Background:The rational prescribing of second-line drugs in type 2 diabetes mellitus (DM) require clear guidelines. There is no sufficient empirical evidence to support the use of one second-line agent over the other and when to initiate second-line drug is still under discrepancy. Objectives: To analyze the utilization pattern and effectiveness of second-line agents in uncomplicated type 2 DM. Methodology: 240 uncomplicated type 2 DM patients who were ≥ 18 years receiving either metformin/sulfonylurea or metformin+sulfonylurea was divided into four add-on treatment group 1, 2, 3, 4; that were added pioglitazone, dipeptidyl peptidase-4(DPP-4) inhibitor, voglibose, and insulin [pre-mixed insulin (30%regular/70%NPH)] respectively and received the second-line agents for a duration of 6 months or longer. Effectiveness was based on the reduction in glycosylated hemoglobin (HbA 1C ), fasting plasma glucose (FPG) and postprandial blood glucose (PPBG) values over 3 and 6 months was done using repeated measures analysis of variance (ANOVA HbA 1C , FPG, and PPBG was statistically significant within each group at each time interval with p-value < 0.001. Conclusion: All the add-on groups exhibited a significant reduction in HbA 1C , FPG, and PPBG over 3 and 6 months. DPP-4 inhibitors exhibited least hypoglycemic episodes. DPP-4 inhibitors are trending and marginally more effective second-line OHA in uncomplicated type 2 DM. Key words: Anti-diabetic drugs, FPG, HbA 1C , PPBG, Second-line agents. Key message: The present study gives information on the effectiveness of second-line agents when used in combination with metformin or sulfonylurea or both in type-2 DM during clinical practice. This study gives a real-world evidence on the glycemic index achieved with second-line add-on drugs having good efficacy and tolerability over a period of 6-months.