The clinical effectiveness and
cost-effectiveness of inhaled insulin in
diabetes mellitus: a systematic review
and economic evaluation
C Black, E Cummins, P Royle, S Philip and
Department of Public Health, University of Aberdeen, UK
* Corresponding author
Health Technology Assessment
NHS R&D HTA Programme
Health Technology Assessment 2007; Vol. 11: No. 33
Inhaled insulin in diabetes mellitus
The two main types of diabetes are type 1
(formerly called insulin-dependent diabetes) and
type 2 (formerly called non-insulin-dependent
diabetes). In type 1, insulin is always required
because the insulin-producing islet cells in the
pancreas have been destroyed. In type 2, the
pancreas can still produce insulin, and treatment
is initially with diet and exercise, but the disease
often progresses, with deteriorating control and
rising blood glucose levels, and a need next for
oral hypoglycaemic agents (OHAs), and later for
insulin in about 30%. The aim of insulin therapy is
to reduce blood glucose to normal levels, without
going too low and causing hypoglycaemia.
Insulin currently has to be given by injection. There
are various types according to duration of action –
short, intermediate and long. Short- and long-
acting insulin both come in two forms: traditional
and the newer analogues. The traditional form of
short-acting insulin is known as soluble. It is given
by injection using an insulin pen, or a syringe and
needle. Insulin can also be given by continuous
subcutaneous infusion by an insulin pump, usually
only in selected patients with type 1 diabetes.
The aim was to review the clinical effectiveness
and cost-effectiveness of a new technology, the
inhaled insulin, Exubera®(Pfizer and Sanofi-
Aventis in collaboration with Nektar
Technologies), a short-acting insulin.
A systematic literature review was conducted and
economic modelling carried out. Literature
searches were done up to November 2005. The
industry model, EAGLE, was used for modelling.
Nine trials of inhaled insulins were found, but
only seven used the Exubera form of inhaled
insulin. The other two used inhaled insulins that
have not yet been licensed. There were five trials
in type 1 and two in type 2 diabetes.
Inhaled insulin is clinically effective, and is as
good as short-acting soluble insulin in controlling
blood glucose. The frequency of hypoglycaemia is
similar. It works slightly more quickly than soluble
insulin. None of the published trials compared it
with short-acting analogues, which would have
provided a better comparison since they also work
slightly more rapidly than soluble. There is also a
problem in most of the trials in that patients were
on combinations of short-acting, and either long-
or intermediate-acting insulin, and both were
changed, making it more difficult to assess the
effects of only the change from soluble to inhaled
The only significant difference between inhaled
and soluble insulin in the trials was in patient
preference. Most patients preferred inhaled to
injected short-acting insulin, and this has some
effect on quality of life measures. However, there
could be some bias operating in the trials. The
control groups mostly used syringes and needles,
rather than pens. As pens are more convenient,
their use might have narrowed the patient
The manufacturer, Pfizer, argues that this patient
preference could lead to improved control in
some type 1 patients, through improved
compliance with treatment, and in some type 2
patients poorly controlled on oral agents, because
a switch to insulin therapy would be more
acceptable if people could use inhaled rather
than injected insulin. These assertions are
There were no trials of inhaled insulin against
continuous subcutaneous insulin infusion (CSII).
Concern has been raised about the long-term
effects of inhaled insulin in the lung. So far, no
serious adverse effects have been seen, but until
many thousands of people have used inhaled
insulin for many years, one cannot rule out some
uncommon or rare, but serious, adverse effects.
Executive summary: Inhaled insulin in diabetes mellitus
The manufacturer’s model (EAGLE) appears to be
a high-quality one. However, the results depend
more on the assumptions fed into the model than
on the model itself. The key assumptions are the
size of the gain in quality of life utility from
inhaling rather than injecting insulin, the effect of
having an inhaled option on the willingness to
start insulin among people with poor diabetic
control on oral drugs, and the effect on glycaemic
control. We consider that the assumptions used in
the industry submission make the cost-effectiveness
appear better than it really would be. The
manufacturer’s submission assumed utility gains of
0.036–0.075 in patients with type 1 diabetes, and
0.027–0.067 in those with type 2, based on an
unpublished utility elicitation study sponsored by
the manufacturer. We thought that these gains were
optimistic and that gains of 0.02 or less were more
likely, on average. However, patients with particular
problems with injection sites might have more to
gain, although they might also be a group with
much to gain from CSII.
A key factor is the cost of inhaled insulin. Much
more insulin has to be given by inhaler than by
injection, and so the cost of inhaled insulin is
much higher than injected. The extra cost
depends on dosage, but ranges from around £600
to over £1000 per patient per year.
The inhaled insulin, Exubera, appears to be
effective and safe, but the cost is so much more
that it is unlikely to be cost-effective.
Recommendations for the further
Additional research is recommended into the
safety, efficacy and cost-effectiveness of inhaled
Black C, Cummins E, Royle P, Philip S, Waugh N.
The clinical effectiveness and cost-effectiveness of
inhaled insulin in diabetes mellitus: a systematic
review and economic evaluation. Health Technol
Health Technology Assessment 2007; Vol. 11: No. 33 (Executive summary)
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