Inhaled Insulin: HbA1c Increase Seen After 1 Year in Youth With Diabetes

Children and adolescents with diabetes who use inhaled insulin may experience a rise in HbA1c levels after a year of treatment, according to an extension of the INHALE-1 trial published in Diabetes Technology & Therapeutics. While the therapy demonstrated safety and increased treatment satisfaction among participants, the observed increase in HbA1c warrants careful consideration, particularly regarding adherence and potential integration with automated insulin delivery systems.

Glycemic Changes Over Time

The INHALE-1 trial initially showed comparable HbA1c levels between youths using inhaled insulin (technosphere insulin, Afrezza) and those receiving rapid-acting analog insulin over a 26-week period. As previously reported by Healio, this initial phase offered a promising alternative for managing blood sugar. However, the one-year follow-up revealed a significant shift. Participants who continued with technosphere insulin for the full year experienced an increase in HbA1c from a baseline of 8.1% to 8.6%, a mean change of 0.46 percentage points (95% CI, 0.22-0.71; P = .001). This increase was most pronounced during the final 26 weeks of the trial, with an additional climb of 0.38 percentage points (95% CI, 0.08-0.67).

Interestingly, those who switched from rapid-acting analog insulin to technosphere insulin at the 26-week mark did not exhibit a significant change in HbA1c levels. This suggests that the impact of inhaled insulin on glycemic control may be more pronounced with prolonged use.

Study Details and Population

The INHALE-1 study enrolled 88 youths who continued with technosphere insulin and 104 who switched to it from rapid-acting analog insulin. Participants ranged in age from 4 to 17 and had either type 1 diabetes for at least six months or type 2 diabetes for at least three months. All participants were receiving multiple daily insulin injections and had baseline HbA1c levels between 7% and 11%. The primary outcome of the extension phase was the change in HbA1c from baseline to one year for the technosphere insulin group and from 26 weeks to one year for the rapid-acting analog group.

Treatment Satisfaction and BMI

Despite the increase in HbA1c, treatment satisfaction remained stable for those continuing with technosphere insulin. Those who switched to inhaled insulin did not experience a change in treatment satisfaction. The group that switched from rapid-acting analog insulin to technosphere insulin saw a reduction in mean BMI percentile, decreasing from 76% at 26 weeks to 73% at one year (P = .002). This suggests a potential benefit of inhaled insulin regarding weight management, whereas further research is needed to confirm this finding.

Expert Perspective and Potential Explanations

Roy W. Beck, MD, PhD, president and medical director of the Jaeb Center for Health Research Foundation in Tampa, Florida, expressed disappointment with the glycemic outcomes but acknowledged the heterogeneity in HbA1c changes among participants. Dr. Beck emphasized the increased treatment satisfaction observed with technosphere insulin.

“When evaluating the data for the main trial and the extension over 52 weeks, the use of inhaled insulin was safe in this pediatric population largely with type 1 diabetes,” Beck told Healio. “during the trial period there was less weight gain and greater treatment satisfaction with technosphere insulin compared with rapid-acting analog. However, these benefits must be balanced against the lack of benefit seen in glycemic metrics with technosphere insulin vs. Rapid-action analog.”

Dr. Beck proposed several potential reasons for the observed HbA1c increase. The rapid onset and shorter duration of action of inhaled insulin require more frequent redosing – approximately 60 to 90 minutes after a prior dose if hyperglycemia persists – a regimen that may be challenging for pediatric patients to adhere to. Underdosing at meals or for corrections, driven by concerns about hypoglycemia, could also contribute to the rise in HbA1c.

Safety Profile

The extension phase of the trial reported 12 adverse events related to technosphere insulin in the original technosphere group and 45 in the crossover group. Most events in the technosphere group were asymptomatic reductions in pulmonary function tests, while the crossover group primarily experienced inhalation-related cough. Severe hypoglycemia occurred in one participant in each group. Two children originally assigned to rapid-acting analog insulin experienced diabetic ketoacidosis, potentially due to nonadherence to insulin therapy. The overall safety profile of technosphere insulin appeared consistent with findings from adult studies.

Implications for Clinical Practice and Future Research

The INHALE-1 data suggest that inhaled insulin can be a safe and potentially beneficial alternative to rapid-acting analog insulin for children and adolescents with diabetes, particularly regarding treatment satisfaction and weight management. However, the observed increase in HbA1c highlights the importance of careful patient selection, thorough education on proper dosing and redosing strategies, and close monitoring of glycemic control.

Further research is needed to determine how to optimize adherence to inhaled insulin therapy in pediatric populations and to explore its potential role in conjunction with automated insulin delivery systems. Dr. Beck suggests that combining the benefits of automated insulin delivery with the rapid action of inhaled insulin could aid minimize postmeal hyperglycemia.

The study was funded by MannKind Pharma. Dr. Beck reports receiving grant funding, study supplies and consultant fees from Beta Bionics, Insulet and Tandem Diabetes Care; grant funding and study supplies from Abbott and Dexcom; grant funding from Bigfoot Biomedical, Embecta, MannKind and Sequel Med; study supplies from Medtronic; consultant fees and study supplies from Novo Nordisk; and consultant fees from Abata, DreaMed, Eli Lilly, Hagar, Vertex, Ypsomed Therapeutics and Zucara, with all funding paid to his institution. Please see the study for all other authors’ relevant financial disclosures. Full study details are available in Diabetes Technology & Therapeutics.

For more information on diabetes management and inhaled insulin, consult with a qualified healthcare professional and refer to resources from organizations like the Social Security Administration and the U.S. District Court.