As inhaled insulin is a novel drug substance intended for chronic administration via a novel route, respiratory safety has been a cause of concern. Consequently, the respiratory safety of inhaled insulin has been studied extensively in both type 1 and type 2 diabetes populations. This brief review will examine the available safety data for inhaled insulin in terms of pulmonary function.

The Inhaled Route of Administration 
The pulmonary route has been the most widely researched non-invasive alternative to subcutaneous administration of polypeptides. It offers the greatest potential for systemic insulin delivery, since some of the features that make the lung so well suited for gas exchange-particularly its huge surface area-also make it an ideal organ for absorption of small molecules into the bloodstream. Human lungs have a large (greater than 100m2), thin (0.1-0.2 micrometers), highly vascular epithelial surface area, permitting rapid passage of insulin from the alveoli into the systemic circulation.¹ The lungs tolerate the administration of polypeptides immunologically and the distal airways lack significant muccocilliary transport, allowing time for absorption. The main disadvantage of inhaled drug delivery is the requirement for a specific particle size (1-3 micrometers) to achieve deep alveolar deposition.²Small peptides-such as insulin (approximately 6,000 daltons)-are readily absorbed, provided they are administered in the form of particles with the ideal particle size.

Factors Affecting Inhaled Insulin Absorption 
Exposure to Tobacco Smoke The use of inhaled insulin is contraindicated in patients who smoke. For safety purposes, patients must have stopped smoking more than six months earlier in order to be considered for treatment with Exubera. This is because the bioavailability of insulin is increased in chronic smokers compared with non-smokers, even some months after smoking cessation. Studies examining inhaled insulin absorption have shown that active smoking increases absorption of inhaled insulin two- to five-fold, which can expose the patient to the risk of hypoglycemia. However, the mechanism by which smoking affects inhaled insulin absorption is still unknown. This is a public health issue and young type 1 diabetics in particular should be told not to commence smoking if they want to benefit from therapy with Exubera. In contrast, the absorption of subcutaneous insulin is not affected by smoking.^3,4 

The effect of passive smoking on the absorption of inhaled insulin has also been studied and-in contrast to the effects of active smoking-the investigators reported that that acute passive smoking caused a decrease in lung permeability, which in turn resulted in a decrease in inhaled insulin bioavailability. However, this did not create a risk for hypoglycemia.5 Likewise, smoking a single cigarette is associated with a decrease in insulin absorption.

Lung Disease 
The use of inhaled insulin is altered in patients with unstable or poorly controlled lung disease. Therefore, inhaled insulin is not recommended for use in patients with asthma, chronic obstructive pulmonary disease (COPD), or interstitial lung disease; patients with screening forced expiratory volume in 1 second (FEV1) <70% predicted; and patients with screening diffusing capacity of carbon monoxide (DLCO) (if performed) <70% predicted. Moreover, in the majority of the clinical studies involving inhaled insulin, patients with the characteristics detailed above were excluded.

In a recent study, the effects of prior administration of the bronchodilators albuterol and fluticasone were assessed on inhaled insulin pharmacokinetics. In the absence of a bronchodilator, mild to moderate asthma was associated with reduced pulmonary absorption of inhaled insulin. Inhaled insulin absorption increased following the administration of albuterol 30 minutes before inhaled insulin relative to inhaled insulin administration without bronchodilator treatment. Prior albuterol administration increased mean maximum insulin concentration (Cmax) amd area under the curve (AUC0-360) by 25-35% in patients with mild asthma and by 45-50% in patients with moderate asthma.6 Accordingly, patients should be informed of the possibility of hypoglycemia should they use Exubera in combination with an inhaled bronchodilator.

The potential clinical implications of intercurrent upper respiratory tract infections on inhaled insulin therapy have also been studied. A retrospective analysis of pooled data from 14 controlled phase II and III clinical trials showed that inhaled insulin was well tolerated and efficacious in the presence of intercurrent upper respiratory tract infections in both type 1 and type 2 diabetes patients.7 Although current data in patients with pneumonia are insufficient to make a clear statement, it may be prudent to err on the side of safety and to switch patients to conventional insulin until the pneumonia resolves.

Effect on Pulmonary Function 
Concerns regarding the potential for pulmonary toxicity with chronic use of inhaled insulin have been raised due to the growth-promoting and immunogenic properties of insulin. Moreover, small reductions in lung function have been reported in both type 1 and type 2 diabetes patients. Therefore, any further effect by inhaled insulin on this reduced baseline pulmonary function may have a potentially clinical impact.8-10 Consequently, the safety profile of inhaled insulin on pulmonary function has been extensively studied throughout its clinical development.