Presentations
Background on inhaled insulin therapy
Francine Kaufman
Los Angeles, CA, USA
Three presentations were given on inhaled insulin therapy in which
the effectiveness of three different inhaled insulin preparations was
compared to that of subcutaneous insulin. As the inhaled insulin arena
expands, it becomes evident that we will need to learn not only how to
compare inhaled to subcutaneous, but each of the inhaled preparations to
another.
Fast- and slow-acting inhaled insulin preparations
The first presentation was by J. Hrkach et al. of Cambridge, MA,
entitled, “AIR insulin: Complete Diabetes Therapy via Inhalation of
Fast-acting and Slow-acting Dry Powder Aerosols.” Hrkach described a
new technique that allows for the production of both fast-acting and
slow-acting insulin. The methodology adds “porosity”, making a
physically large (10-20 mm), low density (<0.1 g/ml), aerodynamically
stable particle that is delivered by a simple, inexpensive device to the
deep lung. In this fashion, it is easily absorbed with high
bioavailability. Hrkach commented extensively on the fact that the
inhaler is small, works on the patient’s breath alone and can easily
deliver one to two puffs that could completely cover the patient with
regards to basal or bolus insulin.
Two preparations were detailed: the inhaled AIR fast-acting and the AIR
slow-acting insulins. The AIR fast-acting was compared to regular human
insulin. The study was done in rats (Table II).
Lung scintigraphy showed that 60–70% was deposited in the lungs and
that this deposition was not dependent on how the animal breathed.
Conclusions
The goal of developing an insulin regimen without needles might be
possible with the inhalation of fast- and slow-acting insulin. The
authors claimed that there was evidence of good bioavailability (38%),
with profiles similar to those of human R and L insulin, and an easy to
use delivery device.
Questions raised
What was unclear was how bioavailability was calculated. Of concern was
the fact that the study duration was only 8 hours. There were no data on
the pulmonary effects of this insulin delivery system – particularly
with regards to phagocytosis of insulin in the bronchopulmonary tree,
whether the system will be efficacious if there is reactive airway
disease or cigarette smoke exposure, and what effect large quantities of
insulin might have on the pulmonary epithelium.
Comparison of insulin administration via inhaler versus injection
in human volunteers
The next presentation on inhaled insulin therapy was presented by R.S.
Fishman et al. entitled “Insulin Administration via the AeroDose
Inhaler: Comparison to Subcutaneously Injected Insulin”, from
Sunnydale, CA. The authors described a breath-activated system that
aerosolized liquid Humulin R insulin (U500); this system was studied in
12 normal volunteers in a randomized, two-way crossover euglycemic clamp
design. Humulin R U500 was given in a dose of 1.5 U/kg by inhalation
compared to 0.15 U/kg of Humulin R given subcutaneously on separate
days. The study was done in the UK on non-smokers.
Results
Serum insulin concentrations and glucose infusion rates were determined
over a 6-hour period after insulin administration by either route (Table
III).
There was relatively little bioavailability, 9.3%, and biopotency,
10.3%. There were no apparent side effects to this short study.
Conclusions
There was more rapid absorption of inhaled insulin compared to injected
insulin. Inhaled insulin may be a viable way to deliver active insulin
to patients before meals. It may be the optimal way to give precise
doses that need to be carefully titrated.
Questions raised
This presentation again raises the question as to how bioavailability is
calculated in inhaled insulin studies. It is an important criterion for
acceptance, and it has not been made clear, in the ever-increasing
number of studies, the best way to calculate and evaluate meaningful
bioavailability data. As more studies emerge with different systems,
there may need to be an established set of criteria used to evaluate
inhaled systems.
Determination of onset of action in healthy volunteers
The final inhaled insulin study was by T. Heise et al. from Neuss, Germany, Groton, CT, and Munich, Germany, entitled “Time-action Profile of an Inhaled Insulin Preparation in Comparison to a
Fast-Acting Analogue and Regular Insulin”. Eighteen healthy male
volunteers (non-smokers) were studied to compare inhaled dry powder to
injected Lispro using the euglycemic clamp.
Results
Inhaled insulin in a dose of 6 mg was compared to either 18 U of the
analogue or 18 U of regular insulin administered subcutaneous. Glucose
infusion rates were followed for 600 minutes.
Conclusions
Inhaled insulin in this study had a faster onset of action than regular
insulin and was similar to that of a fast-acting analogue. It was
unclear as to how the dosages of the analogue and regular insulin were
determined. Again, this study begs that standardized methods of
evaluation be established that can be used in inhaled insulin studies.
Summary
These are promising studies on inhaled insulin and they should be quite
encouraging for the clinician. However, the clinician and the public
will need to be aware that many preparations and technologies are
emerging that might bring forth clinically useful inhaled insulin
products. It is exciting that there might be both basal and bolus
insulins that could be delivered through the pulmonary route. That could
mean no more needles. It appears that the fast-acting insulins presented
in the papers above do have a rapid onset of action like a fast-acting
analogue – these could definitely serve as bolus insulins if future
studies continue to be positive. All of the studies presented need to be
longer to truly determine not just the onset of action, but the duration
of action. We await the results of more trials, including those done in
subjects with diabetes. In the interim, the overriding conclusions will
remain that regardless of the delivery device used or of the
characteristics of the inhaled particles, there is some element of
efficacy to the inhalation of insulin.
