Evolution of a Pulmonary Insulin Delivery System ( Exubera) for Patients With Diabetes

Priscilla A. Hollander, MD

Disclosures

March 05, 2007

Clinical Efficacy of INH

Clinical studies have shown that INH consistently improves glycemic control in patients with type 1 or type 2 diabetes,[16,17,18,19] and consistent with our shorter-term studies, 2 recent studies have demonstrated that INH provides sustained glycemic control with better fasting plasma glucose (FPG) levels and less weight gain than SC insulin when given to type 1[20] (75.1-75.9 kg vs 73.8-75.8 kg) or type 2[21] (87.1-88.8 kg vs 88.4-91.4 kg) diabetes patients over a 2-year period. Moreover, when used in combination with longer-acting SC insulin, INH reduces the number of daily injections needed while providing similar glycemic control to that of standard basal-bolus insulin regimens.

Two 24-week, open-label, randomized, multicenter studies have compared preprandial administration of INH in combination with longer-acting SC insulin with standard basal-bolus insulin regimens in patients with type 1 diabetes.[18,22] In the first of these studies by Quattrin and colleagues,[18] patients were randomly assigned to receive treatment with either preprandial INH plus bedtime ultralente insulin (n = 170) or 2-3 daily SC injections of regular and NPH insulin (n = 164). Mean decreases in HbA1c at week 24 were comparable for both treatment groups, with similar proportions of patients in each group achieving HbA1c levels < 7% ( Table ). Treatment with INH also resulted in a greater mean reduction in FPG (35-mg/dL reduction vs 10 mg/dL with the standard SC insulin regimen) and postprandial glucose concentrations (PPG; -30 mg/dL vs +1 mg/dL, respectively).[18]

In the second study by Skyler and colleagues,[22] patients were randomly assigned to receive treatment with either preprandial INH plus morning and evening SC injections of NPH insulin (n = 163) or preprandial regular SC insulin plus morning and evening NPH insulin injections (n = 165). As in the previous study, mean decreases in HbA1c at week 24 were comparable for both treatment groups, with similar proportions of patients in each group achieving HbA1c levels < 7% ( Table ). Patients in the group receiving INH demonstrated greater mean reductions in FPG than those receiving the regular/NPH SC insulin regimen (-35 mg/dL vs +4 mg/dL, respectively), whereas mean reductions in PPG were comparable for both treatment groups (-21 mg/dL vs -14 mg/dL, respectively).[22]

Several clinical studies have also demonstrated that INH provides effective glycemic control in patients with type 2 diabetes, in combination with longer-acting insulins or oral antihyperglycemic agents (OAs), or alone in patients who have not achieved adequate glycemic control with prior OA therapy.

In a 12-week study conducted by Cefalu and colleagues,[23] patients (N = 26) who were switched to INH in combination with bedtime ultralente SC insulin injections had significantly improved mean HbA1c concentrations compared with baseline (mean reduction, 0.7%), having received standard SC insulin regimens (ie, 2-3 insulin injections daily) prior to study enrollment. These findings were confirmed in a larger, 24-week, phase 3 study conducted by Hollander and colleagues[17] in patients who had previously received multiple daily insulin injections (≥ 2 injections daily).

Patients were randomly assigned to 6 months of treatment with preprandial INH plus bedtime ultralente insulin (n = 149) or a conventional SC insulin regimen that included regular and NPH insulin (n = 150).[17] In this study, the INH regimen provided a mean reduction in HbA1c comparable to that of regular/NPH insulin (0.7% vs 0.6%, respectively; Table ). Of note, significantly more patients receiving the INH regimen were able to achieve HbA1c concentrations < 7% (46.9% vs 31.7% of patients receiving the regular/NPH SC insulin regimen; odds ratio 2.27, 95% confidence interval [CI],1.24-4.14) or < 6.5% (28.7% vs 17.2%, respectively; Table ).[17,24] A significantly greater decrease in mean FPG was seen with the INH-containing regimen, with an adjusted mean difference between treatments of -16 mg/dL (95% CI, -27 mg/dL to -5 mg/dL). The adjusted mean difference in PPG concentrations was also numerically in favor of INH (-9 mg/dL, 95% CI, -17 mg/dL to 8 mg/dL).[17]

In a randomized, controlled study conducted by Weiss and colleagues,[25] patients (N = 68) with type 2 diabetes who had OA therapy were treated for 12 weeks with either their prestudy OA (sulfonylurea and/or metformin) therapy or prestudy OA therapy plus INH. The addition of INH to the existing OA regimen improved glycemic control compared with continuing the existing OA regimen alone ( Table ). Mean HbA1c concentration was reduced by 2.3% in the group receiving INH, compared with only 0.1% in the group receiving OAs alone (P < .001), and 34% of patients in the INH group achieved HbA1c < 7%, compared with 0% of patients receiving OAs alone. INH treatment was also associated with a significantly greater reduction in FPG, with a difference of -61 mg/dL between adjusted mean changes from baseline for each treatment group (P < .001).[25] The postprandial increase in plasma glucose was significantly lower in patients receiving INH plus OAs than in those receiving OAs alone (P = .02).[25]

In another 12-week, randomized, comparative study, patients who were unable to achieve glycemic control (ie, HbA1c remained > 8%) with diet and exercise alone were treated for 3 months with either INH (n = 76) or rosiglitazone (n = 69), in conjunction with a regimen of diet and exercise.[16] INH provided improved glycemic control compared with rosiglitazone ( Table ). The absolute reduction in HbA1c was greater with INH than with rosiglitazone (-2.3% vs -1.4%), and significantly more patients achieved the HbA1c goals recommended by the ADA and AACE. Mean final HbA1c concentrations were 7.2% with INH and 8.0% with rosiglitazone, respectively.

The efficacy of INH has also been evaluated in combination with dual OA therapy. In a 12-week, randomized, comparative study, patients (N = 309) with type 2 diabetes who had baseline HbA1c levels of 8% to 11% and were receiving dual OA therapy (with both an insulin secretagogue and insulin sensitizer) were randomly assigned to treatment with either preprandial INH added to existing OA therapy (n = 103), preprandial INH alone (n = 104), or continued OA therapy alone (n = 99) for 12 weeks.[26] Baseline mean HbA1c values were 9.2%, 9.3%, and 9.3% in each of the 3 treatment groups, respectively.

Consistent with the results of the previously described studies, INH improved overall glycemic control and HbA1c levels when added to or substituted for dual OA therapy ( Table ).[26] Mean HbA1c decreased by 1.9 percentage points in the group treated with INH and OAs, by 1.4 percentage points in the group receiving INH alone, and by 0.2 percentage points in patients continuing dual OA therapy. A larger proportion of patients receiving INH were able to achieve HbA1c concentrations < 7%: 32.0% of those receiving INH plus OAs, and 16.7% of those receiving INH alone achieved this goal compared with only 1% of patients receiving dual OA therapy alone ( Table ).[26] Furthermore, significantly greater reductions in FPG and PPG levels were seen in the group receiving INH. The adjusted mean difference in FPG between INH plus OAs and OAs alone was -53 mg/dL (95% CI, from -66 mg/dL to -44 mg/dL), whereas the adjusted mean difference in PPG between these 2 groups was -76 mg/dL (95% CI, from -93 mg/dL to -58 mg/dL). The adjusted mean difference in FPG between the groups receiving INH alone and OAs alone was smaller: -24 mg/dL (95% CI, from -36 mg/dL to -11 mg/dL), whereas the adjusted mean difference in PPG between these 2 groups was -62 mg/dL (95% CI, from -79 mg/dL to -45 mg/dL).[26]

Patients with type 1 diabetes are currently being recruited for a study to determine simple, safe, and effective guidelines for the titration of the dose of inhaled insulin. Additionally, future trials comparing INH with insulin analogs or trials that evaluate the combination of INH with long-acting insulin analogs might better define the role of INH in the treatment of diabetes.

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