Elsevier

Clinical Therapeutics

Volume 36, Issue 8, 1 August 2014, Pages 1275-1289
Clinical Therapeutics

Inhaled Insulin: A Breath of Fresh Air? A Review of Inhaled Insulin

https://doi.org/10.1016/j.clinthera.2014.06.025Get rights and content

Abstract

Purpose

Despite many advances in diabetes care over the last century, some elements of insulin therapy remain inadequate for optimal care of the patient with diabetes. There is a need for improved pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues to mimic physiologic insulin secretion. In addition, a major barrier to successful insulin therapy has been patient resistance. Alternative routes of insulin administration, including inhaled insulin, have been under investigation for several years. This review discusses the rationale for pulmonary delivery of insulin, compares previous inhaled insulin products, reviews the literature on the safety and efficacy of a current inhaled insulin formulation under investigation, and compares this product with other prandial insulin products.

Methods

English-language studies and reviews of inhaled insulin were searched in MEDLINE, the ClinicalTrials.gov registry (through May 2014), and the US Food and Drug Administration Website.

Findings

Inhaled insulin has several favorable characteristics due to pulmonary anatomy/physiology and the lack of injections. Pharmacokinetic and pharmacodynamic studies have shown a time–action profile suitable for prandial insulin use. Inhaled insulin seems to be safe and effective compared with other prandial insulin products and may be preferable to subcutaneous rapid-acting insulin analogues in terms of time–action profiles and rates of hypoglycemia. Small decreases in forced expiratory volume in 1 second (FEV1) have been shown with inhaled insulin, although this finding is not progressive over time and reverses with cessation of the medication.

Implications

Although several inhaled insulin products have been under investigation, only one (Exubera® [Nektar Therapeutics, San Carlos, California/Pfizer Inc, New York, New York]) was approved by the US Food and Drug Administration, and it was pulled from the market after only a short period of time. Technosphere® insulin (MannKind Corporation, Valencia, California) is currently the only inhaled insulin that remains under investigation. A review of the past and present literature on inhaled insulin is pertinent in understanding the current status of inhaled insulin and its risks and benefits. The current literature suggests that inhaled insulin could be a valuable option for prandial insulin administration, with a favorable risk to benefit ratio in some patients.

Introduction

Improvements in subcutaneous insulin have allowed for more physiologic regimens since its discovery in the 1920s. The development of rapid-acting insulin analogues has improved pharmacokinetic and pharmacodynamic properties of insulin formulations. However, these formulations continue to fall short of physiologic needs to control postprandial hyperglycemia, with delayed onset of action and prolonged effects leading to excessive hyperglycemia after eating and delayed hypoglycemia.1 The importance of tight glycemic control has been shown to prevent and/or delay long-term complications of diabetes.2 The success of insulin therapy, however, depends on its physiologic properties as well as on its proper use. Barriers to patient use of subcutaneous insulin include anticipated pain, anxiety, inconvenience, fear of hypoglycemia, and concern about weight gain.3 Evidence suggests that patients may be reluctant to start insulin when prescribed or to delay starting treatment.4 In one study of patients with type 2 diabetes (T2DM), 28% of subjects reported they were unwilling to start insulin, 45% reported resistance to insulin therapy due to restrictions on daily life (eg, harder to travel, eat out), and 43% of patients reported fear of hypoglycemia.5 Practical issues can also occur (eg, lipodystrophy, lipohypertrophy) from several years of recurrent injections.

It has been >90 years since the first therapeutic use of insulin by Banting and Best. Since that time, researchers have been searching for alternate modes of insulin delivery, including transdermal, ocular, oral, buccal, nasal, rectal, vaginal, and uterine delivery systems. Reports of pulmonary delivery of aerosolized insulin was first shown in the 1920s to decrease blood glucose levels.6 However, these methods have historically failed as insulin delivery systems, primarily due to low bioavailability. For example, oral bioavailability of insulin is limited due to extensive enzymatic and chemical degradation in the gastrointestinal tract and inability to cross intestinal mucosa due to the large hydrophilic nature.7, 8 Currently, several alternative methods of delivery are under investigation. Potential improvements include improved absorption of transdermal insulin-using iontophoresis (electrical currents), low-frequency ultrasound, and transfersomes (lipid vesicles) and increasing bioavailability of oral insulin such as stabilizing degradation and using microspheres to enhance absorption. The use of buccal insulin has also been proposed to overcome some of the aforementioned issues with oral insulin.9

Therefore, there is a need not only for alternative modes of insulin delivery but for a more physiologic, rapid-on/rapid-off, prandial insulin to improve glycemic control and reduce hypoglycemia. The present review focuses on the past and present data regarding the safety and effectiveness of inhaled insulin products as prandial insulin.

Section snippets

Materials and Methods

A systematic search was conducted in MEDLINE and the ClinicalTrials.gov registry (through May 2014) to find English-language studies and review articles of prior and current inhaled insulin products. The following search terms were used: diabetes, glycemic control, inhaled, inhalation, insulin, pulmonary, Exubera®, and Technosphere® insulin. We searched for additional publications in citation sections of the recovered articles. The US Food and Drug Administration (FDA) Website was also reviewed

Pulmonary Delivery of Insulin

Of the alternative modes of delivery investigated thus far, pulmonary delivery of insulin has shown the most promise, perhaps due to advantageous characteristics for medication delivery. Pulmonary delivery of insulin has been shown to have a ~4- to 40-fold increase in bioavailability compared with nasal, rectal, buccal, and conjunctival formulations.10 The lung is highly vascularized with ~500 million alveoli, providing an extremely large surface area (50–140 m2).7 The thin alveolar-capillary

Conclusions

A major unmet need in T1DM is the lack of rapid-on/rapid-off insulin leading to improved postprandial hyperglycemia and reduced delayed hypoglycemia. For the T2DM population requiring insulin therapy, there is not only patient resistance but also clinical inertia on the health care professional’s part to starting insulin. The development of an insulin formulation that has improved pharmacokinetics and pharmacodynamics compared with fast-acting analogues and the needle-less route of

Conflicts of interest

Tricia Santos Cavaiola have indicated that they have no other conflicts of interest regarding the content of this article. Steven Edelman is on the medical advisory boards and speakers bureau for Sanofi, NovoNordisk and Lilly

Acknowledgments

All authors contributed equally.

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