Vascular Health and Risk Management Dovepress

open access to scientific and medical research

Open Access Full Text Article review

Inhaled insulin: overview of a novel route

of insulin administration

This article was published in the following Dove Press journal:

Vascular Health and Risk Management
13 January 2010
Number of times this article has been viewed

Lucy D Mastrandrea Abstract: Diabetes is a chronic disease characterized by inadequate insulin secretion with
Department of Pediatrics, School
resulting hyperglycemia. Diabetes complications include both microvascular and macrovascular
of Medicine and Biochemical Sciences, disease, both of which are affected by optimal diabetes control. Many individuals with diabetes
University at Buffalo, Buffalo, NY, USA rely on subcutaneous insulin administration by injection or continuous infusion to control
glucose levels. Novel routes of insulin administration are an area of interest in the diabetes
field, given that insulin injection therapy is burdensome for many patients. This review will
discuss pulmonary delivery of insulin via inhalation. The safety of inhaled insulin as well as
the efficacy in comparison to subcutaneous insulin in the various populations with diabetes are
covered. In addition, the experience and pitfalls that face the development and marketing of
inhaled insulin are discussed.
Keywords: glycemic control, hemoglobin A1c, inhalation, insulin, type 1 diabetes, type 2
diabetes

Introduction
Diabetes is a class of diseases characterized by elevated blood sugar in the face of
inadequate insulin production or insulin action. The disease affects approximately
23.6 million Americans (8% of the population), and fully one-third of those individuals
are unaware that they have the disease.1 There are two broad categories of diabetes – type 1
(T1DM) and type 2 diabetes (T2DM). Individuals with T1DM are dependent on insulin
for survival and rely on subcutaneous administration by injection or continuous infusion.
Patients with T2DM may control their disease for a time with lifestyle intervention or
oral therapies. However, those who fail these strategies will require insulin to achieve
adequate disease control. Delivery of insulin via inhalation is a potential alternative
to subcutaneous insulin in the management of diabetes. This review will discuss the
rationale for development of pulmonary delivered versions of insulin as well as discuss
the role that inhaled insulin may play in improving long-term diabetes care.

Rationale for intensified diabetes care

Associations between hyperglycemia and the long-term complications of diabetes have
been demonstrated both in animal models and human studies. Elevated glucose levels
Correspondence: Lucy D Mastrandrea lead to significant vascular endothelial cell dysfunction, contributing to morbidities
Women and Children’s Hospital
of Buffalo, 219 Bryant Street, Buffalo, associated with the disease.2 Individuals with diabetes are at risk for both microvascular
NY 14222, USA disease including nephropathy, retinopathy, and neuropathy and macrovascular disease
Tel +1 (716) 878-7588
Fax +1 (716) 888-3827
including both fatal and nonfatal myocardial infarction and stroke. Epidemiologic
Email ldm@buffalo.edu studies have demonstrated a correlation between diabetes and cardiovascular disease.

submit your manuscript | www.dovepress.com Vascular Health and Risk Management 2010:6 47–58 47
Dovepress © 2010 Mastrandrea, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.
Mastrandrea Dovepress

The diagnosis of T2DM increases the risk of coronary heart carbohydrate intake with insulin administration.8 Because of
disease by a factor of 2- to 4-fold,3 while those with T1DM these concerns, intensification of insulin therapy to improve
have about a 10-fold increase in cardiovascular disease com- metabolic control is often delayed, and adherence to injection
pared to age-matched individuals without diabetes.4,5 Large regimens may be suboptimal.
prospective trials, such as the Diabetes Control and Com- Secretion of insulin in response to carbohydrate intake is
plications Trial (DCCT, T1DM)6 and the United Kingdom tightly regulated.9 Insulin is released into the portal venous
Prospective Diabetes Study (UKPDS, T2DM),7 have dem- system to exert effects at the liver initially, suppressing
onstrated that improving metabolic control, as measured by glycogenolysis and gluconeogenisis before acting peripher-
mean glycosylated hemoglobin (HbA1c), decreases the risk ally to stimulate glucose uptake and inhibit lipolyis.10 Current
of microvascular complications. Declines in HbA1c correlate strategies of subcutaneous insulin administration do not mimic
with reductions in both the development and progression of this first-pass effect of insulin on hepatic glucose control.
diabetic retinopathy, nephropathy, and neuropathy, indicating Thus, particularly for fasting/basal glucose control, subcutane-
that addressing hyperglycemia is relevant even in those with ous therapy fails to restore intra-portal insulin concentrations
established complications. These large trials did not show resulting in inappropriate hepatic glucose output. Attempts
declines in macrovascular disease with improved blood sugar to address this therapeutic concern by increasing doses of
control. However, in the Epidemiology of Diabetes Interven- basal insulin may place the patient at risk for hypoglycemia,
tions and Complications Trial (EDIC), a follow-up of the particularly in the fasting state. While available insulin
DCCT, patients who had received intensified therapy for a analogs provide improved coverage of meal-time glucose
period of 6.5 years had a 42% decrease in the risk of a first excursions, timing of insulin administration and careful atten-
cardiovascular event compared to the conventionally treated tion to matching carbohydrate ingestion with insulin dose is
group.6 More recent studies have called into question the goal paramount to limit post-prandial hyperglycemia.
of striving for near-normal glycemic control (HbA1c  6%) Therapies aimed at addressing these concerns include oral
in the T2DM population because of increased risk of cardio- insulin (intestinal absorption and buccal mucosal absorption),
vascular death. Current recommendations in diabetes care are implantable peritoneal insulin pumps, and inhaled insulin.
to aim for as close to euglycemia as possible. While enteral insulin therapy is limited by enzymatic deg-
While intensive therapy is recognized as a means to radation, there are ongoing trials to assess the feasibility of
improve long-term outcomes for patients with diabetes, fewer oral spray insulin in the treatment of T1DM compared to
than 40% of patients achieve the glycemic targets set forth twice daily insulin injections (www.clinicaltrials.gov iden-
by the American Diabetes Association (ADA) and American tifier NCT00668850).11 A recent study demonstrated that
Association of Clinical Endocrinologists (AACE). Barriers to compared to traditional CSII, patients using the implantable
achieving these goals are multi-factorial and include failure of peritoneal insulin pump had reduced HbA1c with more time
patients to accept intensified therapies and inability of current spent in the euglyemic range and less time in the hyperglyce-
regimens to mimic physiologic insulin delivery. mic range. However, this option may be limited by cost and
Intensive therapy in T1DM involves multiple daily sub- does carry the risk of peritoneal infections and implantation
cutaneous injections of insulin (3 to 5 per day) usually with site complications.12 Finally, pulmonary delivery of insulin,
long-acting insulin as basal insulin and short-acting insulin which was first tested in 1924,13,14 has been an area of active
administered just prior to meals. Alternatively, continuous investigation and development.
subcutaneous insulin infusion (CSII) pumps can be used.
For individuals with T2DM, initial management includes The lung as a vehicle
lifestyle interventions such as diet and exercise. However, for drug adminstration
most patients will eventually require oral therapies that Pulmonary delivery of drugs is used extensively in the
stimulate pancreatic β-cell insulin secretion (secretagogues) treatment of respiratory diseases such as asthma, chronic
or improve insulin sensitivity (biguanides or thiazolidinedio- obstructive pulmonary disease (COPD), and cystic fibrosis.
nes). If glycemic goals are not met, insulin therapy must Treatment goals for these disorders are to deliver drugs
be initiated. For patients with diabetes, either intensifying locally to affect bronchospasm (β-agonists), inflammation
(T1DM) or adding (T2DM) insulin therapy can be challeng- (inhaled steroids), and local bacterial infection (antibiot-
ing. Patients often resist transitioning to insulin injections out ics), while limiting systemic effects. The distal lung pro-
of fear and concern about the skill sets needed to correlate vides a large surface area (145 m2) with a thin (0.2 µM)

48 submit your manuscript | www.dovepress.com Vascular Health and Risk Management 2010:6
Dovepress
Dovepress Inhaled insulin for diabetes management

alveolar epithelium allowing for absorption of particles into of clinical protocols. The ideal device should not only
the bloodstream for systemic action.15 Factors which influence deliver insulin in a consistent fashion in order to achieve
the distribution of drugs to the distal lung include particle optimal glycemic control, but also should be convenient for
size, particle speed, and ventilatory parameters. In order patients – both portable and user-friendly. Over the course
for particles to be deposited in the alveolar space, their size of the last 20 years, several companies have worked to
should be between 1 and 3 µM; smaller particles are exhaled develop inhaled insulin systems for patient use. The systems
and particles 5 µM are deposited in the upper airways or differ in the formulation of the inhaled insulin – liquid vs
swallowed.16 Patient cooperation and appropriate ventilator lyophilized powder – and the delivery device with respect to
technique are important to ensure reproducible delivery size, mechanism of insulin release, and regulation of insulin
of drug to the deep lung. Inhalers that allow for release of administration (mechanical vs electronic). The bioavailability
the insulin particles at the start of a deep, slow inhalation of inhaled insulin for each of the devices varies, but is in the
provide the best penetration to the alveolar space.17,18 Rapid range of 10% to 46%, with much of the drug being lost within
shallow inhalations lead to significant losses of the drug in the device or in the oropharynx or upper airways.22 Table 1
the oropharynx and upper airways. Thus, ability to perform summarizes the features of inhaled insulin delivery systems
appropriate breathing maneuvers plays an important role in that have been studied most extensively.
maximizing the effectiveness of inhaled insulin therapy. Exubera® was developed through a collaboration between
Nektar Therapeutics and Pfizer and, in 2006, was approved
Development of inhaled insulin by the Food and Drug Association (FDA) and the European
Shortly after Banting and Best discovered insulin in the early Medicines Agency (EMEA) for treatment of both T1DM and
1920s,19 the first studies using inhaled insulin were per- T2DM. The insulin delivered by this device is a dry powder
formed. In these studies, it was reported that blood glucose formulation packaged in blister packets containing 1 mg or
decreased in response to inhalation of insulin.14,20 In 1987, 3 mg of regular human insulin. The unit doses are delivered
it was demonstrated that nebulized human insulin provided via a mechanical inhaler and are equivalent to 3 units and
blood sugar control comparable to subcutaneous insulin in 8 units of subcutaneously delivered short-acting insulin,
6 children with T1DM.21 However, it was recognized that respectively. Much of the medical literature describing the
the bioavailability of inhaled insulin was significantly lower pharmacokinetics, glucodynamics, and safety profiles of
than that of subcutaneous preparations. Consequently, it was inhaled insulin was obtained from studies using Exubera®.
not until the development of improved delivery devices and However, in October 2007, Pfizer announced that it would
understanding of particle pharmacology that inhaled insulin no longer be selling Exubera® secondary to poor sales and
became ready for clinical study. acceptance.
The AERx insulin diabetes management system (AERx®
Inhaled insulin devices iDMS) was developed by both Aradigm Corporation and
Devices capable of delivering particulate insulin to the Novo Nordisk. This system creates an aerosol of insulin
alveolar space have been developed and studied in a variety droplets from a liquid insulin preparation. The device has

Table 1 Inhaled insulin systems

Inhalation Insulin Insulin equivalentsa Inhaler Method of Device Sizeb Device benefits Current status
system formulation device inhalation
Exubera® Dry powder, 1 mg = 3 U Mechanical User dependent 20 cm × 4 cm Collapsible FDA-approved
blisters 3 mg = 8 U off-market
AERx iDMS® Liquid insulin, 1 AERx unit = 1 U Electronic Guided system 8 cm × 4 cm Download capability No further
blisters development
AIR® Dry powder, 6 mg = 2 U Mechanical Breath actuated 7 cm × 2 cm Small device size No further
capsules 9 mg = 6 U development
Technosphere® Dry powder 6 TU = 1.56 U Mechanical User dependent 10 cm × 5 cm Placebo formulation Phase 3 trials
microspheres, 12 TU = 3.12 U FDA – new drug
cartridges 24 TU = 6.24 U application
Compared to regular insulin; bapproximate size.
a

Abbreviation: TU, technosphere units.

Vascular Health and Risk Management 2010:6 submit your manuscript | www.dovepress.com
49
Dovepress
Mastrandrea Dovepress

electronic controls that guide the user to inhale the insulin glucose concentrations while limiting delayed hypoglycemic
in a reproducible fashion. In addition, the device offers the effects. The majority of studies compare different inhaled
capability to download dosing, use frequency, and inhala- insulin delivery systems to regular insulin administered
tion patterns to aid the prescriber and patient in monitoring subcutaneously which has a peak effect on glycemia
adherence and treatment goals. Although the AERx® system 30–60 minutes after administration and duration of action
was in phase III trials, Novo Nordisk elected to discontinue up to four hours.
further study with this system given the experience of Pfizer
with Exubera®. Pharmacokinetics of inhaled insulin
AIR® insulin system, developed in conjunction with Eli Studies to assess serum concentrations of insulin following
Lilly and Co. and Alkermes Inc. uses a dry powder insulin inhalation have been performed in healthy volunteers as well
with a mechanical inhaler. The inhaled particles are signifi- individuals with both T1DM and T2DM. A summary of the
cantly larger (5 to 30 µM), yet less dense than those of other pharmokinetic parameters for various inhaled insulin devices
systems, and are delivered efficiently to the alveolar space. is provided by Patton et al.22 In a comparison of Exubera®
While this system has been through extensive phase III test- and regular insulin in healthy nonsmoking males, the total
ing, Eli Lilly and partners are not pursuing development of insulin exposure was similar for inhaled insulin and regular
this product at present. insulin.27 However, the time to maximal insulin concentration
The Technosphere® system combines a dry powder recom- (Cmax) was more rapid for inhaled insulin vs regular insulin
binant human insulin (Mannkind Corp.) with the MedTone® (55 min vs 148 min). In an open-label 4-way crossover study
inhaler (Pharmaceutical Discovery Corp.). This system is in healthy volunteers comparing 3 different Technosphere®
currently in phase III trials and is unique in that the partners inhaled insulin doses and regular insulin, similar results were
have developed a placebo formulation for inhalation, allow- found – Cmax was 12 to 17 min for Technosphere insulin and
ing for design of double-blind, placebo controlled studies in 134 min for regular insulin.28 Studies performed with the
patients with T2DM.23 Technosphere® compares favorably AERx® system in patients with T1DM also revealed there
to regular insulin administrated subcutaneously in control- was a more rapid rise in serum insulin in the inhaled group vs
ling postprandial hyperglycemia, suggesting that this formu- regular insulin group.29 However, the intrasubject variabil-
lation may provide improved blood sugar control.24 ity with respect to total insulin exposure was ∼26% for the
While there are other inhaled insulin devices/systems inhaled group, indicating that consistent inhalation tech-
that have been developed, much of the investigation in this niques could play a significant role in diabetes control. Rave
area has been halted. A review of www.clinicaltrials.gov et al compared Technosphere® insulin to regular insulin in
using inhaled insulin as a key word revealed 75 trials, 20 of 16 patients with T2DM.24 Cmax was reached earlier (15 min vs
which were terminated before projected completion dates. 120 min) and was 45% greater for inhaled insulin compared
Only 5 trials of inhaled insulin are listed as either actively to regular insulin. In addition, while the total insulin exposure
recruiting or not yet recruiting, 4 of which are investigating for inhaled insulin was comparable to that of subcutaneous
Technosphere® insulin.25 Mannkind has filed a new drug insulin, the exposure time was shorter with inhaled insulin,
application with the FDA; it remains to be seen whether this suggesting that the risk of delayed hypoglycemia may be less
application will be approved.26 with the inhaled insulin formulation.24

Pharmacology of inhaled insulin Glucodynamics of inhaled insulin

Discussion of the pharmacology of inhaled insulin involves Glucodynamics is measured by determining the infusion
both the study of pharmacokinetics – measurement of serum rate of glucose necessary to maintain euglycemia following
insulin levels following administration of the drug – and the administration of insulin. This parameter determines the
pharmacodynamics – measurement of onset and dura- hypoglycemic effect of therapy. In healthy males receiving
tion of hypoglycemic effect. Most of the inhaled insulin inhaled insulin, rates of glucose infusion were higher in
devices are designed to be used in conjunction with carbo- the first hour after dosing than in those receiving regular
hydrate consumption, targeting control of prandial glucose insulin by injection, correlating with the more rapid rise in
excursions. The ideal system would closely mimic β-cell serum insulin levels.27 This maximal effect on glycemia is
secretion of insulin with rapid onset of action followed by comparable to short-acting insulin analogs. Total glucose
sustained activity over a period of 2–3 hours to control rising consumption was comparable for bioequivalent doses of

50 submit your manuscript | www.dovepress.com Vascular Health and Risk Management 2010:6
Dovepress
Dovepress Inhaled insulin for diabetes management

inhaled vs regular insulin over the entire clamp period.27 In Use of inhaled insulin
individuals with T1DM, the glucose infusion rate profile in treatment of diabetes
showed an early peak rate with inhaled insulin (AERx®) vs Multiple studies have been performed in patients with both
regular insulin with a similar glucose consumption.29 Rave T1 and T2DM to assess the efficacy of inhaled insulin in
et al performed mixed-meal tolerance tests in 16 individu- controlling diabetes. Inhaled insulin has been compared to
als with T2DM and compared the ability of Technosphere® regular insulin or short-acting insulin analogs in patients
insulin and regular insulin to control postprandial glucose with T1DM. Studies including individuals with T2DM have
levels. Both maximal postprandial glucose excursion and assessed the effect of inhaled insulin on diabetes control when
total blood glucose area under the curve were significantly added to oral therapy as well as in comparison to short-acting
lower following use of inhaled insulin in this group, indicat- insulin. Outcome measures have included HbA1c, pulmonary
ing that for similar insulin exposure, glycemic control was function, weight gain, and patient satisfaction.33
improved with inhaled insulin.24 The rapid onset of action
coupled with the ability to exert an effect on glucose levels Type 1 diabetes
for several hours after administration, makes inhaled insulin Current strategies to control blood glucose levels in indi-
a good candidate for control of meal-time glucose levels. viduals with T1DM involve subcutaneous insulin injections
Bioavailability of inhaled insulin is limited by several fac- given multiple times per day (2 to 5) or insulin pump therapy
tors including losses of the drug within the inhalation device, via CSII. In patients receiving injection therapy, they gen-
oropharynx, or upper airways, as well as adequate ventila- erally receive long-acting (basal) insulin 1 or 2 times/day
tory maneuvers to deposit insulin to the lower airways.22 In and short-acting insulin with meals to cover post-prandial
studies using the AERx® device in individuals with T1DM, it meal excursions. Multiple daily injection therapy places a
was estimated that the system efficiency on a unit/kilogram burden on patients and is a significant barrier to optimizing
basis was 13% as measured by glucodynamics compared to adherence to diabetes regimens aimed at improving glycemic
injected regular insulin.29 This indicates that more insulin is control. Inhaled insulin has the potential to replace short-
needed for inhalation therapy compared to injection, a factor acting insulin analogs, eliminating as many as 4 injections
which could play a role in risk of long-term side effects as per day.
well as cost of therapy. Inhaled insulin administered before meals has been
compared in a randomized controlled fashion to regimens
Equivalence dosing of inhaled using regular insulin preprandially and either NPH (twice
insulin daily) or ultralente (once daily). In studies performed using
Pharmacokinetic and glucodynamic studies have been Exubera®, inhaled insulin was noninferior with respect to
performed to determine the equivalence of each inhaled HbA1c changes, although 2-hour postprandial and fasting
insulin formulation relative to subcutaneous insulin.30,31 plasma glucose levels were lower in the groups receiving
These results are summarized in Table 1. In order for inhaled insulin.34,35 In a recent study reported by Garg et al
patients to receive the appropriate amount of insulin to 385 individuals with T1DM were randomized to receive
cover carbohydrate ingestion, they must perform a series either inhaled insulin (AIR®) or regular/lispro insulin before
of inhalations using the doses available for each delivery meals with glargine serving as the basal insulin.36 After
system. For example, a patient normally requiring 10 units 2 years of study, only 20% of study subjects reached a target
of regular insulin could inhale either three 1 mg blisters HbA1c of  7%, and inhaled insulin was demonstrated to
(9 unit equivalents) or one 1 mg blister and one 3 mg blister be inferior to preprandial subcutaneous insulin with respect
(11 unit equivalents) of Exubera® to achieve a comparable to change in HbA1c. When individuals with T1DM were
insulin dose. A study was performed in healthy nonsmoking treated with glargine as basal insulin and randomized to
adults to determine whether different dose combinations of either Technosphere® inhaled insulin or rapid acting insulin
AIR® capsules were interchangeable.32 The pharmacokinetic analog, both groups had comparable decreases in HbA1c at
and glucodynamic results demonstrated that combinations 1 year; however, the inhaled insulin group had significantly
of different AIR® capsule dose strengths were equivalent. lower fasting plasma glucose and 1 hour postprandial glu-
Thus, there is greater flexibility with insulin dosing as well cose levels compared to those on subcutaneous insulin.37
as less glycemic variability when equivalent dose strengths The discrepancies between the studies related to effects
are interchanged in this system. of inhaled insulin on HbA1c may be related either to the

Vascular Health and Risk Management 2010:6 submit your manuscript | www.dovepress.com
51
Dovepress
Mastrandrea Dovepress

inhaled insulin formulation itself or to the basal insulin (–0.69% vs –0.77%; inhaled vs subcutaneous). A further
used in each study. study in individuals with poorly controlled T2DM receiving
oral therapy plus basal glargine demonstrated that the addi-
Type 2 diabetes tion of AIR® inhaled insulin to once-daily glargine resulted
Individuals with T2DM often have complicated medication in a greater improvement in HbA1c (–0.97% vs –0.62%;
regimens when the addition of insulin is considered. Patients inhaled + glargine vs glargine), even when glargine dose
may be taking several different classes of drugs in an effort was titrated to optimize glycemic control. 41 Individu-
to control blood sugars – oral hypoglycemic agents (sulfo- als with T2DM initially randomized to either inhaled or
nylureas or meglitinides) and insulin sensitizers (biguanides subcutaneous insulin in a 12-week proof of concept study
or thiazolidindiones). Rosenstock et al performed a trial in were offered the option of continuing inhaled insulin for
T2DM patients on dual oral agent therapy who continued to 1 year.30 In those who elected to continue inhaled insulin,
have poor glycemic control (HbA1c  8%). Patients were the decrease in HbA1c (–0.78%) was sustained throughout
randomized to continued oral therapy, oral therapy plus the extension trial, indicating that the therapeutic effects on
Exubera®, or Exubera® alone. HbA1c improved by 1.4% glycemic control are durable.42 It should be noted that, thus
(inhaled) and 1.9% (inhaled plus oral agents) compared to far, no clinical trial has demonstrated that inhaled insulin
oral agents alone.38 This suggests that some patients may is superior to subcutaneous insulin for the goal of diabetes
achieve adequate glycemic control on inhaled insulin alone, care – improved glycemic control.
thereby simplifying their treatment regimen. In addition,
individuals randomized to inhaled insulin plus oral agents had Special populations
a greater likelihood of reaching glycemic targets compared Smoking and inhaled insulin
to those on oral agents alone (32% vs 1%).38 It is estimated that 20% to 25% of individuals with dia-
As discussed above, Mannkind Corporation has devel- betes are tobacco smokers.43 Smoking induces both acute
oped a placebo based device for use in clinical trials as a com- and chronic effects on the pulmonary system, including
parator to Technosphere® inhaled insulin. This controls for the vasoconstriction, changes in permeability, and remodel-
attention received by subjects within a study as well as the ing of the bronchioalveolar lining. Therefore, efforts have
motivation factor ascribed to subjects who are randomized to been made to address the effects that smoking has on the
inhaled insulin, in contrast to subcutaneous insulin, that may pharmacokinetics of inhaled insulin. Following administra-
bias study outcomes. Individuals with T2DM suboptimally tion of inhaled insulin, nondiabetic chronic smokers have
controlled on oral agents were randomized in a double-blind a higher Cmax, greater absorption of insulin (AUC0–360), and
fashion to receive either placebo Technosphere® powder shorter time to Cmax nonsmokers.44,45 These data suggest
or Technosphere® insulin before meals.23 Use of inhaled that individuals who smoke would be at higher risk for
insulin resulted in a significant decline in HbA1c compared hypoglycemia when treated with inhaled insulin. Becker
to those using placebo, taking into consideration that HbA1c et al examined the effects of smoking cessation on pharma-
was mildly elevated in all subjects at baseline (8%, inhaled cokinetics of inhaled insulin.46 Within 1 week of smoking
insulin group; 7.8% placebo group). cessation, the Cmax and AUC0–360 after inhaled insulin had
In a study of patients with T2DM on insulin therapy, decreased significantly and approached that of nonsmokers.
subjects received either pre-meal Exubera® plus ultralente Resumption of smoking reversed the effects of smoking
(subcutaneous) or twice daily injections of regular and cessation, with both insulin exposure and glucose utiliza-
NPH insulin.39 There was no difference in the reduction in tion increasing. However, tobacco use is also associated
HbA1c between the groups, although those randomized to with insulin-resistance,47 and Wise et al demonstrated that
inhaled insulin were more likely to achieve HbA1c  7% although nondiabetic smokers had a greater exposure to
(odds ratio 2.27, 95% confidence interval 1.24 to 4.14). In a insulin following inhalation compared to nonsmokers, they
similar population of patients with T2DM, AERx® premeal did not have increased glucose utilization as measured by
inhaled insulin was compared to premeal subcutaneous glucose infusion rates.44 Therefore, particularly in the T2DM
regular insulin, both in combination with bedtime NPH population, the increase in alveolar permeability that leads
insulin.40 After 12 weeks of therapy, there was no differ- to increased insulin absorption following inhalation may be
ence in HbA1c between the two groups, and both groups counteracted by the effects of insulin resistance mediated
experienced a similar decline in HbA1c from baseline both by the disease state and smoking.

52 submit your manuscript | www.dovepress.com Vascular Health and Risk Management 2010:6
Dovepress
Dovepress Inhaled insulin for diabetes management

In contrast to chronic smoking, individuals who are insulin (AUC) was 34% to 41% less.51 The glucodynamic
exposed to passive smoking have a different response effects of inhaled insulin were comparable between healthy
to inhaled insulin. In healthy nonsmokers, exposure to and subjects with mild asthma, while the ability of inhaled
cigarette smoke for 2 hours prior to insulin inhalation insulin to lower serum glucose was decreased in subjects with
resulted in significantly lower insulin bioavailability and moderate asthma. This effect was ameliorated by pretreat-
pharmacokinetic parameters.48 This is similar to the effect ing subjects with a long-acting β-agonist to alleviate airway
of acute cigarette smoking just prior to insulin inhalation narrowing. There were no acute asthma exacerbations as a
by smokers, where the AUC0–360 is not increased.45 Thus, result of insulin inhalation.51
smoking, whether acute or chronic, passive or primary, The prevalence of diabetes in patients with COPD
impacts the pharmacokinetics of inhaled insulin, placing is as high as 12%.52 This disease is categorized as being
patients at risk for fluctuations in blood sugars with result- both restrictive (emphysema) and obstructive (chronic
ing suboptimal metabolic control. bronchitis) in its effects on pulmonary function. These
When inhaled insulin was on the market, it was not complications may limit the ability of individuals to use the
approved for smokers or for those who had smoked within inhalation devices appropriately or may restrict the surface
the previous 6 months. Given the fact that Pfizer and Nektar area available for insulin absorption across the alveolar
Pharmaceuticals announced an increase in lung cancer cases membrane. Rave et al performed a randomized cross-over
in former smokers involved in clinical trials of Exubera®, it study comparing the responses to inhaled vs subcutaneous
is unlikely that any inhaled insulin that comes to market in short-acting insulin in both healthy controls (nonsmokers)
the future will be approved for either smokers or previous and individuals with COPD who had not smoked for lon-
smokers.49 ger than 6 months.53 They demonstrated that while inhaled
insulin was well tolerated in those with chronic lung disease,
Respiratory disease and inhaled serum levels of immunoreactive insulin following inhaled
insulin insulin administration were lower in individuals with COPD,
Because both acute and chronic respiratory diseases have particularly in those with chronic bronchitis compared to
the potential to alter the pharmacodynamic effects of inhaled control subjects. The insulin effect in patients with COPD
insulin, it is necessary to understand how illness and pul- was 60% to 65% of the control subjects. Thus, for those with
monary pathology influence inhaled insulin action. Acute COPD, increased doses of inhaled insulin may be necessary
respiratory illnesses are a common occurrence and are to achieve the same degree of metabolic control. There
accompanied by cough, mucous production, and inflamma- were no acute effects on pulmonary function in response to
tion of the pulmonary tree. In nondiabetic adults, there was insulin inhalation.53
no difference in the pharmacokinetics or glucose response
to inhaled insulin either during the acute or recovery phase Age and inhaled insulin
of an upper respiratory tract infection.50 In addition, pul- Both lung volumes and diffusion capacity change as a func-
monary function tests (PFTs) following administration of tion of age.54 These changes can modulate both delivery of
inhaled insulin were unchanged in the same subjects. These inhaled insulin to the distal airways, as well as absorption
observations suggest inhaled insulin is efficacious even in of the insulin across the alveolar epithelium. Henry et al
the clinical setting of acute upper respiratory infection. demonstrated that in individuals with T2DM, increasing age
Comparable studies have not been performed in subjects (65 years) impacted the ability of inhaled insulin to lower
recovering from lower respiratory tract infections such as glucose levels compared to a younger population (age 18 to
pneumonia. 45 years) while Cmax and AUC0–360 were not different between
Asthma is a chronic disease characterized by inflamma- the two groups.55 These results indicate that, in older patients,
tion and airway hyper-reactivity with periods of exacerbation an increased inhaled insulin dose may be required to achieve
and quiescence. In order for inhaled insulin to be recom- comparable diabetes control.
mended in this population, it must not trigger bronchospasm,
and it must be provide optimal blood sugar control during Adverse effects
acute asthma exacerbations. In a study of non-diabetic sub- The adverse effects of inhaled insulin are summarized in
jects with mild to moderate asthma, it was demonstrated Table 2. There have been no adverse effects uniquely associ-
that compared to healthy subjects, the overall exposure to ated with a specific insulin formulation or delivery device.

Vascular Health and Risk Management 2010:6 submit your manuscript | www.dovepress.com
53
Dovepress
Mastrandrea Dovepress

Table 2 Side effects of inhaled insulin formulations

Side effect Degree of effecta Notes
Cough + Coincident with inhalation, decreased severity over time. Occasionally treatment limiting.
Change in FEV1 +/− FEV1 testing required by FDA prior to initiation of therapy.
Change in DLCO + Decline early in treatment then stable. Reversal of effect upon discontinuation of therapy.
Insulin antibodies + Increased titers compared to subcutaneous formulations. No correlation with pharmacologic effect.
Hypoglycemia +/− Less risk of severe hypoglycemia compared to subcutaneous insulin. Increased risk in insulin naïve
patients.
Weight gain +/− Associated with addition of any insulin to therapeutic regimen in T2DM.  Weight neutral to decrease
in T1DM.
Notes: aDegree to which effect was observed when reported by investigators; +, effect consistently observed; +/−, effect inconsistently observed.
Abbreviations: DLCO, carbon monoxide diffusion capacity; FEV1, forced expiratory volume in 1 second.

Body weight Pulmonary function

One concern with insulin therapy is that, with intensified Given that insulin therapy will be life-long for many
protocols, weight tends to increase. This is particularly diabetics, it is relevant to understand the effects that inhaled
true for patients with T2DM, in whom excess weight gain insulin has on lung function. There are hypothetical concerns
contributes to worsening insulin resistance, with cor- about the toxicity of insulin particulates on the alveolar-
responding need for increased insulin doses. In studies capillary network as well as the growth-promoting effects
enrolling patients with T1DM, there was either no change56 of insulin when it binds competitively, albeit at significantly
or a trend towards less weight gain35,37 in those receiv- lower potency, to insulin growth factor-1 receptors in the
ing inhaled insulin vs subcutaneous short-acting insulin lung.22 Rosenstock et al demonstrated no changes in either
analog. In a study of insulin-naïve patients with T2DM, forced expiratory volume at 1 second (FEV1) , total lung
inhaled insulin monotherapy or in conjunction with 2 oral capacity, or carbon monoxide diffusion capacity (DLCO) in
agents resulted in a mean 2.7 kg weight gain compared to patients with T2DM receiving inhaled insulin for a period of
oral agent therapy.38 However, in individuals with T2DM 12 weeks.38 A 2-year follow-up study in patients with T2DM
previously receiving subcutaneous insulin therapy, there treated with inhaled insulin as an adjunct to oral therapies
was no weight change in those treated with inhaled insulin demonstrated that there was a decrease in FEV1 and DLCO
vs those continued on subcutaneous insulin therapy.30 All at 24 weeks of therapy that did not progress throughout
individuals who transition to intensified diabetes care should the course of the study.57 Interestingly, the oral therapy
be counseled about the risk of weight gain, regardless of group also showed similar declines during the course of the
the therapeutic regimen. study, although the change in FEV1 was slightly greater in
the inhaled insulin group. These findings are comparable
Hypoglycemia to previous studies measuring the annual rate of change in
Treatment strategies aimed at achieving euglycemia carry FEV1 in a group of individuals with T2DM,58 suggesting
the risk of increased number and severity of hypoglycemic that the declines do not reflect adverse effects of the drug,
events.6 Inhaled insulin is associated similar rates of hypogly- but, rather, represent the natural history of the disease with
cemia when compared to subcutaneous insulin in both T1 and respect to lung function.
T2DM populations; no increase in severity of episodes was Short-term (6-month) studies in patients with T1DM have
reported.30,35,56 In a study including subjects with T2DM on demonstrated that DLCO decreases by ∼0.75 to 1.2 mL/min/
oral agent therapy alone prior to study entrance, the incidence mm Hg.34,35 Long-term study of the effects of inhaled insu-
of hypoglycemic events was greater in the cohorts receiv- lin on lung function in patients with T1DM is limited to a
ing inhaled insulin compared to oral agents alone (66% to 4-year extension trial combining patients with both T1 and
76% vs 8%).38 In addition, the rates of symptoms associated T2DM. Annualized changes in FEV1 were -0.057 ± 0.004
with hypoglycemia, including tremor, sweating, and head- L/year in the inhaled insulin group and -0.071 ± 0.023 L/year
ache were higher in the inhaled insulin groups. However, in the control group, while DLCO changes were -0.376 ±
the rate of severe hypoglycemic events, defined as an event 0.067 mL/min/mmHg and -0.673 ± 0.423 mL/min/mmHg,
requiring outside assistance, was not increased.38 respectively.59 Although these experiences suggest that

54 submit your manuscript | www.dovepress.com Vascular Health and Risk Management 2010:6
Dovepress
Dovepress Inhaled insulin for diabetes management

inhaled insulin is safe with respect to lung function, when Quality of life and adherence
Exubera® was on the market, it was recommended that all to therapy
patients have FEV1 tested at baseline, after 6 months of One of the proposed benefits to inhaled insulin therapy is that,
therapy, and annually while taking the drug. For individu- in contrast to injections, it will be accepted more readily by
als with FEV1  70% predicted or a decline 20%, it was patients when insulin therapy must be intensified or when
recommended that the drug be discontinued. Longer-term oral therapy is failing to achieve glycemic goals. Freemantle
studies will help to determine whether the effects of inhaled et al demonstrated that the availability of inhaled insulin as
insulin on pulmonary function have clinical repercussions. a hypothetical treatment option increases the likelihood that
Mild to moderate cough occurs more frequently in indi- patients with poorly controlled T2DM will accept the addi-
viduals receiving inhaled insulin. Coughing episodes were tion of insulin to their therapeutic regimen.69 Alternatively,
usually reported coincident with insulin inhalation.23 How- Bergenstal et al addressed the question of whether having the
ever, both the rate and severity of this effect decreased over opportunity to choose AIR® insulin increased the likelihood
time in studies reporting this outcome.34,35,38 No differences in that individuals with poorly controlled T2DM would choose
cough rates were observed in subjects using Technosphere® any insulin therapy.70 In this study, subjects were random-
inhaled insulin vs Technosphere® placebo powder.23 In ized to receive counseling on therapeutic options to inten-
addition, cough was not a significant contributor to subject sify diabetes management that either excluded or included
withdrawal from clinical studies. inhaled insulin. The study determined that the availability of
inhaled insulin did not increase the likelihood that individuals
Insulin antibodies would add insulin to their treatment regimen. In addition, both
The delivery of insulin whether subcutaneously, intraperito- groups had a comparable improvement in HbA1c regardless of
neally, or by inhalation leads to the formation of circulating whether they added inhaled or subcutaneous insulin.70 Finally,
insulin immunoglobulins.60–62 High circulating levels of insu- patients with T1DM who received Exubera® reported higher
lin antibodies may disrupt glycemic control by 2 mechanisms. overall satisfaction scores and quality of life scores compared
First, the antibodies may bind to the insulin blocking its action to those receiving subcutaneous therapy.35 Rosenstock et al
with resulting hyperglycemia.63,64 Secondly, the insulin may reported that, following a 12-week randomized controlled
then be released from the antibody complex, with inappropri- trial comparing inhaled and subcutaneous insulin, 85% of
ate insulin action (discordant with carbohydrate intake) and patients randomized to inhaled insulin elected to continue the
delayed hypoglycemia.65,66 In rare cases, true insulin allergies drug, and 75% of those randomized to subcutaneous therapy
may develop.62 elected to switch to inhaled insulin. In addition, overall
The experience with inhaled insulin has not unearthed satisfaction with inhaled insulin therapy was sustained for
these concerns. In patients with both T1DM and T2DM, 1 year of therapy and impacted psychological well-being in
levels of insulin antibodies were measured following a positive manner.42 This is an important finding given that
the introduction and use of inhaled insulin. Individuals the glycemic control in these patients was comparable to that
with T1DM using inhaled insulin had a 22% increase in of subcutaneous insulin and did not deteriorate throughout
the median percentage antibody binding compared to those the extension phase of the study,42 suggesting that adherence
treated with CSII therapy.67 For patients with T2DM, the to inhaled insulin therapy remained high.
use of inhaled insulin led to the development of insulin Adherence is the measure that a patient is taking medi-
antibodies. The peak levels were significantly lower than cations as prescribed by their provider. Rates of adherence
those observed in patients with T1DM, and peak antibody are lowest in chronic diseases, and decline with increases in
levels were reached within 6 to 12 months of inhaled insulin daily dosing.71 Claxton et al showed that with four times/day
exposure. Insulin antibody levels increased in all groups medication schedule, the rate of adherence was less than
treated with inhaled insulin; there was no association of 50%.72 Individuals with diabetes often have multiple medi-
antibodies with hypo/hyperglycemia, deterioration of meta- cal problems, necessitating polypharmacy with complicated
bolic control, allergic reactions, or changes in pulmonary dosing schedules. Therefore, any delivery system improving
function testing. Thus, while the delivery of insulin to the adherence in the diabetic population would be welcome.
pulmonary system induces immune responses, these have Measuring adherence to subcutaneous insulin therapy via
not been demonstrated to decrease the effectiveness of syringe is difficult; proxy outcomes are number of prescrip-
inhaled insulin over time.68 tions filled, vials of insulin used, and difference in HbA1c

Vascular Health and Risk Management 2010:6 submit your manuscript | www.dovepress.com
55
Dovepress
Mastrandrea Dovepress

following initiation of therapy. The AERx® system records withdrawal of Exubera® from the market had on the continued
the date and time of each insulin administration as well as the study and development of competing inhaled insulin devices.
adequacy of the inhalation technique. Rates of adherence to The second major development is the report from Pfizer that
preprandial insulin administration were as high as 95% in a there is an increased incidence of lung cancer among former
group of patients with T2DM using the AERx® system, and smokers who were treated with Exubera®.49 As a consequence
97% of patients received less than 5 inadequate doses dur- of this revelation, it is likely that the FDA will limit the use
ing the treatment period studied.73 Thus, this inhaled insulin of inhaled insulin to individuals who have never smoked and
system may serve as a useful tool to aid in acceptance of require extensive postmarketing studies to address issues
insulin and improvement of glycemic control. related to carcinogenicity risk. Finally, with the continued
development of devices that have improved the ability to
Cost of inhaled insulin deliver subcutaneous insulin, including insulin pumps and
The cost of inhaled insulin is significantly higher than that insulin pens, the niche in the diabetes market which inhaled
of subcutaneous insulin since more drug must be inhaled insulin is likely to occupy may be limited. Although the
in order to achieve comparable glycemic control. However, concept of inhaled insulin is attractive, the availability of
a substantial driving force for the development of inhaled subcutaneous insulin regimens that provide intensive diabetes
insulin has focused on the concept that availability of alter- care and the concern about pulmonary function and health
nate insulin delivery systems will increase the likelihood that will significantly affect future development in this area.
those with diabetes will adhere to their treatment regimens. In conclusion, inhaled insulin is a novel route of insulin
In particular, those with T2DM may be more willing to administration which has the potential to become a thera-
start insulin when inhaled insulin is available as an option.69 peutic option in the treatment of both T1DM and T2DM.
Adherence and intensified diabetes care would translate Overall, clinical trials have demonstrated that inhaled insulin
into improved diabetes outcomes, particularly for decreased is noninferior to subcutaneous insulin for improving glyce-
rates of micro- and macrovascular complications. Thus, the mic control. In addition, inhaled insulin serves as relevant
cost-effectiveness of inhaled insulin for quality of life and adjuvant therapy in individuals with T2DM suboptimally
downstream clinical benefits can be considered when evaluat- controlled on oral therapy. The most notable advantage of
ing the economics of inhaled insulin. inhaled insulin over subcutaneous insulin therapy is that it is
Black et al performed an extensive analysis of the cost well accepted by patients and improves overall satisfaction
and cost-effectiveness of Exubera® in patients with T2DM.74 scores. Thus, availability of inhaled insulin may translate to
They determined that the addition of Exubera® to a regimen improved diabetes control and decrease the risk of long-term
which included 2 oral agents was US$1669/year more than diabetes complications.
adding basal glargine. Using a model to calculate cost-
effectiveness assuming that inhaled insulin would improve Disclosure
quality of life and glycemic control over the lifetime of The author declares no conflicts of interest.
the patient, the authors determined that, while quality of
life cost-savings of US$110 to US$220 per patient might References
be realized over 20 years of therapy, this was significantly 1. Centers for Disease Control and Prevention. National diabetes fact
sheet: general information and national estimates on diabetes in the
outweighed by the excess cost compared to basal subcutane- United States. 2007. Atlanta, GA: US Department of Health and
ous therapy – US$14,000 to US$20,700. Given that inhaled Human Services, Centers for Disease Control and Prevention, 2008.
insulin is not superior to subcutaneous therapy with respect URL. http://www.cdc.gov/diabetes/pubs/factsheet07.htm. Accessed
August 26, 2009.
to glycemic control, there would have to be additional direct 2. Bakker W, Eringa EC, Sipkema P, vanHinsbergh VW. Endothelial
patient benefits to improve cost-effectiveness. These analyses dysfunction and diabetes: roles of hyperglycemia, impaired insulin
signaling and obesity. Cell Tissue Res. 2009;335(1):165–189.
will be considered by third party payers when making deci- 3. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk
sions on reimbursement for inhaled insulin. factors, and 12-yr cardiovascular mortality for men screened in the Multiple
Risk Factor Intervention Trial. Diabetes Care. 1993;16(2):434–444.
4. Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determi-
Conclusions nants of coronary artery disease in juvenile-onset, insulin-dependent
Several important issues remain with respect to the likelihood diabetes mellitus. Am J Cardiol. 1987;59(8):750–755.
5. Laing SP, Swerdlow AJ, Slater SD, et al. Mortality from heart disease in
that inhaled insulin will be used clinically in the future. The a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia.
first is the significant impact that the launch and subsequent 2003;46(6):760–765.

56 submit your manuscript | www.dovepress.com Vascular Health and Risk Management 2010:6
Dovepress
Dovepress Inhaled insulin for diabetes management

6. The Diabetes Control and Complications Trial Research Group. The 29. Brunner GA, Balent B, Ellmerer M, et al. Dose-response relation of
effect of intensive treatment of diabetes on the development and progres- liquid aerosol inhaled insulin in Type 1 diabetic patients. Diabetologia.
sion of long-term complications in insulin-dependent diabetes mellitus. 2001;44(3):305–308.
N Engl J Med. 1993;329(14):977–986. 30. Cefalu WT, Skyler JS, Kourides IA, et al. Inhaled human insulin
7. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood- treatment in patients with type 2 diabetes mellitus. Ann Intern Med.
glucose control with sulphonylureas or insulin compared with con- 2001;134(3):203–207.
ventional treatment and risk of complications in patients with type 2 31. Rave K, Nosek L, De la Pena A, et al. Dose response of inhaled dry-
diabetes (UKPDS 33). Lancet. 1998;352(9131):837–853. powder insulin and dose equivalence to subcutaneous insulin lispro.
8. Zambanini A, Newson RB, Maisey M, Feher MD. Injection related Diabetes Care. 2005;28:2400–2405.
anxiety in insulin-treated diabetes. Diabetes Res Clin Pract. 1999;46(3): 32. de la Pena A, Seger M, Rave K, Heinemann L, Silverman B, Muchmore DB.
239–246. AIR insulin capsules of different dose strengths may be combined to yield
9. Prentki M, Matschinsky FM. Ca2+, cAMP, and phospholipid-derived equivalent pharmacokinetics and glucodynamics. Diabetes Technol Ther.
messengers in coupling mechanisms of insulin secretion. Physiol Rev. 2009;11(S2):S75–S79.
1987;67(4):1185–1248. 33. Royle P, Waugh L, McAuley L, McIntyre L, Thomas S. Inhaled insulin
10. Porte D, Sherwin R, Baron A. Ellenberg and Rifkin’s Diabetes Mellitus. in diabetes mellitus. Cochrane Database Syst. Rev. 2004;CD003890.
6th ed. New York: McGraw-Hill. 2003:43–65. 34. Skyler JS, Weinstock RS, Raskin P, et al. Use of inhaled insulin in a
11. ClincalTrials.gov. [homepage on the Internet]. A service of the US basal/bolus insulin regimen in type 1 diabetic subjects. Diabetes Care.
National Institutes of Health. [updated October 13, 2009]. URL: http:// 2005;28(7):1630–1635.
clinicaltrials.gov/ct2/show/NCT00668850. Accessed October 14, 2009. 35. Quattrin T, Belanger A, Bohannon NJV, Schwartz SL. Efficacy and
12. Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved gly- safety of inhaled insulin (Exubera) compared with subcutaneous
cemic control with intraperitoneal versus subcutaneous insulin insulin therapy in patients with type 1 diabetes. Diabetes Care.
in type 1 diabetes:a randomized controlled trial. Diabetes Care. 2004;27(11):2622–2627.
2009;32(8):1372–1377. 36. Garg SK, Mathieu C, Rais N, et al. Two-year efficacy and safety of AIR
13. Laqueur E, Grevenstuk A. Uber die wirkunk intratrachealer zuführung inhaled insulin in patients with type 1 diabetes: An open-label random-
von insulin. Klin Wochenschr. 1924;3:1273–1274. ized controlled trial. Diabetes Technol Ther. 2009;11(S2):S5–S16.
14. Gänsslen M. Uber inhalation von insulin. Klin Wochenschr. 1925;4:71. 37. Bergenstal RM, Kapsner PL, Rendell MS, et al. Comparative effi-
15. Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body cacy and safety of AFRESA and a rapid-acting analog both given
through the lungs. Nat Rev Drug Discov. 2007;6(1):67–74. with glargine in subjects with T1DM in a 52-week study. Diabetes.
16. Usmani OS, Biddiscombe MF, Barnes PJ. Regional lung deposition 2009:A479.
and bronchodilator response as a function of beta2-agonist particle 38. Rosenstock J, Zinman B, Murphy LJ, et al. Inhaled insulin improves
size. Am J Respir Crit Care Med. 2005;172(12):1497–1504. glycemic control when substituted for or added to oral combination
17. Katz IM, Schroeter JD, Martonen TB. Factors affecting the deposition therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern
of aerosolized insulin. Diabetes Technol Ther. 2001;3(3):387–397. Med. 2005;143(8):549–558.
18. Farr SJ, McElduff A, Mather LE, et al. Pulmonary insulin administra- 39. Hollander PA, Blonde L, Rowe R, et al. Efficacy and safety of inhaled
tion using the AERx system: physiological and physiochemical factors insulin (Exubera) compared with subcutaneous insulin therapy in patients
influencing insulin effectiveness in healthy fasting subjects. Diabetes with type 2 diabetes. Diabetes Care. 2004;27(10):2356–2362.
Technol Ther. 2000;2(2):185–197. 40. Hermansen K, Rönnemaa T, Petersen AH, Bellaire S, Adamson U.
19. Bliss M. The Discovery of Insulin. Chicago, IL: University of Chicago Intensive therapy with inhaled insulin via the AERx insulin diabetes
Press; 1982. management system. Diabetes Care. 2004;27(1):162–167.
20. Heubner W, de Jongh S, Laquer E. Uber inhalation von insulin. Klin 41. Rosenstock J, Eliaschewitz F, Heilmann C, Muchmore DB, Hayes R,
Wochenschr. 1924;3:2342–2343. Belin R. Comparison of prandial AIR inhaled insulin alone to intensi-
21. Elliott RB, Edgar BW, Pilcher CC, Quested C, McMaster J. Parenteral fied insulin glargine alone and to AIR insulin plus intensified insulin
absorption of insulin from the lung in diabetic children. Aust Paediatr J. glargine in patients with type 2 diabetes previously treated with
1987;23(5):293–297. once-daily insulin glargine. Diabetes Technol Ther. 2009;11(S2):
22. Patton JS, Bukar JG, Eldon MA. Clinical pharmacokinetics and S63–S73.
pharmacodynamics of inhaled insulin. Clin Pharmacokinet. 42. Rosenstock J, Capelleri JC, Bolinder B, Gerber RA. Patient satisfaction
2004;43(12):781–801. and glycemic control after 1 year with inhaled insulin (Exubera) in patients
23. Rosenstock J, Bergenstal R, DeFronzo RA, et al. Efficacy and safety with type 1 or type 2 diabetes. Diabetes Care. 2004;27(6):1318–1323.
of Technosphere inhaled insulin compared with Technosphere powder 43. Ford ES, Mokdad AH, Gregg EW. Trends in cigarette smoking among
placebo in insulin-naive type 2 diabetes suboptimally controlled with US adults with diabetes: findings from the Behavioral Risk Factor
oral agents. Diabetes Care. 2008;31(11):2177–2182. Surveillance System. Prev Med. 2004;39(6):1238–1242.
24. Rave K, Heise T, Pfutzner A, Boss AH. Coverage of postprandial blood 44. Wise S, Chien J, Yeo K, Richardson C. Smoking enhances absorption
glucose excursions with inhaled Technosphere insulin in comparison of insulin but reduces glucodynamic effects in individuals using the
to subcutaneously injected regular human insulin in subjects with type Lilly-Dura inhaled insulin system. Diabet Med. 2006;23(5):510–515.
2 diabetes. Diabetes Care. 2007;30(9):2307–2308. 45. Himmelmann A, Jendle J, Mellén A, Petersen AH, Dahl UL, Wolmer P.
25. ClincalTrials.gov. [homepage on the Internet]. A service of the US The impact of smoking on inhaled insulin. Diabetes Care. 2003;26(3):
National Institutes of Health. URL: www.ClinicalTrials.gov/ct2/ 677–682.
results?term=inhaled+insulin. Accessed September 23, 2009. 46. Becker RH, Sha S, Frick AD, Fountaine RJ. The effect of smoking
26. Garg SK, Kelly WC. Insulin delivery via lungs – is it still possible? cessation and subsequent resumption on absorption of inhaled insulin.
Diabetes Technol Ther. 2009;11(Suppl 2):S1–S3. Diabetes Care. 2006;29(2):277–282.
27. Rave K, Bott S, Heinemann L, et al. Time-action profile of inhaled 47. Targher G, Alberiche M, Zenere MB, Bonadonna RC, Muggeo M,
insulin in comparison with subcutaneously injected insulin lispro and Bonora E. Cigarette smoking and insulin resistance in patients with
regular human insulin. Diabetes Care. 2005;28(5):1077–1082. noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab.
28. Rave K, Potocka E, Boss AH, Marino M, Costello D, Chen R. Phar- 1997;82(11):3619–3624.
macokinetics and linear exposure of AFRESA compared with the 48. Fountaine R, Milton A, Checchio T, et al. Acute passive cigarette smoke
subcutaneous injection of regular human insulin. Diabetes Obes Metab. exposure and inhaled human insulin (Exubera) pharmacokinetics. Br J
2009;11(7):715–720. Clin Pharmacol. 2008;65(6):864–870.

Vascular Health and Risk Management 2010:6 submit your manuscript | www.dovepress.com
57
Dovepress
Mastrandrea Dovepress

49. Kling J. Inhaled insulin’s last gasp? Nat Biotech. 2008;26(5):479–480. 62. Schernthaner G. Immunogenicity and allergenic potential of animal
50. McElduff A, Mather LE, Kam PC, Clauson P. Influence of acute upper and human insulins. Diabetes Care. 63. 1993;16(Suppl 3):155–165.
respiratory tract infection on the absorption of inhaled insulin using 63. Walford S, Allison SP, Reeves WG. The effect of insulin antibodies on
the AERx insulin Diabetes Management System. Br J Clin Pharmacol. insulin dose and diabetic control. Diabetologia. 1982;22(2):106–110.
2005;59(5):546–551. 64. Peters A, Klose O, Hefty R, Keck F, Kerner W. The influence
51. Wolzt M, de la Pena A, Berclaz PY, Tibaldi FS, Gates JR, Muchmore DB. of insulin antibodies on the pharmacokinetics of NPH insulin in
AIR inhaled insulin versus subcutaneous insulin: pharmacokinetics, gluco- patients with type 1 diabetes treated with human insulin. Diabet Med.
dynamics and pulmonary function in asthma. Diabetes Care. 2008;31(4): 1995;12(10):925–930.
735–740. 65. Seewi O, Jaeger C, Bretzel RG, Schönau E. Insulin binding to
52. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and out- antibodies is a risk factor for inexplicable severe hypoglycaemia in
comes of diabetes, hypertension, and cardiovascular disease in COPD. children with type-1 diabetes mellitus. Exp Clin Endocrinol Diabetes.
Eur Respir J. 2008;32(4):962–969. 2008;116(5):293–297.
53. Rave K, de la Pena A, Tibaldi FS, et al. AIR inhaled insulin in sub- 66. Kim MR, Sheeler LR, Mansharamani N, Haug MT, Faiman C,
jects with chronic obstructive pulmonary disease. Diabetes Care. Gupta MK. Insulin antibodies and hypoglycemia in diabetic patients.
2007;30(7):1777–1782. Can a quantitiative analysis of antibody binding predict the risk of
54. McGrath MW, Thomson ML. The effect of age, body size and lung hypoglycemia? Endocrine. 1997;6(3):285–291.
volume change on alveolar-capillary permeability and diffusing capacity 67. Fineberg SE, Kawabata T, Finco-Kent D, Liu C, Krasner A. Antibody
in man. J Physiol. 1959;146(3):572–582. response to inhaled insulin in patients with type 1 or type 2 diabetes.
55. Henry RR, Mudalier S, Chu N, et al. Young and elderly type 2 diabetic J Clin Endocrinol Metab. 2005;90(6):3287–3294.
patients inhaling insulin with the AERx insulin diabetes management 68. Wolff RK. Safety of inhaled proteins for therapeutic use. J Aerosol Med.
system: a pharmacokinetic and pharmacodynamic comparison. J Clin 1998;11(4):197–219.
Pharmacol. 2003;43(11):1228–1234. 69. Freemantle N, Blonde L, Duhot D, et al. Availability of inhaled insulin
56. Skyler JS, Cefalu WT, Kourides IA, et al. Efficacy of inhaled human promotes greater perceived acceptance of insulin therapy in patients
insulin in type 1 diabetes mellitus: a randomised proof-of-concept study. with type 2 diabetes. Diabetes Care. 2005;28(2):427–428.
Lancet. 2001;357(9253):331–335. 70. Bergenstal R, Freemantle N, Leyk M, Cutler G, Hayes R, Muchmore DB.
57. Barnett AH, Lange P, Dreyer M, Serdarevic-Pehar M. Long-term Does availability of AIR insulin increase insulin use and improve glycemic
tolerability of inhaled human insulin (Exubera) in patients with poorly control in patients with type 2 diabetes. Diabetes Technol Ther. 2009;11(S2):
controlled type 2 diabetes. Int J Clin Pract. 2007;61(10):1614–1625. S45–S52.
58. Davis WA, Knuiman M, Kendal P, Grange V, Davis TM. Glycemic expo- 71. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med.
sure is associated with reduced pulmonary function in type 2 diabetes. 2005;353(5):487–496.
The Fremantle Diabetes Study. Diabetes Care. 2004;27(3):752–757. 72. Claxton AJ, Cramer J, Pierce C. A systematic review of the associa-
59. Skyler JS. Sustained long-term efficacy and safety of inhaled insulin tions between dose regimens and medication compliance. Clin Ther.
during 4 years of continuous therapy. Diabetes. 2004;53:A115. 2001;23(8):1296–1310.
60. Dahl-Jørgensen K, Torjesen P, Hanssen KF, Sandvik L, Aagenaes O. 73. Cramer JA, Okikawa J, Bellaire S, Clauson P. Compliance with inhaled
Increase in insulin antibodies during continuous subcutaneous insulin insulin treatment using the AERx iDMS insulin diabetes management
infusion and multiple-injection therapy in contrast to conventional system. Diabetes Technol Ther. 2004;6(6):800–807.
treatment. Diabetes. 1987;36(1):1–5. 74. Black C, Cummins E, Royle P, Philip S, Waugh N. The clinical effec-
61. Lassmann-Vague V, Belicar P, Raccah D, Vialettes B, Sodoyez JC, Vague P. tiveness and cost-effectiveness of inhaled insulin in diabetes mellitus:
Immunogenicity of long-term intraperitoneal insulin adminstration with a systematic review and economic evaluation. Health Technol Assess.
implantable programmable pumps: metabolic consequences. Diabetes Care. 2007;11(33):1–126.
1995;18(4):498–503.

Vascular Health and Risk Management Dovepress

Publish your work in this journal
Vascular Health and Risk Management is an international, peer- metabolic disorders, particularly diabetes. This journal is indexed on
reviewed journal of therapeutics and risk management, focusing on PubMed Central and MedLine. The manuscript management system
concise rapid reporting of clinical studies on the processes involved is completely online and includes a very quick and fair peer-review
in the maintenance of vascular health; the monitoring, prevention and system, which is all easy to use. Visit http://www.dovepress.com/
treatment of vascular disease and its sequelae; and the involvement of testimonials.php to read real quotes from published authors.
Submit your manuscript here: http://www.dovepress.com/vascular-health-and-risk-management-journal

58 submit your manuscript | www.dovepress.com Vascular Health and Risk Management 2010:6
Dovepress