||Even though 50% of persons with type 2 diabetes are inadequately controlled on one oral agent 3 years after diagnosis, there is continued reluctance to start insulin until oral agent combinations fail. This is due in part to the fear, complexity and inconvenience of daily injections. To evaluate QOL and satisfaction when initiating insulin earlier using pulmonary delivery with Exubera®, we studied 470 type 2 diabetes subjects from Europe, Africa, Asia and South America, poorly controlled on metformin monotherapy and randomized to adding either premeal Exubera®, n=239 (INH) or glibencamide, n=231 (GLB) for 24 weeks. Randomization was stratified [HbA1c = 8-9.5% (LO) and > 9.5-12.0 % (HI)] and medications titrated to goal FPG of 80ϑ140 mg/dL. Patients were 57% male, and had mean±SD age=56±9 yrs, BMI=31.5±5.1 kg/m², and HbA1c=9.5±1.1%. Study discontinuation was 8% for INH and 12% for GLB, P=ns. Hba1c strata was a treatment effect modifier for change in HbA1c and QOL, both P=0.007, but not for satisfaction. In HI, baseline-adjusted Hba1c decreased more for INH (by 2.9±0.1%) than GLB (2.5±0.1%), P=0.01, but not in LO [INH (by 1.5±0.07%) vs GLB (1.6±0.08%)], P=ns. In HI, endpoint Overall QOL was more favorable for INH (468±5) than GLB (454±5), P=0.04, but this benefit was not evident in LO [INH (457±4) vs GLB (467±5)], P=0.08. This modifying effect was consistent across subscales of psychological well being (P=0.02) and vitality (P=0.04). Treatment satisfaction improved comparably between groups and across strata. Conclusions: For individuals failing metformin with HbA1c >9.5%, adjunctive Exubera® therapy exhibited superior glycemic control, improved QOL and comparable treatment satisfaction as compared to adjunctive glibencamide. Delays in using insulin for patients in poor control could lead to unnessary worsening in overall well being and quality of life. When initiated earlier, alternative pulmonary delivery of insulin with Exubera® offers the good glycemic control of insulin along with improved quality of life and patient acceptance.