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

Priscilla A. Hollander, MD


March 05, 2007

Long-term Use of INH Is Safe and Well Tolerated

INH has been shown to be safe and well tolerated with long-term use in several different clinical trials.[16,17,18,22,23,25,26,29,30]

Overall, the incidence and severity of hypoglycemia with INH are similar to that seen with SC human insulins. There are no published studies currently available comparing INH with insulin analogs (eg, insulin lispro); however, studies are under way to enable efficacy and safety comparisons between INH and insulin analogs in the future. Although there has been a trend of lower fasting blood sugar levels with INH, there have been no reports in the literature that indicate an increased incidence of nocturnal hypoglycemia with INH. In the 3 studies comparing INH with standard SC insulin regimens in patients with type 1 diabetes, the overall risk for hypoglycemia was slightly lower for patients receiving INH. In the study by Quattrin and colleagues,[18] the incidence of hypoglycemia was 8.6 events/patient-month with INH compared with 9.0 events/patient-month with the SC insulin regimen (relative risk [RR] = 0.96). Similar results were seen in the study by Skyler and colleagues[22] (9.3 events/patient-month vs 9.9 events/patient-months with the SC insulin regimen; RR = 0.89). In the study comparing INH with an SC insulin regimen in patients with type 2 diabetes, the overall incidence of hypoglycemia was 1.4 events/patient-months vs 1.6 events/patient-months with the SC insulin regimen (RR = 0.89).[17] The incidence of severe hypoglycemic events was low in all of these studies (ie, ≤ 6.5 events/100 patient-months), and was not significantly different between treatment groups.[17,18,22]

In the studies comparing INH with OA therapy in patients with type 2 diabetes, the overall incidence of hypoglycemia was generally low, with ≤ 1.7 episodes/patient-months reported.[16,23,25,26] Although the rates of hypoglycemia episodes were higher with INH than with OA therapy, rates of hypoglycemia were considered comparable to those seen with SC insulin. Given the improved HbA1c values with INH vs OAs, it is not unexpected to see a slightly higher rate of hypoglycemia in the INH group.[16,25,26]

Numerous clinical trials have shown that INH is associated with small changes in pulmonary function (forced expiratory volume in 1 second [FEV1] and carbon monoxide diffusing capacity [DLCO]) that are not progressive, are reversible, and have not been associated with clinical changes.[12,16,17,18,22,23,25] In clinical studies of INH in patients with type 1 or type 2 diabetes, the average mean treatment group differences in the FEV1 were approximately 40 mL over 2 years from a baseline of 3 L.[31] These changes occurred early (by the third month of treatment) and did not progress over the remaining 2-year follow-up. Further, in patients with type 2 diabetes, these changes reversed to that of comparator treatment group levels 6 weeks after discontinuation of INH. The reversibility of pulmonary function changes after long-term treatment with INH has not been studied in patients with type 1 diabetes. In type 1 diabetes, treatment group differences in the mean change from baseline in DLCO after 2 years of treatment were approximately 0.5 mL/minute/mm Hg in patients, favoring SC insulin over INH, and approximately 0.1 mL/minute/mm Hg in type 2 diabetes in favor of INH. Additional, comprehensive, long-term studies are needed to verify pulmonary safety of INH use greater than 2 years and to determine any long-term risks.

Mild-to-moderate cough has been reported in approximately 21% to 31% of patients receiving INH; however, the incidence and prevalence of cough generally decreased over time, and few patients (approximately 1%) have discontinued treatment due to cough.[12,16,17,18,22,23,25]

Because smoking has been shown to increase the permeability of the alveolar-capillary barrier,[32,33] inhaled insulin dose requirements may be lower in smokers. Thus, the effects of smoking cessation on the absorption of INH have been compared in smoking (n = 38) and nonsmoking volunteers (n = 30).[34] At baseline, the smokers had 5-fold higher peak insulin concentrations, 3-fold higher total insulin exposure, and a more rapid time to peak insulin concentration than their nonsmoking counterparts (31 minutes vs 53 minutes in nonsmokers). Three weeks after quitting smoking, however, peak insulin concentrations and total insulin exposure had decreased to 49% and 59% of the levels seen while they were still smoking. After 13 weeks, the changes in inhaled insulin absorption had been partially reversed by quitting smoking.[34] Although further study is necessary to determine the clinical implications of these findings, patients should be encouraged to quit smoking prior to initiation of therapy with INH, as patients who were current smokers or who had smoked in the previous 6 months were excluded from participation in the clinical study program.

Another potential concern with INH includes the development of increased levels of insulin antibodies compared with SC insulin use. The insulin antibodies associated with INH are structurally identical (primarily immunoglobulin [Ig]G) to those seen in response to SC insulin administration. Long-term studies have shown that insulin antibody levels plateau by 12 months of treatment, and that insulin antibody titers rapidly decline after discontinuation of INH.[29] Of interest, no correlation has been observed between insulin antibody concentrations and HbA1c concentrations, and FPG concentrations, PPG concentrations, the incidence of hypoglycemia, insulin dose or serum concentration, the incidence of allergic and/or respiratory adverse events, or lung function.[29,30]

The use of INH is not recommended for patients with underlying lung diseases (eg, asthma or chronic obstructive pulmonary disease [COPD]) because the safety and efficacy of INH in this population have not been established, and is contraindicated in patients with unstable or poorly controlled lung disease because of the potential for wide variations in lung function to affect the absorption of INH and subsequently increase the risk for hypoglycemia or hyperglycemia.[31] A study in nondiabetic subjects[31] showed that the absorption of INH was 20% lower in those with mild asthma (without bronchodilator treatment) compared with those without asthma, whereas the absorption was approximately 2-fold higher in nondiabetic subjects with COPD compared with those without COPD. The administration of a bronchodilator (ie, albuterol) 30 minutes before INH resulted in a 25% to 50% mean increase in insulin AUC and Cmax in nondiabetic subjects with mild (n = 36) and moderate (n = 31) asthma.

There do not appear to be any differences in the pharmacokinetics of INH in patients over the age of 65 years compared with their younger counterparts.[31] Combined safety data from controlled phase 2/3 studies[31] in which INH was administered to patients with type 1 or type 2 diabetes (n = 1975; most had type 2 diabetes) included 266 patients ≥ 65 years of age, and 30 patients were ≥ 75 years of age. There were no differences in changes in HbA1c or the rate of hypoglycemia according to age.


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