Most adults with type 1 diabetes switching from an insulin pump or multiple daily injections to inhaled insulin (Afrezza) needed to increase their dose of the inhaled product to achieve target glycemic control, an analysis of the INHALE-3 trial indicated.
After starting with a higher initial conversion dose than recommended under current labeling, patients received an average of 36 units of the inhaled technosphere insulin at the beginning of the phase IV study. At weeks 17 and 30, respectively, average doses increased to 48 and 52 units, reported Jennifer Rittenberry, MD, of MannKind Corporation, the maker of the product.
At 17 weeks, 57% of patients had dose increases (i.e., more than 4 units from the initial dose), 26% maintained their starting dose (within 4 units), and 17% had dose decreases (more than 4 units from the initial dose).
At 30 weeks, 74% had dose increases, 17% maintained their starting dose, and 9% had decreases, according to findings presented at the American Association of Clinical Endocrinology annual meeting.
"Every patient has individual insulin needs that can change based on meal patterns, physical activity, other illnesses or medications, but this study helps characterize what typical technosphere insulin-based doses are," said Rittenberry. "Many subjects still needed additional technosphere insulin titration toward glycemic control goals, and a small number needed a decrease or maintained the initial higher conversion dose during this trial."
Current labeling advises matching the inhaled insulin units to the injected mealtime dose of rapid-acting insulin analog. After titration to achieve glycemic control, inhaled insulin doses can be 40% to 80% higher than the injected mealtime dose, Rittenberry said.
As prior studies of inhaled insulin had shown better glucose lowering with a higher conversion dose than the current prescribing information, the INHALE-3 study used a higher upfront dose. Patients started with a dose determined by rounding the usual injected mealtime rapid-acting insulin analog units to the nearest whole number, multiplying by two, and then rounding down to the nearest 4-unit cartridge of inhaled insulin.
Previously reported primary outcome results of the trial showed that at week 17, patients switching from an insulin pump or multiple daily injections to the inhaled insulin maintained their glycemic control, if using the inhaled product as intended -- 26% did have some degree of worsening of HbA1c versus 3% for those who remained on their usual care.
"Insulin effect is a function of delivery, so inhaled insulin is not unit-to-unit equivalent to subcutaneous rapid-acting insulin," said Rittenberry. "Technosphere insulin has a unique delivery method, bioavailability, and pharmacodynamics leading to a very different clinical effect per unit compared to rapid-acting analogs."
Faster insulin absorption is associated with higher peak concentration but a shorter duration of exposure, she explained. Compared with injected rapid-acting insulin, inhaled insulin has a much quicker glucose lowering effect, but a shorter duration of activity and lower overall glucose disposal.
First approved in 2014 for patients with type 1 or 2 diabetes, the ultra-rapid-acting inhaled insulin comes in 4-unit, 8-unit, or 12-unit cartridges. Doses can be made with combinations of cartridges taken in series, titrated to the patient's glycemic needs.
In the 30-week INHALE-3 study, 123 patients with type 1 diabetes on continuous glucose monitoring (CGM) were randomized 1:1 to technosphere inhaled insulin with long-acting basal insulin degludec (Tresiba) or usual care for 17 weeks. To enroll, patients needed to be on multiple daily insulin injections, on an automated insulin delivery system, or a pump without automation.
After 17 weeks, 93 patients continued in a 13-week extension phase and received the inhaled insulin and degludec.
Baseline characteristics for the 35 patients with no missing dosing data were as follows: mean age was 46 years, 51% were women, and their body mass index was 27.9. Mean HbA1c was 7.7% and diabetes duration was over 25 years, with 49% using insulin injections, 40% on an automated insulin delivery system, and 11% on a pump without automation.
Average bolus and basal insulin dose at baseline was 23.9 units each, a 50:50 ratio. At the beginning of the trial, participants were on a 60:40 bolus-to-basal ratio. By week 17, this changed to a 65:35 ratio and by week 30 to a 70:30 ratio.
From the start of the trial to week 30, dosing of the inhaled insulin increased at each meal: breakfast (from 9 to 12 units), lunch (11 to 13 units), and dinner (12 to 15 units).
"By the end of the 30 weeks, there were definitely people taking 4 units, but there were a lot of people taking higher doses than that -- 8, 12, 16 units [were] pretty common doses for meals, some of them needing even more than 28 units," said Rittenberry. "If you need higher doses than 12, then you just take multiple cartridges in series."
No new safety signals popped up, she said. Rates of hypoglycemia (<70 mg/dL) and severe hypoglycemia (<54 mg/dL) as measured by CGM were similar between groups. One case of severe hypoglycemia occurred in the inhaled insulin group due to a delay in starting a meal after already dosing.
Cough was the most common treatment-related adverse event, but it was typically brief and during the time of inhalation.
Disclosures
The study was sponsored by MannKind Corporation.
Rittenberry reported employment with MannKind Corporation.
Primary Source
American Association of Clinical Endocrinology
Source Reference: Rittenberry J, et al "Inhaled insulin dosing in a randomized trial in adults with type 1 diabetes (T1D)" AACE 2025.
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