Inhaled Insulin for Diabetes Mellitus

Tarun K. Mandal

Disclosures

Am J Health Syst Pharm. 2005;62(13):1359-1364. 

In This Article

Safety

A concern of many clinicians is the possibility of long-term effects from the intraalveolar deposition of insulin within the lungs, since insulin is known to have growth-promoting properties.[27,28] The safety of inhaled insulin has been studied extensively; however, the long-term safety of these products has not been established. To date, clinical data have not indicated increased cellular proliferation or growth promotion in patients receiving orally inhaled insulin, but these studies have not exceeded four years in duration. Similarly, limited short-term (12 weeks) data have shown no substantial changes in lung function in patients with type 2 diabetes receiving preprandial subcutaneous or inhaled regular insulin via the AERx iDMS, in combination with NPH insulin at bedtime.[29]

The most important concern is the immunologic safety of these products. The high dose of inhaled insulin, delivered to the large alveolar surface, triggers the lungs' respiratory defenses, including humoral and cellular immunity, resulting in the production of antiinsulin antibodies. The formation of antiinsulin antibodies also occurs with subcutaneous administration of insulin.[3] The primary reason antibody production occurs is the presence of impurities in the drug product. For example, beef insulin is more immunogenic than pork insulin, and human insulin is the least immunogenic of the commercially available insulin products. In one study, human insulin antibodies caused a local allergic reaction in 2% of patients, with evidence of systemic allergy observed in less than 0.1%.[3] Moreover, administration of insulin by continuous subcutaneous infusion is more immunogenic than only a few injections per day.[3] Irrespective of the type of pulmonary delivery system, inhaled insulin produced more insulin antibodies compared to subcutaneous injection.

Preliminary safety reports showed a higher insulin antibody response in patients treated with Exubera and a long-acting insulin administered by subcutaneous injection compared with patients treated with longacting subcutaneous insulin alone.[30] As a result, long-term safety studies are being conducted by the manufacturer to determine the role of insulin antibodies in the metabolic control of diabetes and the effect of inhaled insulin on the immune systems.

In a recent study of Exubera in patients with type 1 and type 2 diabetes who had previously received subcutaneous insulin, antibody responses were highest after treatment with inhaled insulin in patients with type 1 diabetes.[31] The author also reported that insulin immunoglobulin G (IgG) antibody levels were stable for up to two years in the group previously receiving subcutaneous insulin, and low IgG antibody levels appeared after one year among patients with type 2 diabetes who had not previously received insulin therapy.[32]

Heise et al.[33] reported the results of a randomized clinical trial evaluating the effect of antibodies developed after inhaled insulin therapy. To identify potential adverse effects on postprandial glucose level, 45 patients with type 1 diabetes were randomized to receive NPH insulin at bedtime and preprandial administration of either subcutaneous regular insulin or inhaled insulin for 24 weeks. The group treated with Exubera showed substantially higher antiinsulin antibody concentrations, but the blood glucose profiles and overall metabolic effects were indistinguishable between groups. This observation indicates that insulin antibody does not impact postprandial glucose control.

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