Inhaled insulins - a valid option in the treatment of diabetes?

Development of inhaled insulins thus far

The first experiments with inhalation of insulin were performed only shortly after the discovery of insulin in the beginning of the last century. However, it was not until 2006 that the first inhaled insulin (and the first ever non-injectable insulin) entered the market under the name of Exubera®. Despite the appealing concept for patients not having to deal with insulin needles any longer, only a year later Exubera® was withdrawn from the market for commercial reasons. High production costs, combined with other contributing factors, e.g. the rather large design of the inhalation device, the cumbersome dose preparation and the required lung function tests that came along with the prescription have been debated as reasons for the lack of commercial success. Add to this uncertainty on the potential increased risk of lung cancer with Exubera® which was made official a year after market withdrawal resulting in an abrupt halt of almost all other inhaled insulin developments shortly thereafter.

Mannkind was the only company that pursued their development and their inhaled insulin product Afrezza® gained F.D.A. approval in 2014. The inhaler was much smaller, much easier to handle and promised a new start for the line of inhaled insulins. In order to launch the product Mannkind partnered up with Sanofi to bring Afrezza® to patients, however, two years later Sanofi cancelled the partnership, again due to disappointing sales.

Photo Credits: By Patrick J. Lynch, medical illustrator (Patrick J. Lynch, medical illustrator) [CC BY 2.5 (http://creativecommons.org/licenses/by/2.5)], via Wikimedia Commons

Pros and Cons of inhaled insulin

With two rather (at least from a commercial point of view) disappointing stories for inhaled insulin products in recent years, the question we must ask ourselves is: Are inhaled insulins a valid option for the treatment of diabetes?

To answer this question, advantages and disadvantages of inhaled insulin have been listed below:

Advantages

Painless, non-invasive administration

The necessity to inject insulin may delay start of treatment with insulin and hinder adequate treatment of diabetes mellitus.

Strong patient preference

Besides the advantages mentioned here, there are other aspects particularly appealing to patients with diabetes when it comes to inhaled insulin, such as the absence of injection-related lipodystrophy and convenience in product administration to name a few.

Ultra-Rapid insulin absorption

Inhaled insulin is absorbed ultra-rapidly into the blood stream based on the principle that the insulin reaches the alveoli within seconds, transcends into the blood stream and becomes available through circulation. The pulmonary route is one of the most effective ways to administer drugs allowing a rapid onset of action.

Lower fasting and post prandial plasma glucose

Inhaled insulins have shown to yield lower fasting plasma glucose values and lower 2 hours- post prandial glucose values compared to subcutaneous insulin.

Low rates of hypoglycemic episodes

Inhaled insulins have causes fewer hypoglycemic episodes compared to subcutaneous insulin.

Less weight gain

Inhaled insulins have shown to lead to less weight gain compared to insulin injection therapy.

Disadvantages

Safety concerns

In 2008 it became public that there had been 6 newly diagnosed cases of primary lung cancer among patients who had been treated with Exubera®. Although all of these patients had a history of smoking, one may remain in doubt.

Impairment of lung function

Lung function declines with insulin inhalation. Patients who start on inhaled insulin need to have a normal lung function and need regular checks during treatment as per FDA requirement.

Dose selection

As the inhaled insulin is delivered in prefilled cartridges, inhaled insulin can only be dosed in discrete dosing steps, e.g. 4 U per cartridge. Multiple inhalations (and cartridge replacements) may be necessary to administer the adequate dose.

Amount of insulin needed

When administering insulin via inhalation, much higher doses are needed due to the fact that only a small percentage of the powder reaches the lungs (therefore the bloodstream, respectively) resulting in high costs of production.

Coughing

The most common adverse event with dry inhalation powder-inhaled insulin has shown to be cough (incidence approx. 30%).

Need for a sophisticated inhalation device

Although the devices to administer inhaled insulin have progressed significantly since Exubera® (which had the dimensions of a box of Pringles), there is still room for improving both their appearance and functionality.

Need for training of inhalation technique

The correct inhalation technique is crucial for the bioavailability of the product, therefore, prior to starting treatment with inhaled insulin inhalation training is needed.

There are quite a few factors that need to be taken into consideration, as demonstrated above. A factor that could not be allocated clearly to either table is the target HbA1c. Although inhaled insulins lead to an overall improvement of HbA1c and their noninferiority to prandial insulins have been proven, the change in HbA1c was demonstrated to be more effective when treated with subcutaneous insulin. Despite all considerations however, the advantages for certain groups of patients, e.g. for those with needle phobia or increased risk of hypoglycemia may have a huge impact on their quality of life.

And there is more on the horizon

Dance Biopharm Inc. is currently working on a liquid inhaled insulin formulation that, in first studies with the product, has already proven to have omitted some of the disadvantages known for inhaled insulins such as coughing, the so-far oversized inhalation device and high costs of production.

Eventually only the future will tell how much acceptance inhaled insulins will gain among patients, however, not taking advantage of an additional option to treat a potentially life-threatening disease is not something we should just watch go by.