The Tangled Story of Inhaled Insulin

Inhaled Insulin Finally Made it to Market but Will It Last?

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In 1921, physicians first started injecting people with insulin.  Ever since this time, researchers have been keen on figuring out how to administer insulin without a needle.  Despite much investigation, however, we have only recently figured out how to administer insulin without a syringe. 

Scientists first tried to administer insulin via either the nasal passage or by mouth.  However, the epithelial lining of the nasopharynx and gastrointestinal tract are impermeable to insulin.

  Eventually, scientists turned their efforts to the lungs intent on developing a form of insulin that could be inhaled.  In the early 2000s, there were 7 types of inhaled insulin in the works.

In 2006, the FDA approved Exubera which was made by Pfizer.  Exubera was only on the market for 13 months before Pfizer pulled it.  Despite an estimated $2-billion-a-year market for the drug, Exubera proved too hot for Pfizer to handle.  First, Exubera was linked to a higher risk of lung cancer in those who took it.  Specifically, in a clinical trial with a sample size of 4740 patients, 6 patients taking Exubera developed lung cancer; whereas, only 1 of 4292 patients in the control group developed lung cancer.  (In retrospect, smoking likely confounded the results of the study as the goal of the study was to figure out how smoking affected the safety and efficacy of Exubera not to figure out whether Exubera caused lung cancer.)  Second, the device used to deliver Exubera was cumbersome and expensive; patients didn't like it.

The high-profile failure of Exubera scared all other once-potential competitors except MannKind Corporation.  In June 2014, MannKind garnered FDA approval for Afrezza, a second-generation inhaled insulin.

Unlike Exubera, Afrezza is administered with a handy little device called Dreamboat.  Moreover, Exubera required that the user stand in a "cloud" of inhaled insulin while the Dreamboat is more akin to an asthma inhaler.

The dry powder in Afrezza is a microparticle formulation composed of "Technosphere insulin" which is made up of insulin and proprietary particles called Technospheres.  The excipient in Afrezza is a water-soluble proprietary compound called fumaryl diketopiperazine (FDKP) which is safe and almost completely excreted by the kidneys (urinated out).  FDKP is soluble in basic or neutral pH.  Technosphere insulin microparticles are ideally suited to penetrate the deepest parts of the lungs and cross into circulation.

Afrezza is currently approved for use by adults with type 1 and type 2 diabetes before meals.  (Afrezza is a substitute for short-acting subcutaneous or injectable insulin.) Afrezza is a short-acting insulin which reaches peak blood concentration about 15 minutes after inhalation and wears off after 3 hours.  Of note, adults who take Afrezza still need to continue taking long-acting insulin shots.

As should probably be expected from any inhaled medicine, the most common adverse effect of Afrezza is cough.  Additionally, in clinical trials, participants with type 2 diabetes taking Afrezza were at slightly higher risk of developing diabetic ketoacidosis (DKA) a potentially life-threatening complication.

  Of note, people who smoke or have COPD shouldn't take Afrezza.

Based on results from clinical trials, Afrezza poses no increased risk for the development of lung cancer.  However, Afrezza may slightly compromise breathing ability, and pulmonary function should be monitored in people taking the drug.  Furthermore, Afrezza increases levels of anti-insulin antibodies more than treatment with subcutaneous (injection) insulin.  Rest assured, however, that this increase in anti-insulin antibodies causes no adverse effects that we know of.

In 2015, Sanofi teamed with MannKind to create a market for Afreeza.

However after than less than a year, disappointing sales of the product caused Sanofi to terminate the partnership and stop pushing Afreeza. Apparently, few physicians were prescribing the product. Finally, it may be the end of the line for inhaled insulin. 
Selected Sources

Kennedy M, Masharani U. Pancreatic Hormones & Antidiabetic Drugs. In: Katzung BG, Trevor AJ. eds. Basic & Clinical Pharmacology, 13e. New York, NY: McGraw-Hill; 2015.  Accessed August 10, 2015.

Article titled "A second-generation inhaled insulin for diabetes mellitus" by G Ledet and co-authors published in American Journal of Health-System Pharmacy in 2015.  Accessed on 8/10/2015.





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