OBJECTIVE The Qatar Study was designed to examine the efficacy of combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with long-standing poorly controlled type 2 diabetesmellitus (T2DM) onmetformin plus a sulfonylurea. RESEARCH DESIGN AND METHODS The study randomized 231 patients with poorly controlled (HbA1c >7.5%, 58mmol/mol) T2DM on a sulfonylurea plus metformin to receive 1) pioglitazone plus weekly exenatide (combination therapy) or 2) basal plus prandial insulin (insulin therapy) to maintain HbA1c <7.0% (53 mmol/mol). RESULTS After a mean follow-up of 12months, combination therapy caused a robust decrease in HbA1c from 10.0 6 0.6% (86 6 5.2 mmol/mol) at baseline to 6.1 6 0.1% (43 6 0.7mmol/mol) compared with 7.160.1%(5460.8mmol/mol) in subjects receiving insulin therapy. Combination therapy was effective in lowering the HbA1c independent of sex, ethnicity, BMI, or baseline HbA1c. Subjects in the insulin therapy group experienced significantly greater weight gain and a threefold higher rate of hypoglycemia than patients in the combination therapy group. CONCLUSIONS Combination exenatide/pioglitazone therapy is a very effective and safe therapeutic option in patients with long-standing poorly controlled T2DM on metformin plus a sulfonylurea .