Inhalable insulin is a powdered form of insulin, delivered with an inhaler into the lungs where it is absorbed.^[1] In general inhaled insulins have been more rapidly absorbed than subcutaneous injected insulin, with faster peak concentration in serum and more rapid metabolism.^[2]

Exubera, developed by Inhale Therapeutics (later named Nektar Therapeutics), became the first inhaled insulin product to be marketed, in 2006 by Pfizer,^[3] but poor sales led Pfizer to withdraw it in 2007.^[4] Afrezza, a monomeric inhaled, ultra rapid-acting insulin developed by Mannkind, was approved by the FDA in 2014 and is the only inhaled insulin commercialized at the moment.^[5]

Insulin was discovered by Sir Frederick G Banting, Charles H Best, and JJR Macleod from the University of Toronto in 1921 as an injectable agent.^[6] German researchers first introduced the idea of inhalable insulin in 1924.^[7] Years of failure followed until scientists realized they might be able to use new technologies to turn insulin into a concentrated powder with particles sized for inhalation.^{[citation needed]}

In the 1980s Nektar Therapeutics developed technology to make insulin into small particles, technology then licensed to Pfizer. Alkermes developed a delivery device that they licensed to Eli Lilly and Company.^[7]

Once concrete methods were developed, human tests began in the late 1990s.^[7] In January 2006, the U.S. Food and Drug Administration (FDA) approved the use of Exubera, a form of inhalable insulin developed by Pfizer.^[3] It was approved in the UK in August 2006 but reimbursed by the National Health Service only for people who had problems with needles.^[8] It was not reimbursed by any US insurer.^[9] A 2007 systematic review concluded that the inhaled hexameric insulin (Exubera) "appears to be as effective, but no better than injected short-acting insulin. The additional cost is so much more that it is unlikely to be cost-effective."^[10] In 2007, Pfizer announced that it would no longer manufacture or market Exubera. According to Chairman and CEO Jeffrey Kindler this was because Exubera "failed to gain acceptance among patients and physicians".^[4]

At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulin including Alkermes working with Eli Lilly and Company,^[11] MannKind Corporation,^[12][13] and Aradigm working with Novo Nordisk. By March 2008, except for MannKind's Afrezza product, all of these products had been discontinued because investors all decided to withdraw funding.^[14]

On March 16, 2009 MannKind submitted a new drug application for their inhalable insulin. In 2011 the FDA denied approval of Afrezza; because the design of the delivery device had changed, it requested additional clinical trials to ensure that people would use it the same way as the earlier versions.^[15] After conducting further studies, Mannkind submitted a new application, and in June, 2014, the FDA approved Afrezza for both Type I and Type II adult diabetics, with a label restriction for patients having asthma, active lung cancer or COPD.^[5][16] In 2014 Mannkind and Sanofi agreed that Sanofi would take over manufacturing and marketing of Afrezza,^[17] but Sanofi said it was dropping the effort in January 2016 due to poor sales of $7.5 million in 2015;^[18] the companies formally terminated the agreement in November 2016.^[19] At the time that Sanofi announced it was dropping the product Mannkind said it would continue alone,^[18] and it had taken over manufacturing and relaunched the drug by July 2016.^[19] According to results presented at the 2018 meeting of the American Diabetes Association (ADA), Afrezza increases the time that blood glucose levels remain in optimal range (74 – 106 mg/dl), reducing both spikes in blood glucose and time in hypoglycemia in adults with Type I diabetes, compared to insulin Aspart.^[20]