The effects of insulin on airway function: repercussions for intra-tracheal insulin delivery and for asthma therapeutics

According to WHO, there are some 130 million diagnosed diabetics in the worlds, a figure that is predicted to increase to 300 million by 2025.  The majority of patients suffer from type 2 diabetes however type 1 diabetes (also known as insulin-dependent diabetes (IDDM) or juvenile-onset diabetes) is common affecting 10-15% of all diabetes sufferers.

The market for diabetes therapeutics is also rising with global sales reportedly topping $8.1 billion for the 12 months to September 2000, a 19% increase over the previous 12 months (for a full analysis of diabetes therapeutics and market opportunities click here). Oral antidiabetic drugs, the leading class of drugs used to treat the disease, accounted for almost 63% of sales during this period, while sales of insulin stand at around 30%. Further increases are inevitable and the market for diabetes medications could exceed $20 billion by 2006. The largest unmet need in the diabetes market is improved delivery of insulin. Currently, the predominant mode of insulin administration is subcutaneous injection, which is extremely unpopular among patients and consequently much effort is being placed on identifying new insulin delivery technologies, with inhaled formulations representing one strategy under development. In order to develop such formulations it is critical to demonstrate that airway function remains unimpaired in response to chronic exposure to insulin; this is particularly so given that airway smooth muscle can switch between mitogenic hypocontractile and hypercontractile states.

In their recent EJP paper, Gosens et al have reported that pretreatment of bovine tracheal smooth muscle cells with insulin reduced the mitogenic activity of various growth factors. In addition in organ culture studies the treatment of tracheal strips with insulin for 8 days produced an increased maximal responsiveness to either methacholine or KCl. This suggests that chronic exposure to insulin increases the general contractility of tracheal smooth muscle by acting distal to smooth muscle receptors.

Most experience with inhaled insulin has been obtained using either dry powder formulation in the Nektar Pulmonary Inhaler/Exubera device or the AERx Insulin Diabetes Management System. Nektar is developing Exubera, in collaboration with Pfizer. Although phase III studies were completed in July 2001, further studies were initiated due to changes in FDA guidelines governing inhaled therapeutics. Following the report of this potential delay in regulatory filing, analysts predicted that launch would take place between 2002 and 2003, generating peak sales of anywhere between $250 million and $1.25 billion by 2006. Launch has yet to take place and Pfizer, Aventis, and Nektar have not offered guidance regarding a new filing timetable.

AERx entered phase III evaluation in 2002, and is being developed by Aradigm Corporation in collaboration with NovoNordisk. AERx uses liquid insulin that is converted into an aerosol containing very small particles, and an electronic device suitable for the rapid transfer of molecules of insulin into the bloodstream. A very recent phase IIb study of 107 diabetics treated for 12 weeks was published by Hermansen et al (2004). The therapeutic efficacy of insulin delivered in this fashion was similar to that in patients treated sub-cutaneously while adverse events were similar in the two groups. No major safety concerns were raised during the trial. In an earlier acute study it was shown however that asthmatic subjects absorbed less insulin than healthy subjects, resulting in less reduction of serum glucose. No acute effects of a single dose of inhaled insulin on airway reactivity were observed however it remains to be seen whether adverse effects are observed in this risk group especially if prolonged treatment with higher dosages of insulin is required to achieve therapeutic activity

From 1980 to 1996, the number of Americans afflicted with asthma more than doubled to almost 15 million, with children under five years old experiencing the highest rate of increase (see our recent analysis of current and breaking asthma therapeutics). The steady rise in the prevalence of asthma constitutes an epidemic, which by all indications is continuing. In 1990, the annual cost of asthma to the U.S. economy was estimated to be $6.2 billion, with the majority of the expense attributed to medical care. A 1998 analysis using different methods estimated the cost of asthma in 1996 to be over $11 billion per year.

The cause for the increase in asthma incidence is unclear although many epidemiological studies have been conducted. Of relevance to Gosens' study, a body of evidence suggests a lower prevalence of asthma and atopy symptoms in patients with type I diabetes mellitus. The observation that insulin produces a shift towards a hyper-contractile state suggests that poorly controlled diabetics may, as a result of reduced plasma insulin levels, display reduced airway smooth muscle contractile activity explaining this negative association. This is supported by animal studies showing that airway contractility is reduced in a model of diabetes and further investigation of this link could lead to the development of novel approaches to the treatment of asthma.

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