The concept of inhaled insulin was initially investigated
in 1924,1 but the first demonstration of its glucose-lowering
effect in an animal model system occurred only in 1971.2 The presence of a large surface area (approximately 140
m2) provides the physiological rationale for use of the
respiratory tree for delivery of polypeptide drugs such
as insulin. The alveoli are lined by very thin (0.1–0.2 µm),
vesiculated and richly perfused epithelial cells, which
are highly permeable and devoid of any enzymatic digestion.
The key technological event for using this route for drug
delivery is to ensure the dispersal of insulin particles,
because large-sized particles will not reach the alveolar
tree. The nature of aerosol particles is dependent on their
mass median aerodynamic diameter (MMAD), which is a function
of the geometric diameter and density of the particle.
Particles with an MMAD of 1.5–2.5 µm are capable
of deposition in the lung alveoli. In the alveoli, insulin
particles are taken up in the vesicles, transported across
the capillary membrane and released into the blood stream.
In addition to particle diameter, smoking, upper respiratory
infection and asthmatic airway disease can also affect
the delivery of insulin to the alveoli.
The ideal pulmonary device to deliver insulin should be
portable, easy to use with minimal patient education, rechargeable,
moisture proof and capable of emitting a constant dose
to the lungs without being affected by the inhalation rate
of the patient. There are three main projects involving
inhaled insulin, namely Exubera (Nektar/Pfizer/Aventis),
AERx (Aradigm/Novo Nordisk) and AIR (Alkermes/Eli Lilly).
While dry insulin in the Exubera device is combined with
mannitol, glycine and sodium citrate, that in AIR is combined
with dipalmitoyl glycerol-phosphocholine, a normal component
of alveolar surfactant. The AERx device delivers a fine
particle liquid aerosol spray.
The bioavailability of inhaled insulin is approximately
10%–13% of subcutaneous insulin, which necessitates
an 8–10-fold higher dose requirement using this delivery
system. Studies have shown that the onset of action of
inhaled insulin varies from 5 to 15 minutes. The peak action
of inhaled insulin (45–60 minutes) is faster compared
with regular insulin but similar to that observed with
short acting analogues.3 The duration of action of inhaled
insulin (4–6 hours) has been demonstrated to be longer
than that of short acting insulin analogues (3–5
hours).4 This faster onset and longer duration of action
of inhaled insulin makes it more suitable for postprandial
glycaemic excursion coverage without causing late postprandial
The acute effect of cigarette smoking includes mucosal
irritation, reflex changes in muscle tone of the bronchial
tree and increased vasoconstriction, thus decreasing peak
flow, forced vital capacity (FVC), and forced expiratory
volume (FEV1) and has an adverse effect on the regional
distribution of blood flow.5 Recent
studies show that while the maximum insulin concentration
following inhaled insulin
is significantly more in smokers compared with non-smokers,
smokers are less sensitive to insulin than non-smokers
irrespective of the route of administration. Hence, despite
the increased peak insulin concentration seen in smokers,
the glucodynamic effect is partially offset, most likely
because of increased insulin resistance.6,7 This effect
on peak insulin concentration tends to normalize with cessation
of smoking,8 while resumption of smoking completely reverses
the effect of cessation of smoking. In view of the significant
effect of cessation and resumption of smoking on the pharmacokinetics
of inhaled insulin, it should not be used in people with
diabetes who choose to continue smoking. This is consistent
with the recommendation that people with diabetes should
refrain from smoking altogether. However, ex-smokers can
be considered for inhaled insulin use if their other pulmonary
functions remain normal.
Individuals with an acute upper respiratory tract infection
do not have any alteration in the pharmacokinetics of inhaled
insulin. Hence, such individuals need neither discontinue
therapy with inhaled insulin nor make any dose adjustments.9,10 There have been concerns about the long term potential
impact of inhaled insulin on pulmonary function. However,
in the majority of studies, pulmonary functions are not
affected by inhaled insulin, though there is greater decrease
in diffusion capacity for carbon monoxide.
Data from clinical trials suggest that inhaled insulin
is quite safe. Cough of mild-to-moderate severity is the
commonest side-effect, which decreases during treatment
and neither disturbs the patient’s routine nor necessitates
discontinuation of treatment. The overall incidence of
hypoglycaemia appears to be more with inhaled insulin compared
with injectable insulin. Relatively higher insulin-binding
antibody titres are seen with inhaled insulin as compared
with injectable insulin. However, this has not been shown
to be associated with any adverse clinical consequences
such as hypoglycaemia or erratic glycaemic control.11
Trials of inhaled insulin have been conducted in patients
with type 1 and type 2 diabetes mellitus. In two large
studies involving more than 300 subjects with type 1 diabetes,
inhaled insulin was compared with conventional regimens
using injectable insulin. Mean glycosylated haemoglobin
(HbA1c) decreased comparably in the two groups and a similar
proportion of individuals attained target HbA1c values.12,13 However, treatment satisfaction was significantly more
in patients on inhaled insulin. Overall satisfaction with
inhaled insulin was also reported to be significantly more
(35.1% v. 10.6%) by Gerber et al.14 The intra-subject variability
was reported to be comparable between patients receiving
inhaled insulin and subcutaneous insulin, thereby confirming
the reproducibility of this route of delivery.3 Data from
these studies suggest that inhaled insulin provides glycaemic
control comparable to that with a conventional insulin
regimen and provides greater overall patient satisfaction
than subcutaneous insulin.
In subjects with type 2 diabetes, inhaled insulin has either
been compared with regimens involving oral hypoglycaemic
agents (OHAs) or with conventional insulin therapy in subjects
with secondary OHA failure. Rosenstock et al.15 in an open
label, randomized controlled trial compared inhaled insulin
alone, inhaled insulin and OHA combination, and OHA alone
for 12 weeks and found that inhaled insulin improved glycaemic
control and HbA1c when added to or substituted with OHA.
In subjects with suboptimal control on diet and exercise,
pre-meal inhaled insulin resulted in better glycaemic control
compared with rosiglitazone.16 In patients with secondary
OHA failure, inhaled insulin and a bedtime dose of ultralente
insulin resulted in similar glycaemic control compared
with a regimen using twice daily subcutaneous pre-mixed
insulin.17 The proportion of patients reaching a target
HbA1c of <7% was more in the inhaled insulin group.
In another study, inhaled insulin immediately before meals
was compared with subcutaneous fast-acting human insulin
administered 30 minutes before meals, both in combination
with evening NPH insulin. While no significant difference
was observed in HbA1c, fasting serum glucose was significantly
lower in the inhaled insulin group compared with the subcutaneous
group.18 In a trial involving patients with inadequate
control despite therapy with a sulphonylurea and/or metformin,
the addition of inhaled insulin resulted in significantly
greater reduction in HbA1c.19 These studies suggest that
in patients with type 2 diabetes, inhaled insulin improves
glycaemic control when added to ongoing OHA therapy and
provides glycaemic control comparable with the conventional
subcutaneous insulin regimen.
Some important questions remain unanswered, which will
influence the eventual place of inhaled insulin in the
therapeutic options for people with diabetes. These include
long term efficacy, tolerance and pulmonary safety, impact
of immunogenicity, use in patients with respiratory disease
and long term acceptability, especially in patients with
type 2 diabetes. The cost of therapy, which at present
is considerably more than that of injectable insulin, together
with practical issues related to inhalation devices will
also have an effect on therapy with inhaled insulin. In
view of these pending issues, the National Institute for
Health and Clinical Excellence (NICE) in the UK does not
yet recommend inhaled insulin for therapy of patients with
diabetes except in the context of clinical studies. NICE
is also in the process of performing a cost–benefit
analysis of this therapy to help reach a recommendation
on its use in routine clinical practice.
In conclusion, inhaled intrapulmonary insulin offers an
attractive and viable alternative to subcutaneous injections
for delivery of insulin in people with diabetes. Inhaled
insulin has faster onset of action and therefore can be
taken just prior to a meal. The relative bioavailability
of inhaled insulin is lower than that of subcutaneous insulin,
which leads to an increase in dose requirements by 8–10-fold.
Therapy with inhaled insulin can cause a mild-to-moderate
cough, which usually does not interfere with the patient’s
routine activities. In both patients with type 1 and type
2 diabetes, treatment with inhaled and injectable insulin
results in comparable glycaemic control, though with significantly
greater patient satisfaction in those receiving inhaled
insulin. There remain some unanswered questions regarding
long term use, convenience and cost–benefit ratio
of inhaled insulin which will guide future recommendations
for its use in the standard medical care of patients with
- von Heubner W, de Jongh SE, Laquer E. Uber inhalation
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- Wise S, Chien J, Yeo K, Richardson C. Smoking enhances
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- Himmelmann A, Jendle J, Mellen A, Petersen AH, Dahl
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- Mather LE, Clauson P, Uy C, Kam P, McElduff A. Pharmacokinetics
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- McElduff A, Mather LE, Kam PC, Clauson P. Influence
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Department of Endocrinology and Metabolism
All India Institute of Medical Sciences