Inhaled insulin

Insulin injections have long been an ordeal for some patients, and alternative forms have been in development for decades. Inhaled insulin has been long awaited by those with both Type 1 and Type 2 diabetes mellitus. This section will review the history of inhaled insulin, its development, efficacy, side effects and potential advantages in diabetes care.

Early History of Inhaled Insulin - Exubera

Allergic reactions, pain and discomfort following insulin injections dominated the early years of insulin therapy. Injections are still the most reliable and effective means of administration of insulin, but are greatly disliked by some patients, and the transition to insulin has often been feared by patients with Type 2 diabetes mellitus.

First Jab: Guy Rainsford cartoon
First Jab: Guy Rainsford cartoon

Alternative forms of administration have long been sought. These include oral, trans-dermal, rectal and nasal routes. Many studies have shown that insulin can cross any mucosal surface, but that much is lost in the process. The inhalation route has been a tempting alternative to the traditional subcutaneous route given its large surface area for absorption and easier accessibility compared to the others.[1]

The first inhaled insulin approved for adult use was Exubera. The medication was released to the market in the US January 2006 with much hype and fanfare. However, despite 11 years of trial and development and 1 year of use, the manufacturer Pfizer withdrew the medication in 2007.[2] Issues included the device itself, being extremely bulky and awkward to utilize. Dosing was complicated as Exubera was dispensed in milligrams rather than the traditional units. Additionally dosing was inflexible. Using greater than 1 to 3 milligrams (3-8 units) required combinations and multiple inhalations. Small doses were difficult to administer, excluding patients who are sensitive to small changes in insulin dose. Cost, long term safety studies and the development of insulin pen technology all contributed to the demise of Exubera. [3] Due to its failure and the issues just discussed, most other companies attempting to develop inhaled insulin products abandoned their clinical trial and programs.

Exubera delivery device
Exubera delivery device

Furthermore, Pfizer announced following withdrawal of Exubera that there had been a non-significant yet notable increase in the number of cases of lung cancer (6 vs 1 on comparator). All had occurred in smokers, but this raised concerns about the potential mitogenic effect of high local concentrations of insulin in the lung. [4]

The reasons for Exubera's failure were multiple: cost, efficacy, patient selection, convenience, device complexity and safety as noted above. Additionally the company that marketed Exubera had little experience in the diabetes sector. In the US, it attempted to project this modality as "all-encompassing" for patients with diabetes mellitus and marketed the product widely rather than attempting to utilize the "niche" that was available: e.g. needle phobia, patients who are otherwise unsuitable for injections or pump therapy, and some other special circumstances.

Technosphere Inhaled Insulin

One company, Mannkind continued development of their inhaled insulin product and was approved in the United States in early 2015 under the name Afrezza. The insulin is a freeze-dried powder delivered via a small inhaler device, thus releasing insulin which is rapidly absorbed into the systemic circulation. [5]

Technosphere insulin has a metabolic profile that closely mimics the plasma profile of prandial insulin of individuals who do not have diabetes.[6]

Afrezza Device
Afrezza Device

When the insulin is inhaled, microparticles can reach the deep lung. They then dissolve rapidly at physiological pH, allowing absorption of insulin and its other component: fumaryl diketopiperazine (FDKP). The time to maximum insulin concentration is 12-15 minutes. FDKP is then excreted in the urine unchanged.[7], [3]

Recent studies involving Type 1 and Type 2 DM patients have shown efficacy of inhaled technosphere insulin. In the type 1 study, it was noted inhaled insulin was non-inferior to aspart with each group receiving basal insulin. There was however less hypoglycemia, less weight gain but an increase in cough in the inhaled insulin group. The type 2 study also noted inhaled insulin non inferior to injectable, this time premixed aspart. There was no difference in treatment satisfaction though patients did prefer less injections.[8][9] Afrezza was noted to have a peak of action at ~ 12-15 minutes compared with 45-60 minutes for Exubera. [10]

Concerns with inhaled insulin were noted in several studies, including a mild non productive cough after inhalation, noted in up to 44% of individuals. There was also a small decline in FEV1. [10]

A recent study noted that inhaled insulin in both Type 1 and Type 2 patients was associated with less weight gain and a smaller decrease in HbA1c. Quality of life did not differ significantly. [11]

Those who wish to consider inhaled insulin will need spirometry or pulmonary function testing (PFT) as a baseline and follow-up studies at 6 months and annually thereafter. Those with COPD, active smokers or declining pulmonary function should not use inhaled insulin.

Future Considerations

The advent of inhaled insulin has added another therapeutic option for people with diabetes. It can be complex to initiate and may not be ideal for all. Patients need careful monitoring and the dosages of insulin available can be a limiting factor. However, when utilized in the proper patient, it can improve glucose control and improve patient satisfaction. Further evaluation of this modality will be needed to determine its long term effects and safety. If studies confirm safety and efficacy, it will achieve a place in the treatment of people with diabetes.

References

  1. ^ Mitri J and Pittas AG; Inhaled insulin -what went wrong Nat Clin Pract Endocrinology Metab: 5 (1) 24; 2009

  2. ^ http://www.nytimes.com/2007/10/19/business/19pfizer.html?ref=business

  3. ^ Mathieu C.. Inhaled insulin: gone with the wind?. Diabetologia. Springer Science + Business Media; 51(1):1-5. Available from: http://dx.doi.org/10.1007/s00125-007-0875-x

  4. ^ http://www.pfizer.com/news/press_releases/pfizer_press_releases.jsp?rssUrl=http://mediaroom.pfizer.com/portal/site/pfizer/index.jsp?ndmViewld=news_view&ndmConfigId=1010794&newsId=20080. cited 2008 Apr 16

  5. ^ Boss AH, Petrucci R and Lorber D; Coverage of Prandial Insulin Requirements by Means of an Ultra-Rapid-Acting Inhaled Insulin: JDST 6 (4): 773 2012

  6. ^ Potocka E, Havorka R, Baughman R, Klein O, Delweg S, Umpleby M, Haworth P, Mills R, Boss AH and Richardson PC; Characterization of metabolism parameters following Technosphere insulin and insulin lispro. Diabetes 59: Suppl 1: A413 2010

  7. ^ Richardson PC and Boss AH. Technosphere insulin technology; Diabetes Technology and Therapeutics 9: Supplement 1; 565 2007

  8. ^ Bode B, McGill JB, Lorber D, Gross JL, Chang P-C and Bregman DB and (Affinity 1 Study Group); Inhaled Technosphere Insulin Compared with Injected Prandial Insulin in Type 1 Diabetes: A Randomized 24 Week Trial. Diabetes Care published ahead of print July 15, 2015, doi:10.2337/dc15-0075

  9. ^ Peyrot M and Rubin RR; Patient reported Outcomes in Adults with Type 2 Diabetes Using Mealtime Inhaled Technosphere Insulin and Basal Insulin Versus Premixed Insulin. Diabetes Technology and Therapeutics 13: 1201 2011

  10. ^ Derosa Giuseppe. Inhaled insulin: weighing the pros and cons. The Lancet Diabetes & Endocrinology. Elsevier BV; 3(11):834-835. Available from: http://dx.doi.org/10.1016/s2213-8587(15)00317-4

  11. ^ Pittas Anastassios G. Efficacy, safety, and patient acceptability of Technosphere inhaled insulin for people with diabetes: a systematic review and meta-analysis. The Lancet Diabetes & Endocrinology. Elsevier BV; 3(11):886-894. Available from: http://dx.doi.org/10.1016/s2213-8587(15)00280-6

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