Project Summary/Abstract The current ADA/EASD recommendation for glucose control in newly diagnosed T2DM patients who are free from CVD and renal disease is to start on metformin and sequentially add other glucose lowering agents upon metformin failure to maintain HbA1c <7.0%. The recently completed GRADE study, which had tested the efficacy of 4 glucose lowering agents (sitagliptin, glimepiride, liraglutide and glargine insulin) in maintaining the treatment goal in metformin failing T2DM patients, has demonstrated that the vast majority (67-75%) failed to maintain the treatment goal at 5 years, suggesting of inability of sequential add on approach on maintaining durable reduction in the HbA1c. Initial combination therapy is an alternative therapeutic approach for glucose control in T2DM patients. The VERIFY study has demonstrated that subjects initiated on combination of metformin plus vildagliptin had 26% lower failure rate than subjects started on metformin and had vildagliptin added in metformin-failing subjects. Nonetheless, 43% of subjects receiving initial combination of metformin plus vildagliptin failed to maintain HbA1c <7.0% at 5 years. We have demonstrated in EDICT study that, initial combination therapy with agents that correct known pathophysiologic defects present in T2DM will produce durable reduction in the HbA1c. Initial combination with pioglitazone plus exenatide BID produced long lasting reduction in the HbA1c in patients with T2DM and 68% of subjects maintained HbA1c <6.5% at 6 years. Nonetheless, this combination had some limitations. Approximately, one third of subjects failed to maintain the treatment goal and bone mineral density has decreased in women > 50 years. These limitations can be avoided by using dual GLP-1 /GIP agonist in combination with pioglitazone. Thus, the present study is a comparative effectiveness study comparing the efficacy and durability of HbA1c reduction by two initial combination therapies, one therapy (pioglitazone