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[IPk] Two cheers for inhaled insulin

I apologise for sending a rather long email, but I wanted to share an
article from The Lancet today. It's by Edwin Gale, my former diabetes
specialist in Bristol, and he is commenting on the results of some initial
trials on the new inhaled insulin. The last paragraph touched me.



Many years ago a 29 year-old patient said to me, "Look, I've given myself
two injections a day for 17 years. That's more than 10 000 injections. I
just can't face doing it any more". There was little comfort to offer at
the time, but what would I say to him now? Today's Lancet carries a report
by Jay Skyler and colleagues of a comparison between inhaled insulin and
conventional therapy in patients with type 1 diabetes, and shows that one
daily injection of long-acting insulin plus three preprandial inhalations
gives glucose control similar to that of two or three insulin injections a
day. Three cheers? Or only two?

Inhaled insulin is not a new idea. The first paper came out in 1924 and
other routes, such as transdermal, oral, nasal, intestinal, and rectal,
were also extensively investigated in the early days of insulin therapy.
These and later studies have repeatedly shown that effective doses of
insulin can be delivered without injection, but that only a small and
erratic fraction of the amount administered reaches the circulation.
Inhalation has emerged as the most promising route for the non-invasive
administration of peptides or proteins since, as every medical student
knows, the surface area of the alveoli is around 100 m2 or half a tennis
court. Smaller proteins are absorbed faster, and although it remains a
mystery how these molecules get from the airspaces into the blood, insulin
(MW 5700, 2.2 nm) is absorbed well. Inhaled insulin peaks at least as
rapidly as a fast-acting analogue injected under the skin, and has a longer
duration of effect. Intra-individual variability of absorption is
reportedly no greater than that of injected insulin. Some of the inhaled
insulins in development contain bile salts, which enhance absorption, but
the Pfizer preparation consists of dry insulin dispersed by aerosol into
particles sufficiently fine to drift into the distal twigs of the
respiratory tree. The absence of an absorption enhancer reduces the risk of
adverse reactions but may also reduce bioavailability. Cigarette smoking is
an effective means of increasing absorption of insulin and other peptides,
but this is a finding best ignored. On present evidence inhalation delivers
a small but above all reproducible fraction of the inhaled dose safely and
rapidly into the blood stream.

The results of this study will bring hope to many, but Skyler and
colleagues are at pains to say that their report provides no more than
"proof of concept". This caution is fully justified. The first and obvious
point is that inhaled insulin does not abolish the need for insulin
injections, although it may allow people to get by on only one a day.
Long-acting insulins are necessary in type 1 diabetes and still have to be
given by injection. It is also much too early to conclude that inhaled
insulin is as good as conventional injections; the sample size was too
small to exclude a clinically significant treatment difference between the
groups, and the study period was too short. The tougher comparison with
multiple-injection therapy and fast-acting insulin analogues has yet to be
done. Finally, there is the inescapable fact that inhalation is not, and
never will be, an efficient way of taking insulin. Patients on inhaled
therapy in this study required an average of 1272 mg of insulin per day,
equivalent to some 350 units, as against the previous daily dose of 18
units of soluble insulin. Inhalation is thus likely to be a costly and
clumsy alternative to the needle.

Many patients will wish to try inhaled insulin if it reaches the market,
and parents of children with diabetes would welcome a treatment that
enabled topping up with painless administration of insulin, although the
value of inhaled preparations for this purpose has yet to be confirmed.
Meanwhile the publication policy of the company suggests that their sights
are set on type 2 diabetes. Pfizer is noted for putting a member of the
marketing department in charge of each product-development team, and the
submission of today's report, which appears 18 months after first
presentation at a scientific meeting, was presumably timed to maximise the
media impact of an uncontrolled study in type 2 diabetes due to be
published soon in the USA. Type 2 diabetes and the US market are where the
big profits will be made. Inhaled insulin will be a dream for the marketing
department, so it is worth emphasising that injection therapy has moved on
since my patient saw me 20 years ago. Needles have become smaller and
sharper, a development that has probably benefited patients more than
anything that the insulin chemists have achieved over the same period. Most
injections can be virtually painless. When given with a pen-injector
device, injections will take some beating in terms of cost, efficiency,
precision of dosing, size of device, and convenience, since a pen injection
can be given in less time than it takes to draw a single deep breath. One
wonders why the patients in this study seem to have been using syringes.
Ultimately, however, the real issue is not cost or convenience, but quality
of glucose control. There are no soft options in the war against diabetes.

Whatever the practical limitations of inhaled insulin, the deeper meaning
that this report will hold for many people should not be overlooked.
Diabetes is intangible yet all-pervasive, and alters the whole context
within which an individual lives his or her life. It changes the
self-image, the social relations, the daily existence, the hopes and dreams
of those who are affected. For people trapped within this subculture the
needle is not just an irksome necessity, but a symbol of their bondage to
an invisible parasite. The medical community should therefore join with
them in celebrating this small step forward, in the knowledge that when the
hype subsides, the hope will remain. And so, two cheers for inhaled
insulin. No cheers at all for a world where children die because they
cannot get any insulin at all, a scandal that could be remedied for about
1% of the development costs of each new luxury insulin.


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