COPENHAGEN — Two-year data on the only approved inhaled-insulin treatment show that it has minimal adverse effects on pulmonary function, according to two new studies supported by Pfizer Inc., which manufactures the product (Exubera).

“It's safe, effective, and easy,” said Dr. Jay Skyler, who presented one of the studies at the annual meeting of the European Association for the Study of Diabetes. The findings offer reassuring evidence about possible effects on pulmonary function, which “lots of people have been concerned about,” he said in an interview. Two previous short-term studies (12 and 24 weeks) of inhaled insulin in patients with type 1 diabetes showed similar findings, but a longer-term study was needed, he added.

Dr. Skyler's study involved 580 patients with type 1 diabetes who were 18–65 years of age and had normal lung function. All were treated with basal insulin and were randomized either to subcutaneous prandial insulin (290 patients) or to inhaled prandial insulin (290 patients) three times daily for 2 years. The primary end point of the study was pulmonary function; secondary end points included blood sugar levels (HbA_1c), fasting plasma glucose (FPG), hypoglycemia, and body weight.

The data showed slightly decreased pulmonary function (less than 2% of baseline values) in subjects using inhaled insulin, compared with subcutaneous insulin. “The changes were small, occurred early [by 3 months], and did not progress,” said Dr. Skyler, who is a professor in the division of endocrinology, diabetes, and metabolism at the University of Miami.

The incidence of cough was more common in people using inhaled therapy (38% vs. 13%); however, it was predominantly a mild cough that was rarely productive and rarely occurred at night. “Other studies have shown this small change in pulmonary function reverses when the medication is stopped. We are stopping the medication now and then plan to resume it 6 months later to demonstrate this,” said Dr. Skyler.

HbA_1c levels were maintained in both groups throughout the study, but FPG levels were improved in the inhaled-insulin group, compared with the subcutaneous insulin group (from 170.1 to 156.8 mg/dL, compared with 166.9 to 173.5 mg/dL). The overall rate of hypoglycemic events was similar in both groups; however, there were fewer severe hypoglycemic events in patients using inhaled insulin (2.8 vs. 4.1 events per 100 subject-months, relative risk 0.67). In addition, patients using inhaled insulin experienced less weight gain than did patients using subcutaneous therapy (0.7 kg vs. 2.0 kg), he reported.

A striking difference between the two groups was the level of insulin antibodies, which was markedly elevated in the inhaled-insulin group, said Dr. Skyler. “Antibodies occur in response to any peptide that's given, and there is a greater proclivity to form antibodies anytime something is given across a mucosal surface. What's interesting in this study is that the antibodies went up, and started going down after a year.”

He said the issue is not whether antibodies form, but the fact that they had no adverse effect. “They don't impair the action of the insulin in any way or lead to any other adverse effect, and that's consistent with what we know about injected insulin as well.”

In addition to being the principal investigator for Pfizer on this study, Dr. Skyler has chaired Pfizer's global Exubera advisory board and has also worked with all the other companies that are developing inhaled insulin: Novo Nordisk Inc., MannKind Corp., Eli Lilly and Co., and Kos Pharmaceuticals Inc.

A second Pfizer study presented as a poster was designed identically but included 635 patients with type 2 diabetes, rather than type 1 disease. A total of 319 subjects were randomized to the inhaled-insulin arm, whereas 316 received subcutaneous therapy, reported Dr. William Cefalu, professor and chief of the division of nutrition and chronic diseases at the Pennington Biomedical Research Center in Baton Rouge, La., and colleagues. The center is affiliated with Louisiana State University.

For the same primary and secondary end points, the study's results were similar to those of the Miami study, except that all hypoglycemic events, including severe events, were comparable in both groups.

“These data support previous findings that Exubera is an appropriate treatment for adult patients with [type 2 diabetes]. Availability of Exubera may provide an opportunity to increase the acceptance of insulin therapy, and thus improve glycemic control” in patients with type 2 diabetes who are suboptimally controlled on oral agents, wrote the authors.

Dr. Cefalu has served as research investigator for several inhaled-insulin studies for Pfizer and on Pfizer's inhaled-insulin advisory boards. He has worked with all other companies developing inhaled insulin.

74003_fx1.sml

Patients who used inhaled insulin had slight decreases in pulmonary function that occurred early and did not progress. Cough was reported by 38%. Pfizer Inc

Inhaled Insulin Had Little Effect on Lung Function