Objective: To examine the efficacy and safety of combination therapy with exenatide plus pioglitazone vs basal/bolus insulin in patients with poorly controlled type 2 diabetes mellitus (T2DM) with very high hemoglobin A1c (HbA1c) (.10%) receiving sulfonylurea plus metformin and with a long duration of disease. Design and Participants: Participants (n = 101) in the Qatar Study with very poor glycemic control (HbA1c .10%) and a long duration of diabetes (10.9 years) receiving maximum/near-maximum doses of sulfonylurea plus metformin were randomly assigned to receive pioglitazone plus weekly exenatide (combination therapy), or basal plus prandial insulin (insulin therapy), to maintain HbA1c ,7.0%. Results: Baseline HbA1c was 11.5% 6 0.2% and 11.2% 6 0.2% (P = not significant) in combination therapy and insulin therapy groups, respectively. At 6 months, combination therapy caused a robust decrease in HbA1c to 6.7%60.1% ( =24.8%) compared with 7.4%60.1% (=23.8%) in subjects receiving insulin therapy. Combination therapy was effective in lowering the HbA1c independent of sex, ethnicity, or body mass index. Subjects in the insulin therapy group experienced significantly greater weight gain and a 2.5-fold higher rate of hypoglycemia compared with patients receiving combination therapy. Conclusion: Exenatide/pioglitazone combination therapy is an effective and safe therapeutic option in patients with poorly controlled T2DM receiving metformin plus sulfonylurea with very high HbA1c (.10%).