A dry powder formulation of recombinant regular insulin (technosphere insulin, Afrezza) is now approved for use in adults with diabetes. It consists of 2to 2.5-μm crystals of the excipient, fumaryl diketopiperazine, that provide a large surface area for adsorption of proteins like insulin. After inhalation from the small, single-use device, pharmacokinetic studies show that peak levels are reached in 12–15 minutes and decline to baseline in 3 hours, significantly faster in onset and shorter in duration than subcutaneous insulin. Pharmacodynamic studies show that median time to maximum effect with inhaled insulin is approximately 1 hour and declines to baseline by about 3 hours. In contrast, the median time to maximum effect with subcutaneous insulin lispro is about 2 hours and declines to baseline by 4 hours. In trials, inhaled insulin combined with injected basal insulin was as effective in lowering glucose as injected rapid-acting insulin combined with basal insulin. It is formulated as a single-use color coded cartridge delivering 4, 8 or 12 units immediately before the meal. The manufacturer provides a dose conversion table; patients injecting up to 4 units of rapid-acting insulin analog should use the 4-unit cartridge. Those injecting 5–8 units should use the 8-unit cartridge. If the dose is 9–12 units of rapid-acting insulin pre-meal then one 4-unit cartridge and one 8-unit cartridge or one 12-unit cartridge should be used. The inhaler is about the size of a referee’s whistle. The most common adverse effect of inhaled insulin was cough, affecting 27% of trial patients. A small decrease in pulmonary function (forced expiratory volume in 1 second [FEV1]) was seen in the first 3 months of use, which persisted over 2 years of follow-up. Inhaled insulin is contraindicated in smokers and patients with chronic lung disease, such as asthma and chronic obstructive pulmonary disease. Spirometry should be performed to identify potential lung disease prior to initiating therapy. During the clinical trials, there were two cases of lung cancer in patients who were taking inhaled insulin and none in the comparator-treated patients.
Immunopathology of Insulin Therapy
At least five molecular classes of insulin antibodies may be produced in diabetics during the course of insulin therapy: IgA, IgD, IgE, IgG, and IgM. There are two major types of immune disorders in these patients: 1. Insulin allergy—Insulin allergy, an immediate type hypersensitivity, is a rare condition in which local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies. In severe cases, anaphylaxis results. Because sensitivity is often to non-insulin protein contaminants, the human and analog insulins have markedly reduced the incidence of insulin allergy, especially local reactions.
2. Immune insulin resistance—A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Rarely, the titer of insulin antibodies leads to insulin resistance and may be associated with other systemic autoimmune processes such as lupus erythematosus.
Injection of animal insulin preparations sometimes led to atrophy of subcutaneous fatty tissue at the site of injection. Since the development of human and analog insulin preparations of neutral pH, this type of immune complication is almost never seen. Injection of these newer preparations directly into the atrophic area often results in restoration of normal contours.
Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same site. However, this may be corrected by avoiding the specific injection site.