Abstract
Achieving optimal glycemic control, preventing acute events, and minimizing the risk of chronic complications while maintaining a high quality of life are the primary goals of effective diabetes management. However, many insulin-treated people with type 1 diabetes and type 2 diabetes are not achieving the recommended glycemic goals. In addition to the known acute and chronic complications of hyperglycemia, hypoglycemia is a common occurrence that imposes significant health risks. Although rapid-acting and ultra-rapid-acting insulins have demonstrated improved glycemic and safety outcomes over human regular insulin, their delayed onset and extended duration of action, as well as the risk for dosing errors, make hypoglycemia a frequent event for people using these therapies. Technosphere inhaled insulin is a viable option for mealtime insulin coverage and post-meal corrections, providing a “fast on, fast off” insulin activity profile that closely aligns with the timing of glucose absorption from meals to achieve desired postprandial glycemic control while likely minimizing the risk of hypoglycemia. This article discusses the advantages of TI over injected rapid-acting insulin analogs in addressing hypoglycemia fear and the other barriers associated with treatment adherence.
Introduction
Achieving optimal glycemic control, preventing acute events, and minimizing the risk of chronic complications while maintaining a high quality of life are the primary goals of effective diabetes management. However, many insulin-treated people with type 1 diabetes (T1D) and type 2 diabetes (T2D) are not achieving the American Diabetes Association-recommended HbA1c target of <7%. 1 Despite innovations in analog insulin formulations and glucose monitoring technologies, only 25.2% of this population in the United States is achieving this goal. 2
There are several factors impacting insulin adherence. In an early global survey of 1530 insulin-treated patients, 180 with T1D and 1350 with T2D, 28.4% of respondents reported that “fear of hypoglycemia” was a major barrier to adherence, followed by embarrassment about injecting in public (27.7%) and needle aversion (24.2%). 3 Weight gain (16.3%) and injection pain (12.9%) were also common responses.
In 2014, MannKind Corporation (Westlake Village, CA) introduced the Afrezza® Inhalation System, which utilizes Technosphere® inhaled insulin (TI) as its therapeutic component. In this article, we discuss the advantages of TI over injected rapid-acting insulin analogs (RAAs) in addressing hypoglycemia fear and the other barriers associated with treatment adherence.
Scope of the Problem
Hypoglycemia is common among people with T1D and in those with intensively treated T2D. 4 Hypoglycemia is categorized according to glucose levels and urgency for assistance: Level 1, hypoglycemia alert 54–69 mg/dL); Level 2, clinically significant hypoglycemia (<54 mg/dL); and Level 3, severe hypoglycemia (associated with cognitive impairment requiring external assistance). 5 The annual incidence of severe hypoglycemia ranges from 3.3% to 13.5%. 6
While Level 1 hypoglycemia may occur with mild symptoms (e.g., shakiness, palpitations, confusion, cognitive impairment), these symptoms may be intensified with Level 2 hypoglycemia and can escalate to increased risks for falls, injuries, and motor vehicle accidents if left untreated. 7 If allowed to progress to Level 3 hypoglycemia (severe), these risks may include arrhythmias, ischemia, and sudden cardiac death, and symptoms may worsen to the point where emergency department treatment and hospital admission are needed.7,8
In addition to the increased mortality risk associated with severe hypoglycemia, recurrent episodes of hypoglycemia can lead to impaired awareness of hypoglycemia, resulting in a continuous cycle of recurrent hypoglycemia. 9 Moreover, repeated severe episodes have been linked to neuronal injury, dementia (in older patients), profound fear of hypoglycemia, and reduced quality of life.7,10,11
In addition to its clinical impact, both Level 2 and Level 3 hypoglycemia have a significant economic impact on individuals with diabetes and the health care system. These episodes are frequently associated with short-term consequences, including impaired performance of activities, the utilization of emergency medical services, hospital admissions, outpatient clinic visits, and increased consumption of diabetes management supplies.12–14 The financial burden on health care payers is further exacerbated by the ongoing need for acute and preventive care, including emergency services, hospitalizations, and increased patient surveillance. 15 While the indirect economic impact of hypoglycemia on employer-related costs has not been extensively studied, work absenteeism, reduced workplace productivity, and presenteeism following severe hypoglycemic episodes can exact significant costs.11,12,16–18
Hypoglycemia also adversely affects glycemic management, contributing to increased health care resource utilization, diminished quality of life, and challenges in overall diabetes self-management.7,12 Hypoglycemic episodes are also associated with significant social and psychological issues, including persistent worry, depressive symptoms, within-family conflict, perceived stigma, and an elevated psychosocial burden. 19
Limitations of RAA and ultra-RAA insulins
Managing T1D with intensive insulin therapy either with multiple daily insulin doses or insulin pump therapy (traditional or hybrid closed-loop) is the most physiological method for achieving optimal glycemic control. Although current ultra-RAAs are an improvement over early-generation RAA insulins in terms of quicker onset and additional flexibility in dosing, their efficacy for A1C lowering and safety in terms of rates and incidences of severe hypoglycemia risk were not significantly different. 20 Nevertheless, dosing errors based on timing and overcorrection of hyperglycemia remain a problem. In a recent analysis of the EudraVigilance pharmacovigilance database, Popa Ilie et al. uploaded a total of 152,806 Individual Case Safety Reports (ICSRs) that were submitted until July 2024. 21 The investigators identified 63,844 (41.8%) ICSRs that were reported for RAA formulations. The highest proportion of insulin dosing errors was found in adults with T1D and insulin-requiring T2D, aged 18–24 years. The investigators concluded that while dosing errors among older adults in this group were likely due to missed doses, incorrect timing, or difficulties in managing complex regimens, stress and irregular schedules in adolescents and emerging adults (aged 18 to <25 years) likely contributed to these errors. Studies have shown that adolescents and emerging adults were more likely to miss or dose late for meal doses compared with younger children and older adults (aged ≥45 years).22–24 Given their delayed onset and extended duration of action,25,26 as well as the risk for dosing errors, RAA and ultra-RAA formulations with durations of action of 4–7 h are still less than ideal for reducing hypoglycemia. Inhaled insulin offers a potential solution to this challenge.
TI inhaled insulin
The Afrezza inhaled insulin delivery system utilizes TI, a dry powder formulation of recombinant human insulin designed to replicate the physiological and metabolic effects of endogenous insulin while minimizing postprandial glycemic excursions. 27 TI comprises recombinant human insulin adsorbed onto Technosphere microparticles composed of fumaryl diketopiperazine, an inert excipient that crystallizes into microparticles approximately 2.0–2.5 µm in diameter, a particle size that is considered optimal for deposition in the deep lung, where the large, highly perfused surface area and thin alveolar epithelium facilitate rapid systemic absorption.27–29 This bypasses the slower subcutaneous absorption and hepatic degradation.30,31
The pharmacokinetics of TI demonstrate significantly faster absorption compared with subcutaneous RAAs.27,32 In a hyperinsulinemic-euglycemic glucose clamp study, Heinemann et al. reported a median time to maximum plasma concentration (Tmax) of approximately 8 min following administration of 12 units of TI, compared with 50 min with 8 units of insulin lispro. 27 The TI plasma levels returned to baseline within 180–240 min, compared with approximately 280 min for insulin lispro. Moreover, the rapid hepatic action of TI facilitates faster suppression of endogenous glucose production, which enhances its efficacy in meeting prandial insulin requirements. 33
Safety and efficacy studies
Type 1 Diabetes
Recent studies have demonstrated that treatment with TI significantly reduces postprandial glucose excursions compared with RAA, with a lower or similar incidence of.34–36
In a randomized meal challenge study of 122 adults with T1D treated with nonautomated pump therapy (non-AID 37 ), automated insulin delivery (AID), or multiple daily insulin injection (MDI) therapy, Hirsch et al. reported that participants who were randomized to TI therapy with their usual RAA insulin experienced a smaller postprandial glucose excursion (P = 0.01), shorter times to peak glucose (P = 0.006), and lower peak glucose (P = 0.01). 34
The treatment group difference in area under the curve for glucose >180 mg/dL over 2 h was less with TI versus RAA (adjusted difference: 212 mg/dL, 95% CI: 222–22, P = 0.02). Only one participant in each group experienced glucose <70 mg/dL. The investigators observed trends favoring TI in both the prior AID and non-AID users, but with more favorable trends for non-AID users.
Findings from a randomized, open-label, multicenter study that assessed changes in postprandial glucose excursions showed similar findings. 35 Akturk et al. compared the use of mealtime TI with RAA in 60 patients with T1D and showed similar findings. 35 Investigators reported significantly lower postprandial glucose excursions over the 1–4 h post-meal period compared with RAA therapy, with less time spent in hypoglycemia (<60 mg/dL, <50 mg/dL, both P < 0.5). In addition, investigators observed weight loss in the TI cohort, but weight gain in the RAA cohort (P = 0.006), despite a higher prandial TI dose.
In the randomized, phase 3, multicenter AFFINITY-1 study, Bode et al. investigated the effect of TI treatment plus basal insulin compared with RAA plus basal insulin on incidences of hypoglycemia in 375 adults with T1D treated with basal insulin plus TI or RAA. 38 The investigators observed significantly fewer hypoglycemia events (≤70 mg/dL) per patient per month compared with the RAA cohort (9.8 vs. 14.0, respectively) and fewer severe events per patient per month (0.081 vs. 0.145, P = 0.10, respectively).
The use of inhaled insulin in the pediatric T1D population has not previously been well studied; however, recent findings from the INHALE-1 trial, a randomized, open-label, non-inferiority study, showed promising results. 39 In the study, 230 pediatric patients aged 4–18 years were randomized to basal insulin plus TI or RAA. The primary endpoint was a non-inferior change in HbA1c levels after 26 weeks. Over the 26-week study period, no between-group differences were observed in pulmonary function or hypoglycemia. While the full intent-to-treat (ITT) analysis exceeded the prespecified non-inferiority margin of 0.4% (0.435%), this was driven largely by the variability of one patient who did not adhere to the study protocol. However, a modified ITT (mITT) analysis, which excluded this subject, met the predetermined threshold (0.370%). A 26-week extension phase in which all remaining MDI patients were switched to TI therapy is still ongoing.
Similar findings of minimal hypoglycemia risk were observed in an earlier dosing study by Haller et al., which included 27 patients, average age 13.3 years. They observed three measurements of Level 1 (<70 mg/dL) hypoglycemia in three subjects, and one measurement of Level 2 (<54 mg/dL) hypoglycemia in one subject during the first 60 min of TI dosing. No incidents of severe hypoglycemia were observed. 40
Type 2 Diabetes
Safety studies in T2D have also shown lower rates of hypoglycemia with TI therapy compared with RAA treatment. In the safety analysis conducted as part of a randomized, 24-week study of 309 adults with T2D, average age 58.5 years, Hoogwerf et al. observed significantly lower hypoglycemic event rates among patients treated with TI compared with RAA therapy. 37 The percentage of patients reporting ≥1 hypoglycemic event for TI therapy was 43% versus 54% (P = 0.035). However, the event rate (events/patient/month) for severe hypoglycemia was identical between the treatment groups (0.3).
In an earlier systematic review and meta-analysis, Pittas et al. assessed safety findings from 13 randomized controlled trials. 41 The investigators observed that TI therapy was associated with a lower risk of severe hypoglycemia compared with placebo, injected RAA, and oral antidiabetes medications (odds ratio: 0.61, 95% CI: 0.35–0.92) in five trials. The average weight loss in three studies averaged 1.1 kg.
Summary
Clinical trials have demonstrated that TI effectively mitigates postprandial hyperglycemia while minimizing the risk of late postprandial hypoglycemia, particularly beyond 2–5 h following a meal.38,42–44 The short duration of action of TI also reduces the risk of insulin “stacking,” thereby enabling the safe administration of correction doses within 1–2 h after the preceding dose. 35 TI can be administered at bedtime to manage hyperglycemia with a reduced risk of nocturnal hypoglycemia. 35
Authors’ Contributions
C.J.L. and E.S.: Conceptualization, writing—original draft, and writing—review and editing.
Footnotes
Acknowledgment
The authors wish to thank Christopher G. Parkin, MS, CGParkin Communications, Inc., for his editorial assistance.
Funding Information
Development of this article was funded by an unrestricted grant from MannKind Corporation.
Disclosure Statement
C.J.L. has received research support from the NIDDK and Helmsley Foundation and industry support paid to the Icahn School of Medicine at Mount Sinai from Abbott Diabetes, Dexcom, Insulet, Novo Nordisk, Senseonics, and Tandem. C.J.L. has received consulting fees from Eli Lilly and Dexcom outside of this work. E.S. has received research support from the NIH, Breakthrough T1D, Abbott Diabetes Care, Dexcom, Insulet, Tandem, MannKind, and DEKA/Sequel, and served on advisory boards for NIDDK, Zucara, and Eli Lilly.