Inhaled Insulin Less Effective in Diabetics With Lung Ailments

COPENHAGEN — Inhaled insulin is less effective in diabetic patients with chronic lung conditions such as asthma and chronic obstructive pulmonary disease, compared with patients who have healthy lungs, according to data from two industry-sponsored studies presented at the annual meeting of the European Association for the Study of Diabetes.

However, in patients with mild asthma, predosing with a bronchodilator can result in inhaled insulin exposures similar to those for patients without asthma.

The asthma study was supported by Pfizer, manufacturer of the only approved inhaled insulin treatment, Exubera. Eli Lilly & Co. supported the other study.

Exubera is not approved for use in diabetic patients with asthma or chronic obstructive pulmonary disease (COPD), said Robert J. Fountaine, Pharm.D., of Pfizer's department of global research and development, who presented the Exubera study. Studies are under way to support long-term safety and efficacy in those patients.

Dr. Fountaine's open-label crossover study included 67 nondiabetic subjects with asthma: 30 with moderate asthma (those with a mean unmedicated forced expiratory volume [FEV1] of between 50% and 80% of predicted values); and 37 with mild asthma (defined as between 80% and 100% of predicted values). Also included were 19 healthy, nonasthmatic subjects.

All nonasthmatic subjects received inhaled insulin (3 mg) alone on days 1 and 3, whereas the asthmatic subjects received one of the following regimens in a randomized sequence on days 1, 3, 5, and 7: inhaled insulin alone, 180 mcg of the bronchodilator albuterol (a short-acting β-agonist) followed by inhaled insulin 30 minutes later, albuterol followed by inhaled insulin 10 minutes later, or the inhaled corticosteroid fluticasone (440 mcg) followed by inhaled insulin 30 minutes later.

Investigators collected blood samples at set times, beginning 30 minutes before insulin dosing until 360 minutes after, from which serum insulin and C-peptide levels were calculated. They also performed spirometry before and 10 minutes after each inhaled insulin dose, and before and 30 minutes after each albuterol dose.

The results showed that in the absence of albuterol, pulmonary absorption of inhaled insulin was reduced in patients with mild to moderate asthma, compared with nonasthmatic patients, said Dr. Fountaine. However, prior dosing with albuterol 30 minutes before insulin inhalation increased insulin absorption by 25%–35% in patients with mild asthma (resulting in absorption rates that approximated those in healthy subjects) and by 45%–50% in those with moderate asthma (resulting in absorption rates that were still lower than those seen in nonasthmatic subjects). The administration of fluticasone before inhaled insulin did not adversely affect insulin pharmacokinetics, and spirometry testing showed that inhaled insulin did not interfere with the efficacy of albuterol, he said.

The Lilly-sponsored study evaluated the company's inhaled insulin system, AIR, which is still under development. It found a reduced metabolic effect of inhaled insulin in nondiabetic patients with COPD, compared with healthy patients and compared with subcutaneous insulin administration, said Dr. Klaus Rave of Profil Institut für Stoffwechselforschung in Neuss, Germany.

The study included 15 subjects with healthy lungs and 27 with COPD, of whom 13 had chronic bronchitis and 14 had emphysema. All received two separate doses of inhaled insulin (5.2 mg each) and one dose of subcutaneous insulin (12 U). A euglycemic glucose clamp was used to assess glucodynamic responses, and serum insulin measurements were used to assess pharmacokinetics. Pulmonary function tests and spirometry were also performed.

The results showed that although total insulin exposure and metabolic effect was similar in all subjects after subcutaneous insulin, it was reduced after inhaled insulin in patients with COPD. Insulin exposure after inhaled insulin was cut by 22% in those with emphysema and by 44% in those with chronic bronchitis, compared with healthy subjects. The metabolic effect of inhaled insulin was reduced by 33% in those with emphysema and by 40% in those with chronic bronchitis.

There was no difference in pulmonary function tests done before and after inhaled insulin, but spirometry results showed an FEV1 decline after inhaled insulin and insulin administered subcutaneously, warranting a long-term safety evaluation of inhaled insulin in COPDpatients.