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Inhaled insulin: a diabetes innovation

Inhaled insulin (Exubera; Pfizer) was launched in the UK in August 2006. It is a dry-powdered, human, regular insulin that is made into an aerosol mechanically by a handheld device at the time of inhalation. The powder is prepackaged in 1mg and 3mg foil packets that deliver the equivalent of around three and eight units of insulin. The large surface area of the lung enables the large insulin molecule to cross from the alveoli by transcytosis. It is then released and taken up by endothelial cells to be released into the bloodstream.
Inhaled insulin acts rapidly with peak plasma levels between 30 and 90 minutes after inhalation, similar to rapid-acting insulin analogues, but it has a slightly more prolonged action than the rapid-acting analogues.(1)

Who cannot use inhaled insulin?
In people with normal lung function insulin absorption through the lungs is predictable, but it can be more rapid in smokers. In people with severe asthma and severe chronic obstructive pulmonary disease (COPD) it is slower.
Inhaled insulin is therefore contraindicated in people with:

  • Poorly controlled, unstable or severe asthma.
  • Current smokers or those who have smoked in the past six months.
  • Those with severe COPD.
  • In patients with congestive cardiac failure.
  • In pregnancy.
  • It is licensed for use in people over 18 years of age, so it cannot be used in children.

Does inhaled insulin work?
A number of studies have been published comparing inhaled insulin with subcutaneous insulin in type 1 and type 2 diabetes. In these studies the long-acting insulin has remained the same, but inhaled insulin has replaced short-acting insulin. Overall glycaemic control, as assessed by HBA1c, is the same with inhaled insulin as with injected short-acting insulin. So the conclusion is that inhaled insulin works as well as injected short-acting insulin. The National Institute for Health and Clinical Excellence (NICE), in its draft report published on its website, agrees with this conclusion.(2)

Is inhaled insulin safe?
There have been concerns about the long-term effects of inhaled insulin on lung function. In the studies carried out so far, pulmonary function was generally unaffected. Long-term studies to assess any changes in pulmonary function are underway.
In the meantime, lung function tests in the form of the measurement of FEV1 (forced expiratory volume) should be carried out before therapy with inhaled insulin is initiated and during treatment at appropriate intervals. This FEV1 testing will need to be arranged by the person initiating treatment. It is therefore likely that inhaled insulin will only be started in secondary care initially.
Insulin antibodies to both human and animal insulins have been reported. In studies with inhaled insulin, patients developed increased insulin antibody serum binding, but there was no correlation with parameters of clinical effectiveness, such as HBA1c or fasting plasma glucose. From the studies it seems that antibody levels plateau after around 12 months and do not correlate to effectiveness measures or adverse events
(eg, hypoglycaemia).

What are the side-effects of inhaled insulin?
Hypoglycaemia rates are reported to be slightly lower with inhaled insulin compared with subcutaneous insulin, and weight gain in some studies has been less on inhaled insulin.
Coughing is the main side-effect of inhaled insulin and is reported in around 10-20% of subjects, but it reduces in intensity and frequency with time. In a study in people with type 2 diabetes, 9% reported coughing but no patient withdrew from the study because of it.
Effectiveness of inhaled insulin does not alter significantly in the presence of upper respiratory tract infections, so people continue with inhaled insulin when they have a cold.
In all the studies reported so far, patient satisfaction in the inhaled insulin group has been greater than in the subcutaneous insulin group.

How is the inhaler device used?
The device is larger than the inhalers that are used in respiratory medicine (see picture on page 40). There are five steps to using the device (see Box 1). If further doses of insulin are required the process is repeated.

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The device needs to be cleaned weekly, and the transjector (the part involved with insulin aerosolisation) needs to be changed every two weeks. The whole device itself needs replacing after a year.
Mechanisms are in place to get replacement inhalers sent out to people within 24 hours if it should break.

What doses of inhaled insulin are needed?
Inhaled insulin should be taken around 10 minutes before a meal. One milligram of inhaled insulin roughly equates to around three units of subcutaneous insulin. In recently reported studies the main daily inhaled insulin dose was 14mg in people with type 1 diabetes and 17mg in type 2 diabetes. Several insulin inhalations per meal, using combinations of the 1mg and 3mg dried insulin blister packs, may therefore be needed.

Patient satisfaction and costs of inhaled insulin
In the trial programme, perception of tolerability of the regimen and ease of use were significantly greater in patients on inhaled insulin. A large proportion of patients randomised to inhaled insulin chose to continue with that regimen. These findings held regardless of type of diabetes or whether inhaled insulin was added to subcutaneous insulin therapy or oral agents.
Costs comparisons clearly depend on the amount of insulin needed for control, but typical subcutaneous insulin costs are around £300-400 per year. Inhaled insulin costs are likely to be around £1,200-1,500 per year.

What does NICE say about inhaled insulin?
NICE is in the process of conducting a technical appraisal of inhaled insulin for the treatment of diabetes (types 1 and 2). The second appraisal consultation document was published on the web in June.2 The closing date for comments on that was 12 July. The final appraisal document is due for publication in October 2006. This second appraisal document states that:

  • Inhaled insulin is not recommended for the routine treatment of people with type 1 or type 2 diabetes.
  • Inhaled insulin is recommended as a treatment option for people with type 1 or type 2 diabetes who have an HBA1c above 9% despite other therapeutic interventions and adequate educational support and who are unable to start or intensify insulin because of either:
    i.  A proven injection phobia diagnosed by a psychiatrist or psychologist; or
    ii. Severe persistent problems with injection sites (for example, as a consequence of lipohypertrophy).
  • In patients receiving inhaled insulin under these circumstances, treatment should only be continued beyond six months if a decrease in HBA1c level of more than 1% is achieved and the HBA1c level is maintained at less than 10%.
  • Initiation of inhaled insulin treatment and monitoring of response should be carried out in a specialist centre.
  • Data on the use of inhaled insulin according to this guidance should be collected as part of a prospective observational study. The data collected should include individual patient outcomes.

The future of inhaled insulin
The decision by national bodies to recommend the use of inhaled insulin is based on clinical and cost-benefit considerations. The Scottish Medicines Committee has said that it is not going to recommend the use of inhaler insulin in Scotland on cost grounds.
If the final NICE recommendation for England is similar to that of the second draft, there will clearly be a very slow-measured and assessed initiation of inhaled insulin in specialist centres for people with severe injection site problems or needle phobia when this has been diagnosed by the psychiatric or psychological services.
Healthcare professionals treating people with diabetes on a regular basis, such as diabetologists, diabetes specialist nurses and GPs with an interest in diabetes, are much more likely to have experience of trying to help, encourage and optimise blood glucose control in people who are reluctant to start insulin or intensify insulin because of a fear of injections or a reluctance to have more injections. In the UK, psychiatrists and psychologists have had little experience of dealing with needle phobic people with diabetes.
In my opinion the decision to consider inhaled insulin in the group of people with diabetes with needle phobia should be made by them, in consultation with the diabetes team
looking after them.
In a health service where one of the main political "drivers" for change is the policy of "patient choice" it seems strange that people with genuine needs cannot "choose" to try inhaled insulin without first being referred to the mental health service!

References

  1. Morton-Eggleston E, Barrett EJ. Inhaled insulin (editorial). BMJ 2006;332: 1043-4.
  2. National Institute for Health and Clinical Excellence. Diabetes (type 1 and 2), inhaled insulin. Appraisal Consultation Document. London: NICE; 2006. Available from: http://www.nice.org.uk/page.aspx?o=332283