Inhaled Insulin Shows Short-term Safety

The pulmonary safety of the first inhaled insulin on the market is still holding up after 3 years, according to two studies presented at the American Diabetes Association's 67th Scientific Sessions, held June 22–26 in Chicago.

While many physicians familiar with the research agree that Exubera, manufactured by Pfizer Inc., may be a plus for needle-phobic patients who need insulin, the new safety data allay some—but not all—concerns about the novelty diabetes therapy, critics say.

Since its approval in January 2006, some physicians have expressed concerns about Exubera—a rapid-acting human insulin for preprandial use. One fear is that Exubera could potentially have negative effects on lung function that could even lead to progressive damage or tumors. Some physicians note that Exubera's safety cannot be compared with that of other drugs delivered via the lungs, like anti-inflammatory asthma therapies, because insulin is a growth protein and could possibly even trigger an immune response.

Inhaled Insulin

According to the two recent open-label studies, adverse pulmonary effects linked to Exubera are minor, occur early, and are nonprogressive at 3 years. The studies examined lung function in two groups of about 600 patients in whom Exubera was stopped and restarted. One group included patients with type 1 diabetes; the other included patients with type 2 diabetes. The studies' findings are consistent with those of earlier analyses.¹

When patients with type 1 or type 2 diabetes switched from a combination of Exubera and injected insulin regimen after 2 years to a straight subcutaneous regimen for 6 months, decrements in patient lung function completely reversed.^2,3 Subsequently, when preprandial Exubera was re-instituted for 6 months, patients did reexperience small decrements in lung function. But these effects remained minor and nonprogressive during a 6-month follow-up. Meanwhile, the comparative treatment groups maintained similar levels of glycemic control and hypoglycemia throughout.

“These data give an added level of comfort about pulmonary safety,” says Jay Skyler, MD, study co-author and associate director of the Diabetes Research Institute at University of Miami Miller School of Medicine. “In fact, with so many patients still unwilling to adequately control their blood glucose with injected insulin, I question why many of them haven't tried this option.”

ONGOING QUESTIONS AND CONCERNS

Despite the accumulated lung-safety data thus far, and the many studies suggesting patients prefer inhaled insulin over preprandial injections, physicians have not wholeheartedly embraced Exubera.^4–6 Persistent roadblocks include higher costs than for injectable insulin, insurance coverage inconsistencies, question-able efficacy at achieving optimal glycated hemoglobin (A1C) levels, and a delivery device (about the size of a standard flashlight) that is relatively bulky compared with the new breed of smaller insulin needles and pens.

Exubera represents just one of every 500 prescriptions written for insulin in the U.S., according to a New York Times business report last spring.⁷

A large part of the ongoing concern appears to stem from a lack of data on Exubera's pulmonary effects beyond 3 years.

“As far as safety, it's clear now that any changes in pulmonary function from inhaling insulin are small and reversible over 3 years, but no one knows yet how they'll play out after 5, 10, or 20 years,” says endocrinologist David Nathan, MD, director of the Diabetes Center at Massachusetts General Hospital and professor of medicine at Harvard Medical School in Boston.

A few years of experience with a novel drug like Exubera are not enough to guarantee that it is truly risk-free, asserts Irl B. Hirsch, MD, director of the Seattle-based Diabetes Care Center at University of Washington Medical Center. That's especially true, he says, for patients diagnosed with diabetes at an early age—a group that often needs insulin therapy every day for decades.⁸ Hirsch is waiting for more long-term data on Exubera's effects to see if prescribing it would be appropriate for such patients.

Unlike other aerosolized medications administered through the lungs, insulin is a protein with potent growth-promoting properties and the potential for triggering an immune response in the airways, says Hirsch. Because only about 10 percent of this dry-powdered insulin is actually bioabsorbed, >10 times the required amount of insulin must be inhaled to achieve a proper dosage, Hirsch explains.⁸

These properties raise concerns that repeatedly inhaling insulin particles could cause dangerous cumulative insults, increasing patients' risks for fibrosis or lung tumors, he says.

Skyler says that ongoing clinical trials have not revealed evidence of such risks.

“Honestly, I'm amazed that people still raise these concerns [about long-term risks] because they are highly unlikely on a statistical basis,” he says. He believes the chances of Exubera posing progressive lung problems are so slim, they're irrelevant.

“The surface area of the lung is about the size of a tennis court, and each time you use inhaled insulin, it's like hitting that tennis court with an amount of material that has the surface area of a handkerchief or less,” Skyler explains. “Then that material is disseminated.”

A GODSEND FOR SOME?

Other important questions about inhaled insulin remain, researchers say. For example, can patients using inhaled insulin lower their A1C to levels recommended by ADA as well as they can with subcutaneous insulin? Can it improve patient compliance with insulin therapy?⁸

What's more certain is that Exubera offers appeal to patients averse to injecting insulin, says Martin Abrahamson, MD, medical director of Joslin Diabetes Center and associate professor of medicine at Harvard Medical School. He believes Exubera is well suited for two categories of patients: those who need insulin to improve their glucose control but who flatly refuse to inject it before meals; and type 2 diabetes patients who need to add meal-related insulin doses to their oral agents, but fear injecting it.^9,10

“We can always use more safety data, but if this option can get people who need it to start using prandial insulin sooner, I think inhaled insulin should be a clear option,” Abrahamson contends. “In the long term, improving glucose control is what we're all striving to do for our patients because we know the risks of not doing so.”

John Buse, MD, ADA president-elect for medicine and science, agrees. “It's a little mysterious that there are millions of people with diabetes who still have inadequately controlled glucose and who are not taking any insulin,” says Buse, who is also a professor of medicine and director of the Diabetes Care Center at University of North Carolina at Chapel Hill. “To the extent that Exubera gets people to take insulin who otherwise wouldn't, I think it's a great thing.” ▪