Inhaled insulins: their potential in the treatment of diabetes mellitus.

The inhalation of insulin was conceptualized by the mid-1920s, but the first successful testing of inhaled insulin occurred in the mid-1990s. The lung has proven to be an organ well capable of absorbing insulin in a reproducible and dose-dependent manner. At present, two concepts of pulmonary insulin delivery at relatively advanced stages of development have been investigated in several published studies. The first involves the Exubera device, a system consisting of a formulation of insulin in a dry and amorphous powder, which is then packaged into blisters. A special delivery system generates a pulse of compressed air, which causes the insulin to form a white fog in a transparent reservoir that can be inhaled by deep breathing. The second approach is the AERx insulin Diabetes Management System, which uses an aqueous formulation of insulin, delivered as an aerosol generated by a special, microprocessor-controlled, inhalation device. This device is capable of monitoring the patient's inspiratory flow and guiding the inhalation by a microelectronic feedback system. The therapeutic efficacy and safety of these inhaled insulins seem comparable to those of subcutaneous insulin regimens; however, inhaled insulins do not appear to achieve significantly better glycemic control. Several other concepts for the pulmonary delivery of insulin are also being developed. With the incidence of diabetes mellitus, especially type 2 diabetes, dramatically increasing worldwide, patients with type 2 diabetes appear to be an important target group for new modalities of insulin delivery. In this group, the onset of insulin treatment is frequently delayed due to the fear of self-injection, preventing effective glycemic control. Patient acceptance of inhaled insulins is excellent and no serious adverse effects have been observed to date. Further advantages of inhaled insulins are the more rapid onset of insulin action and a mitigation of postprandial glucose excursions. However, there are some open questions. The most important concerns the possible long-term effects of insulin inhalation on the lung, as insulin is known to have growth-promoting properties. Thus far, there are no observations of the effects of inhaled insulin on lung structure and function that extend beyond 10 years. In patients with pulmonary disease, the smaller cumulative alveolar surface may cause problems in absorption, and in smokers the action of inhaled insulin has been shown to be stronger and with a faster onset. Furthermore, treatment with inhaled insulin requires larger doses of insulin compared with the subcutaneous route of insulin administration to achieve the same systemic effect, and the costs of this therapy could therefore be significantly higher than the costs of present insulin therapies.