbatore, in a period of six months from February 2021 to August 2021 we did research according to our aim and used ANOVA statistical test whenever it needed. Our study results demonstrate, the improvement in the addition of glimipride 2mg to metformin 500 mg has modest beneficial then glipizide 5 mg in terms of efficacy and cost. In terms of safety, both drugs are having similar safety profiles. Current research also assessed the medication safety by using the Naranjo scale.