Is Inhaled Insulin Closer to Reality?

These data were generated to satisfy a request by the US Food and Drug Administration for additional information about the CV safety profile of Afrezza. 

The first study was a pooled analysis of 4467 patients with type 1 or type 2 diabetes from 9 different phase 2/3 clinical trials. Patients had been treated with either Afrezza or standard diabetes treatment, which included oral agents and/or insulin, for a minimum of 3 months and up to 2 years. CV outcomes were compared for the 2 treatment groups.

When Afrezza was compared with standard treatment, there were no differences in the rates of CV events between patients with type 1 and those with type 2 diabetes. Ischemic events were low overall, and were similar in the 2 groups, as were the occurrence of cerebrovascular, coronary artery disease, and arrhythmic events.

A second, much smaller, prospective crossover study assessed a cohort of healthy men (n = 26) and women (n = 22) in an in-patient setting over the course of 12 days. The effects of 2 different doses of Afrezza (20 mg and 40 mg), with moxifloxacin 400 mg serving as an active control, or placebo, were rigorously monitored at multiple time points after each dose.

Results of this study showed no clinically significant differences in treatment groups for heart rate, QT intervals, or cardiac morphology.

With these results indicating no added CV risk, a MannKind company spokesperson described the New Drug Application for Afrezza as "complete, and ready for consideration of approval."

With the approval process back on track, the remaining question is: will patients actually use inhalable insulin?

A third study of inhaled insulin addressed the issue of patient satisfaction. In this 16-week randomized multicenter study, adults with type 1 diabetes used mealtime Afrezza in combination with insulin glargine, or used insulin lispro in combination with insulin glargine. Participants were then administered the Inhaled Insulin Treatment Questionnaire, which assesses measures of diabetes worries (including concerns about control), perceptions of insulin therapy, treatment satisfaction, and treatment preference.

Survey outcomes revealed similar perceptions for both inhaled and injected treatments for the domains of diabetes worries, treatment preference (for efficacy), and treatment satisfaction relative to blood sugar control. However, insulin perception subscales for convenience, comfort, and ease of regimen adherence showed a significant difference, favoring the Afrezza plus glargine cohort.

Study investigator Mark Peyrot, PhD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland, asks the question: "Does this mean that patients will be more compliant?"

"We cannot say for sure that that's true, because in clinical trials the staff works very hard to get patients to take their medication. However, whether it's easier to do it when you're out in the real world" remains to be determined, Dr. Peyrot noted. He recalled that there have been previous studies showing that when patients switched from vial and syringe insulin administration to a pen, pen users were more adherent.

"My patients don't mind the needles -- it's really quite painless," said Dr. Joel Zonszein, director of the Clinical Diabetes Center at Montefiore Medical Center in the Bronx, New York. "It's the glucose monitoring that they have to do that is painful, and inhaled insulin won't change that."

The perceptions of his patients aside, Dr. Zonszein voiced concerns about safety issues unrelated to CV events. "There is some fear among many physicians about giving insulin through the lungs, to the alveoli acting as a growth factor that could cause cancer."

Dr. Zonszein admitted that to date this has not been observed with Afrezza treatment, however, he points out that such effects might only emerge after years of exposure -- and indefinite long-term use is a given for many patients with type 2 diabetes. "Will a lesion appear at 5 years, at 10? It is a fear expressed by many of my colleagues."

He also wonders how a patient with a chronic lung condition, or even a bad cold, might use the product. "Would we have to do pulmonary function tests?" For Dr. Zonszein, there are still important questions to be answered.

American Diabetes Association (ADA) 71st Scientific Sessions: Abstracts 0933-P, 0922-P, and 0940-P. Presented June 26, 2011.