Article Summary Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes. Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering K, Hendler R, Lan S-P, Cefalu WT. Ann Intern Med. 2005;143:549-558. Objective: To investigate whether inhaled insulin given as monotherapy or in combination with dual oral agent therapy can improve glycemic control in patients with type 2 diabetes after combination oral therapy has proved unsuccessful, to compare the effectiveness of inhaled insulin with that of dual oral agent therapy alone, and to assess the tolerability and safety of inhaled insulin treatment given over a 3-month period. Methods: An open-label, 12-week, parallel-group, multicenter, randomized trial was conducted in 48 outpatient centers in the United States and Canada. Included were male and female patients from 35 to 80 years of age who had been diagnosed with type 2 diabetes and whose hemoglobin A1c levels remained uncontrolled after a stable dual oral agent regimen had been followed for 2 months. Patients were randomly assigned to (1) take premeal inhaled insulin along with their existing oral combination regimen (n=102), (2) receive premeal inhaled insulin monotherapy (n=105), or (3) continue their existing regimen of oral agent combination therapy alone (n=102). The primary efficacy endpoint was change in hemoglobin A1c level from baseline to 12 weeks. Secondary endpoints included changes in fasting plasma glucose level and 2-hour postprandial glucose concentration, percentage of participants who achieved adequate or good glycemic control during the study, number and severity of hypoglycemic episodes, weight gain, and fasting lipid values. An analysis of covariance model was used to assess treatment group differences. Results: Reductions in hemoglobin A1c level at 12 weeks were significantly greater with both inhaled insulin treatments compared with oral agent therapy alone (1.67 vs 1.18 percentage points, [these are differences in mean adjusted a1c] respectively; P<0.001). A hemoglobin A1c level less than 8.0% was achieved by 86 patients (86.0%) in the inhaled insulin plus oral combination regimen, 57 (55.9%) of those who received inhaled insulin alone, and 18 (18.8%) of patients given only the oral combination treatment. At week 12, fasting plasma glucose levels and 2-hour postprandial glucose concentration were reduced to a greater extent and mean body weight showed greater increases in the inhaled insulin treatment groups. Rates of overall hypoglycemia were 1.7 and 1.3 in the inhaled insulin plus oral combination and the inhaled insulin monotherapy groups, respectively, and 0.1 in the combined oral treatment group. Mean changes from baseline in fasting lipid levels were similar among all groups; however, triglyceride levels decreased in both inhaled insulin groups and increased in the oral agent combination alone group. Over 3 months of treatment, inhaled insulin was well tolerated. The most commonly reported adverse event with inhaled insulin treatment was treatment-related hypoglycemia. Conclusions: This study demonstrated that inhaled insulin is an effective agent for patients with type 2 diabetes who have been unable to attain glycemic control (ie, hemoglobin A1c, fasting and postprandial glucose levels, and triglycerides) with oral combination treatment alone. The effectiveness of inhaled insulin improves when it is combined with oral agents; with this combination, glucose control is enhanced, fasting glucose concentrations are reduced, and glucose-lowering effects are sustained beyond the postprandial period. Inhaled insulin therapy was well tolerated in this study, with hypoglycemia and weight gain reported. Inhaled insulin had no reported effect on pulmonary function.