Background: Metformin when used in combination with other drugs such as Tenegliptin, voglibose and glimepiride is effective and well tolerated in diabetes management. The aim of the study was to compare the efficacy and safety of combination of metformin with Tenegliptin, voglibose and glimepiride in patients with type 2 DM. Methods: In this prospective, randomized clinical trial study 150 patients were included. The patients were divided into three groups, each group comprising of 50 patients. In all the patients fasting plasma glucose, 2 hours postprandial plasma glucose, and hemoglobin A1c (HbA1c) level were assessed before starting the treatment and after completion of the treatment. Group I consisted of patients who were prescribed metformin 500 mg with Tenegliptin 20 mg, in Group II, consisted of patients who were prescribed metformin 500 mg with voglibose 0.2 mg, and Group III, consisted of patients who were prescribed metformin 500 mg with glimepiride 1 mg. The outcome of the therapy was based on the level of improvement in the blood parameters. Results: There was a significant reduction of HbA1c, fasting plasma glucose and 2 hours postprandial plasma glucose levels at the start and after 12 weeks of treatment in all the groups. Intergroup comparison between both the groups revealed no significant difference in terms of glycaemic control. Conclusion: From above results it was concluded that all three groups have equal efficacy in controlling the fasting plasma glucose, 2 hours postprandial plasma glucose and HbA1c level.