Inhaled Insulin: a Promising Option with Room for Growth?

July 24, 2015

Advances in delivery methods renewed interest in the development of an inhaled form of insulin. We explore the history, pros and cons, and future of this fast-acting, short-duration drug.

Interest in inhaled insulin isn’t really new. The concept was first studied in 1924, soon after the discovery of insulin itself. At that time, researchers recognized that drug delivery could take advantage of the huge surface area of the lungs-about the size of a tennis court. Because the required dose was about 30 times the injectable dose, though, the route was pretty much abandoned.1

Advances in delivery methods since the 1980s brought renewed interest in inhaled insulin. Nebulizers, aerosols, metered-dose inhalers, and dry powder inhalers offered the advantage of smaller sized particles that could improve delivery to the alveoli.1

Other challenges concerned the nature of the formulation. Insulin is not breathable and may be retained in the lungs or find its way to the gastrointestinal tract. Advances have recently been made in the development of spray-dried insulin powders and nanoparticles that increase absorption in alveoli. Higher doses of inhaled insulin, however, are still generally needed because the drug disperses throughout the airways.2

[[{"type":"media","view_mode":"media_crop","fid":"39791","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_8530060173564","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4008","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 160px; height: 154px; float: right;","title":"© Photo Africa/Shutterstock.com","typeof":"foaf:Image"}}]]Exubera: The First Inhaled Insulin

In January 2006 the FDA approved Exubera (Pfizer, New York NY), the first inhaled insulin to enter the US market.3 Exubera used recombinant human insulin that was spray dried and consisted of particles with diameters between 1 and 5 µm.  This formulation brought insulin bioavailability to about 60%, representing a major advance.1

One advantage of Exubera was its rapid absorption. Patients with both type 1 (T1DM) and type 2 diabetes (T2DM) reached peak insulin concentrations much quicker with Exubera than with regular insulin (49 minutes vs. 105 minutes, respectively).3

Exubera proved to be a market failure, though, and was withdrawn in October 2007. Problems included a bulky inhaler and patient rejection, perhaps related to the need for periodic lung function tests. Additionally, Exubera’s limited dosing options (just two strengths) required some patients to inhale multiple times. Finally, the FDA issued a warning about nonsignificant lung cancer with Exubera use, which could have played a role in poor sales.1

A New Generation: Afrezza/TI

In January 2014, the FDA approved a second generation inhaled insulin called Technosphere Insulin (TI), or Afrezza.4 Afrezza currently represents the only inhaled insulin on the US market.

Afrezza uses a rapid-acting recombinant human insulin dissolved in a dry powder, which allows for inhalation. The insulin is incorporated into microspheres about 2 to 3 µm in size, which can be absorbed into the alveoli.2

The new Dreamboat inhaler (or Gen2) is much smaller, more convenient, and offers more dosing flexibility than the Exubera inhaler.1

Advantages of Afrezza

Afrezza may have similar efficacy as oral and injectable rapid acting insulins. In a trial involving 3017 patients (1026 with T1DM and 1991 with T2DM), after 24 weeks patients on Afrezza experienced similar reductions in HbA1c compared to those on aspart.4 Similarly, in adults with T2DM receiving oral antidiabetic medications, after 24 weeks Afrezza showed similar efficacy in reducing HbA1c compared to placebo.4

Because Afrezza has a faster onset of action and shorter duration than rapid acting injectables, it may carry lower risk for hypoglycemia.5 Afrezza reaches peak insulin concentrations in about 15-30 minutes (compared to 60 minutes for injectable rapid acting insulin), and lasts for about 180 minutes (compared to 300 minutes for rapid acting injectables).5

Another advantage includes potentially less weight gain with Afrezza compared to injectable insulin,4 though weight gain compared to placebo has been reported.6

Disadvantages of Afrezza

One of the main drawbacks of Afrezza may be a dry cough.5 Other common adverse effects include hypoglycemia and throat pain or irritation.4

Inhaled insulin can cause bronchospasm, and Afrezza carries a boxed warning about this risk. Patients with asthma, chronic obstructive pulmonary disease, or active lung cancer, as well as smokers and ex-smokers who have stopped within the last 6 months, should not use Afrezza.6

Long-term decline in pulmonary function represents a concern, necessitating periodic pulmonary function tests. Patients who experience 20% or more decline in FEV1 (forced expiratory volume) should stop taking Afrezza.6

Other concerns include rare reports of lung cancer with use of Alfrezza, and high cost-almost twice as much as injectable short acting insulins.6

Further Study

The FDA has required further study about the risk of bronchospasm with Afrezza use in patients with chronic lung disease. It has also required a change in the Dreamboat inhaler design by 2016, because the mouthpiece cover could pose a potential choking hazard. Further study is also needed into the safety and efficacy of Afrezza in children, the risk of diabetic ketoacidosis and hypoglycemia with Afrezza, and a five-year safety trial to assess lung cancer risk and change in pulmonary function. The last trial will also look at cardiovascular risk.

Development of new formulations will also be needed to improve bioavailability of inhaled insulin. Nanocarriers such as polymeric micelles may be a promising approach. Examples of insulin-loaded micelles that have been developed include Soluplus (SOL), Pluronic F68 (F68), Pluronic F108 (F108), and Pluronic F127 (F127), with F127 being perhaps especially promising.7

Take-home Points

• Development of inhaled insulin was hampered by problems in the delivery method and formulation of the insulin.

• Exubera was the first inhaled insulin on the US market, but suffered from problems like a bulky inhaler, restrictive dosing, patient and physician rejection, and an FDA warning about possible lung cancer risk.

• Afrezza is the only current inhaled insulin on the US market.

• Advantages of Afrezza include similar efficacy as injectable insulin and oral antihyperglycemics, quick onset of action and short duration of action, as well as possibly less weight gain and less risk for hypoglycemia than injectable insulin.

• Disadvantages of Afrezza include cough, bronchospasm, high cost, as well as possible long-term decline in lung function and risk of lung cancer.

References:

1. Kugler AJ, et al. Inhaled technosphere insulin: a novel delivery system and formulation for the treatment of types 1 and 2 diabetes mellitus. Pharmacotherapy. 2015 Mar;35(3):298-314.

2. Cahn A, et al. New forms of insulin and insulin therapies for the treatment of type 2 diabetes. Lancet Diabetes Endocrinol. 2015 Jun 4. [Epub ahead of print]

3. FDA Approves First Ever Inhaled Insulin Combination Product for Treatment of Diabetes - 2006 press release (exubera). Accessed July 14 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108585.htm.

4. FDA approves Afrezza to treat diabetes – 2014 press release. Accessed July 14 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm.

5. Bode B. Reduced Hypoglycemia Risk with an Inhaled Insulin Compared to Injected Prandial Insulin in Type 1 Diabetes – audio/slide show. Accessed July 14 at http://professional.diabetes.org/Adv_SearchResult.aspx?kwd=inhaled%20insulin&sr=global&ResType=ALL&typ=0&adv=True.

6. Medical Letter. An inhaled insulin (Afrezza). JAMA. 2015 Jun 2;313(21):2176-2177.

7. Andrade F, et al. Biological assessment of self-assembled polymeric micelles for pulmonary administration of insulin. Nanomedicine. 2015 Jun 3. [Epub ahead of print]