Although inhaled insulin is comparable to injected insulin in controlling high blood sugar, its use should be reserved for diabetic patients who cannot or will not use needles, according to a new study.

That's because its long-term safety has yet to be established, says Lisa Ceglia, MD, of the Tufts-New England Medical Center in Boston, a researcher on the study.

"For the time being, the most worrisome concern is the effect inhaled insulin may have on lung function," Ceglia tells WebMD. The review article shows that one of the most common side effects of such therapy is increased coughing and a mild decrease in test scores that measure lung function.

"Are there other things to worry about? Possibly," Ceglia says. "But pulmonary toxicity is the issue we focused on because of the way the therapy is administered."

The findings are published in the November issue of the Annals of Internal Medicine.

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Short-Term Trials

Ceglia's team reviewed 16 trials of inhaled insulin involving 4,023 patients with type 1 or type 2 diabetes.

Most of the trials lasted only 12-24 weeks. The longest trial lasted two years. It evaluated Exubera, Pfizer Inc.'s inhaled insulin delivery system. Pfizer is a WebMD sponsor.

In January 2006, Exubera became the first new insulin delivery option to be approved by the FDA since insulin was discovered in the 1920s. Pfizer launched the drug in the U.S. market in September 2006.

"All of the trials were open-label, meaning that the patients knew what they were getting," Ceglia says. None of the trials used the so-called "double-dummy" technique, in which patients receive an inhaler and injections without knowing which one contains insulin.

Although that other technique may have produced more definitive results, it was not used because the trial designers considered it "logistically difficult and cumbersome."

"What these trials were designed to do is prove non-inferiority," says Larry Deeb, MD, president of medicine and science at the American Diabetes Association in Alexandria, Va. Deed was not connected with the study. "All Pfizer had to do was prove that inhaled insulin was as good as subcutaneous insulin, not that it was superior."

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Inhaled Insulin Worked

Ceglia's analysis showed that inhaled insulin was "comparable" to injected insulin in controlling blood sugar. Its effects were "just slightly less" than those of injected insulin, Ceglia says.

Though injected insulin had a small advantage over inhaled insulin in reducing blood sugar, the same number of patients on either therapy achieved a benchmark of diabetes control: a hemoglobin A1c level of less than 7 percent.

"Clearly, inhaled insulin is not an improvement over subcutaneous insulin, a drug [with] which we've had 80 years of experience," Deeb tells WebMD. "Doctors should tell patients who are already doing well on subcutaneous insulin that they shouldn't expect to do any better if they switch to inhaled insulin."

But Ceglia's analysis also showed high levels of patient satisfaction with inhaled insulin therapy.

She suggested this may be related to the "novelty of the new delivery method" and cautioned it remains to be seen if patients will be as enthusiastic and adherent to inhaled insulin therapy over the long term.

"It's exciting that this new therapy is out," Ceglia says. "It's been in development for a long time. We'll just have to wait and see how it goes."

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Safety Concerns

Ceglia's analysis doesn't raise any immediate alarm. "Certainly there was nothing in the first two years that was frightening," she says.

But that doesn't mean there are no concerns. Leading the list is inhaled insulin's long-term effect on lung function.

Even in the short term, patients on inhaled insulin are more than three times as likely as those on injected insulin to develop a dry cough. "This appears to be an immediate reaction to the inhalation and doesn't seem to progress over time," Ceglia says.

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Lung Damage?

More worrisome, patients on inhaled insulin were more likely than those on injected insulin to experience a mild decrease in lung function. The mild decrease in lung function happened early in the study and did not worsen over two years.

Another potential problem is severe hypoglycemic reactions, which were shown to be as likely with inhaled insulin as with injected insulin. That could be because inhaled insulin devices don't yet allow for finer dosing adjustments that may be necessary to avoid hypoglycemia, according to the study.

"Based on the trials we analyzed, we can't make any definitive conclusions about the safety of inhaled insulin," Ceglia says. "Like any new drug, however, inhaled insulin is going to have to be tested further and assessed for its long-term efficacy and safety."

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Because of long-term safety concerns, Ceglia's team recommends that inhaled insulin be reserved for patients without pulmonary problems, who oppose injections and would otherwise not receive appropriate and timely therapy for their diabetes.

When contacted by WebMD, Pfizer officials said they were reviewing Ceglia's analysis. They issued a statement reiterating their belief that Exubera "represents a major advance in the treatment of diabetes.

"In clinical trials, Exubera was found to be as effective as short-acting subcutaneous insulin injections, and to significantly improve blood sugar control when added to oral medications," the statement reads. "This is reflected in the Exubera product labeling in the United States and European Union."

By Rick Ansorge, reviewed By Louise Chang, MD

SOURCES: Lisa Ceglia, MD, division of endocrinology, diabetes, and metabolism, Tufts-New England Medical Center, Boston. Larry Deeb, MD, president of medicine and science, American Diabetes Association, Alexandria, Va. Pfizer statement from Rebecca Hamm, U.S. Pharmaceuticals Public Relations, Pfizer, New York. Ceglia, L. Annals of Internal Medicine, November 2006; vol 145: pp 665-675.