In this episode of Diabetes Dialogue, hosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and co-director of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, are joined by Roy Beck, MD, PhD, executive director of the Jaeb Center for Health Research, to discuss the INHALE-3 trial, an adult study evaluating technosphere inhaled insulin (Afrezza) in comparison to standard diabetes therapies, including automated insulin delivery (AID) systems.

Beck outlined his center’s transition from ophthalmology-focused research to becoming a key player in diabetes trials over the last 25 years, particularly in technology-driven therapies. The conversation explores inhaled insulin’s pharmacokinetic profile—its rapid onset and short duration, which more closely mimics physiologic insulin responses than injected rapid-acting analogs.

The INHALE-3 trial randomized adults with type 1 diabetes (T1D), including nearly 50% who were on AID systems, to either continue their current regimen or switch to once-daily insulin degludec plus Afrezza for meals and corrections. Surprisingly, Beck highlighted participants willing to suspend AID use to try the inhaled approach, allowing for a head-to-head comparison. The study met its primary non-inferiority endpoint for HbA1c, with outcomes from Afrezza plus basal insulin comparable to those achieved with AID and multiple daily injections.

However, Beck emphasized the heterogeneity in response. Approximately 30% of participants switching to Afrezza achieved notably better glycemic control (including greater reductions in HbA1c and less time >250 mg/dL), while a similar proportion performed worse, largely depending on their engagement and dosing frequency. CGM use was required in the study, enabling patients to re-dose Afrezza postprandially as needed, a key factor in those who succeeded.

Beck also indicated that overnight glycemic control remained a challenge. While Afrezza performed well during daytime periods, AID systems outperformed it overnight—an expected finding given AID’s strength in basal modulation. Weight gain was also lower in the Afrezza group, offering an additional potential advantage.

Hosts discussed real-world use cases combining AID with Afrezza, with Beck sharing his son’s personal success using Afrezza alongside Tandem Diabetes’ Control-IQ in sleep mode, a workaround to prevent algorithmic overlap. He noted future integration could be more seamless with upcoming Bluetooth-enabled Afrezza inhalers or AID systems capable of receiving inhalation data.

Safety data showed bronchospasm was rare in the trial, with no confirmed cases attributable to Afrezza. Cough was the most common side effect, generally mild and transient, while active asthma and smoking remained contraindications. Isaacs and Bellini highlighted Afrezza’s potential as an underutilized but powerful option in the diabetes toolkit, particularly for patients seeking alternatives to injections or pumps, or looking for greater control over postprandial excursions.

Chapters

00:00:01 Introduction and Background of Dr. Roy Beck

00:02:16 Overview of Inhaled Insulin

00:06:31 INHALE-1 Pediatric Study

00:07:21 INHALE-3 Adult Study

00:11:18 Study Results and Participant Outcomes

00:19:57 Challenges and Future Directions

00:26:44 Side Effects and Safety Concerns

00:31:09 Conclusion and Final Thoughts