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Evidence-Based Diabetes Management September 2016

Afrezza: Treating Diabetes in a Physiologic Manner

R. Keith Campbell, MBA, BPharm, CDE
Professor R. Keith Campbell, MBA, BPharm, CDE, now retired from Washington State University College of Pharmacy, highlights the clinical advantages of Afrezza based on the evidence as well as his personal perspective.
Afrezza Is Impressively Effective

Afrezza is human insulin, and insulin is known to lower blood glucose levels when used appropriately. Like all insulins, Afrezza requires individualization and adequate dosing. A consequence of its PK/PD profile is that the dose of Afrezza required to control glucose will probably be numerically higher than SC RAA. If the healthcare provider and patient do not titrate the dose to an adequate blood glucose control, they might believe it does not work.

Lung Issue Perspective

The delivery of Afrezza via the lungs has raised concerns about administration of medications via this route. Years of study and delivery of medications into the lungs has generally shown positive risk benefit. However, in clinical trials with Afrezza, although there were no cases of lung cancer reported in the comparator group, the Afrezza group had 4 (2 cases while on study and 2 cases reported spontaneously 2 years after the end of the trial). The observed incidence was 0.73 cases per 1000 patient-years compared with an expected rate of 1 or 2 cases per 1000 patient-years in patients with diabetes (among smokers plus nonsmokers). These numbers are insufficient to draw conclusions about an association between Afrezza and cancer. A 5-year randomized controlled safety study is planned as part of postmarketing requirements.

Spirometry. There is a risk of bronchospasm when any dry powder is inhaled by persons with hyper-reactive airways. Spirometry is required by the FDA to screen out patients with underlying lung disease prior to starting treatment in order to avoid the risk of bronchospasm. Follow-up testing (at 6 months and annually thereafter) is to confirm the absence of obstructive lung disease. A pulmonary substudy is included as part of the 5-year safety study.1

Cough. After hypoglycemia, cough was the most common adverse event in phase 3 studies of Afrezza. The cough was generally mild and dry, occurred within 10 minutes of inhalation, was transient, and declined with continued use. In phase 2 and 3 studies, 27% of patients treated with Afrezza reported cough; 2.8% discontinued treatment due to cough.2

Accessibility and Cost

Afrezza is an FDA-approved medication and is being marketed by MannKind Corporation through its salesforce. Available throughout the country, and generally covered by national payers for commercially insured lives, Afrezza has a unique cost-benefit profile because of its PK/PD profile and resultant less severe hypoglycemia. It enables patients to have real-time flexibility to correct their elevated sugars and does not require an insulin pump. Patients on Afrezza have the potential of saving themselves from multiple co-pays for their needles and other accessories associated with insulin pumps and pens. In addition, patients do not have to manage sharps hazards and disposal for their mealtime insulin. The price of injectable insulin has been increasing, at a compounded annual rate of more than 20%, for the last several years to an average price point of about $19 per day, while alternatives, such as Afrezza with a fixed price per cartridge, may range from $9 to $18 per day.13 A prior authorization is often required to help patients get started, but unfortunately, this is likely causing many patients to forego the benefit of this novel treatment option if their doctors don’t go the extra step to get it approved.

The majority of patients with diabetes are not at their ideal treatment goals, which creates opportunity for health plans, doctors, and patients to manage the postprandial impact insulin can have. Although there are some unknowns to the long-term use of Afrezza, the known risks and complications that patients with diabetes face with elevated sugars are well established. Afrezza has been studied up to 4 years in clinical trials in over 8000 patients, and the future trials that are planned will continue to articulate the PK/PD profile to demonstrate real-time disease control.
 
The PD effect of SC therapy is much like a super tanker: once launched, it can change course only very slowly. Patients have no choice but to adapt their schedules to meet the demands of insulin. Afrezza is more like a speedboat: its shorter duration of action permits navigation between the risks of hyperglycemia and the consequences of hypoglycemia. 



Author Information: The author retired from the Washington State University College of Pharmacy in 2013 after 45 years and remains a distinguished professor emeritus of pharmacotherapy. He has lived with type 1 diabetes for 67 years and has used an insulin pump for 37 years, 9 months.
 
Disclosures: The author serves on the advisory board on insulin for Novo Nordisk.

Source of Funding: None.
References

  1. FDA approves Afrezza to treat diabetes [press release]. Silver Spring, MD: FDA; June 30, 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm. Accessed September 4, 2016.

  2. Afrezza (insulin human) inhalation powder [package insert]. Danbury, CT: MannKind Corporation; 2014.

  3. Baughman RA, Heise, Grant ML, et al. Technosphere insulin inhalation powder (TI) displays earlier onset and shorter duration than insulin lispro (lispro). Diabetes. 2016;65(suppl 1A):100-LB.

  4.Bode BW, McGill JB, Lorber DL, Gross JL, Chang PC, Bregman DB; Affinity 1 Study Group. Inhaled Technosphere insulin compared with injected prandial insulin in type 1 diabetes: a randomized 24-week trial. Diabetes Care. 2015;38(12):2266-2273. doi: 10.2337/dc15-0075.

  5. Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycaemia. Diabetologia. 2003;46(suppl 1):M2-M8. doi: 10.1007/s00125-002-0930-6.

  6. Bruttomesso D, Pianta A, Mari A, et al. Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients. Diabetes. 1999;48(1):99-105. doi: 10.2337/diabetes.48.1.99.

  7. Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW. Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes. Diabetes. 1988;37(6):736-744. doi: 10.2337/diab.37.6.736

  8. Monnier L, Lapinski H, Colette C. Postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26(3):881-885.

  9. Potocka E, Hovorka R, Baughman R, et al. Characterization of metabolism parameters following Technosphere insulin and insulin lispro. American Diabetes Association 70th Scientific Sessions. 2010; Abstract 1561-P.
  10. Howey DC, Bowsher RR, Brunelle RL, Woodworth JR. [Lys(B28), Pro(B29)]-human insulin: a rapidly absorbed analogue of human insulin. Diabetes. 1994;43(3):396-402.

  11. Visentin R, Giegerich C, Jäger R, et al. Improving efficacy of inhaled Technosphere insulin (Afrezza) by post-meal dosing: in-silico clinical trial with the University of Virginia/Padova type 1 diabetes simulator [published online June 22, 2016]. Diabetes Technol Ther. doi: 10.1089/dia.2016.0128.

  12. Lehtonen H-M, R Järvinen R, Linderborg K, et al. Postprandial hyperglycemia and insulin response are affected by sea buckthorn (Hippophaë rhamnoides ssp. turkestanica) berry and its ethanol-soluble metabolites. Eur J Clin Nutr. 2010;64(12):1465-1471. doi:10.1038/ejcn.2010.173.

13. Insulins: prices and information.  GoodRx website. Insulins. http://www.goodrx.com/insulins. Accessed September 4, 2016.
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