Inhaled Insulin AFREZZA Ineffective, Can Damage Lungs

In 2014, the Food and Drug Administration (FDA) approved AFREZZA, the only inhaled insulin product currently available in the U.S. This powder insulin is inhaled into the lungs, distinguishing it from other insulins, which must be injected.[1],[2]

Inhaled insulin is less effective than injectable insulin and causes a host of side effects that range from unpleasant coughing to severe shortness of breath — and possibly lung cancer. Only one other inhaled insulin has ever been approved in the U.S. This drug, EXUBERA, was withdrawn from the market after only two years, following poor sales and mounting evidence of lung cancer risks.[3] AFREZZA will almost certainly share the same fate.

Using mealtime insulin

Insulin works by regulating the amount of glucose (sugar) in the blood and can be used to help keep blood sugar levels within a healthy range for people with Type 1 or 2 diabetes.[4] Insulin treatment always should be paired with a healthy diet and regular exercise, which are the cornerstones of treatment for anyone with diabetes.[5]

AFREZZA is a short-acting "mealtime" insulin.[6] Mealtime insulins work quickly and can help the body adjust to spikes in blood sugar that occur as food is digested.[7] In contrast, longer-acting insulins, sometimes called basal insulins, take longer to work but can last 12 hours to a full day, making them useful for managing blood sugar between meals.[8],[9] Mealtime insulin is generally regarded as an option of last resort for patients who fail to achieve blood sugar control on one of these longer-acting basal insulins.[10],[11]

AFREZZA has not been shown to be more effective in controlling blood sugar than injectable mealtime insulin. In fact, the best evidence suggests that the product is less effective.

Ineffective drug, unethical testing

The FDA rejected the first application to approve AFREZZA for sale in the U.S. in 2009, in part due to evidence that AFREZZA was less effective in maintaining blood sugar control than regular injectable mealtime insulin.[12]

AFREZZA's manufacturer modified the inhaler device used to administer the insulin and tried again.[13] In clinical testing among subjects with Type 1 diabetes, the new AFREZZA inhaler still was inferior to injected mealtime insulin in controlling blood sugar.[14] Subjects with Type 1 diabetes who took AFREZZA also were five times as likely to experience diabetic ketoacidosis, a serious, life-threatening orgcondition that occurs when the body lacks adequate insulin to process sugar for energy, leading to the accumulation of acidic substances called ketone bodies and increased acidity in the blood.[15]

AFREZZA appeared to perform slightly better in a clinical trial in people with Type 2 diabetes who were already taking high doses of metformin (GLUCOPHAGE) or at least two other diabetes pills.[16] But in this trial, subjects in the control group were provided a placebo, not injectable mealtime insulin or another standard treatment option. This made AFREZZA appear effective at controlling blood sugar, even though it probably is less effective than other available treatments.[17] Such withholding of standard treatment from the control group was unethical.

Damage to the lungs

Inhaled insulin powder causes unique lung-related side effects not present with injectable insulin. The most common side effects are merely unpleasant. But the drug's more serious side effects can be devastating and sometimes fatal.

Minor lung-related side effects were extremely common: About a quarter of subjects who received AFREZZA in clinical trials experienced coughing, compared with only about 6 percent of subjects who received a placebo or injected insulin.

AFREZZA carries a black-box warning instructing doctors not to prescribe it to patients with asthma or chronic obstructive pulmonary disease (COPD) because it causes acute bronchospasms (sudden difficulty breathing due to narrowing of the airways) among these patients.[18]

Disturbingly, AFREZZA also negatively affects lung function in patients with healthy lungs. In clinical trials, subjects with diabetes were twice as likely to experience worsening lung function when using AFREZZA (6 percent) as those on injected insulin (3 percent).[19] These data came from trials that lasted slightly less than six months, leaving serious unanswered questions about the effects of the drug on long-term lung function.[20]

Most troubling, AFREZZA may increase the risk of lung cancer. Insulin promotes cell growth,[21] and concentrating insulin in the lungs over a long period may lead to the growth of cancerous tumors.[22] Cancer cases are rare in clinical trials, yet in clinical testing for AFREZZA, four subjects who received the drug developed lung cancer, compared with none who received a placebo or injectable insulin.[23] Even more unusual, two of the lung cancer cases were nonsmokers, for whom lung cancer is much less common.[24]

The inhaled insulin EXUBERA, which was withdrawn from the market in 2008, provides further evidence of lung cancer risks with inhaled insulin. Subjects who received EXUBERA in premarket clinical trials were nearly four times more likely to be diagnosed with lung cancer than subjects who did not.[25] They also were nearly three times more likely to die of lung cancer.

When the FDA approved AFREZZA, it also ordered the manufacturer to conduct a large, five-year randomized, controlled study to assess the risk of lung cancer and other serious but rare side effects.[26] Unfortunately, this study is not scheduled to be completed until 2023.[27]

What You Can Do

Do not start to use inhaled human insulin (AFREZZA) for diabetes treatment. If you already are using the drug and require mealtime insulin, work with your doctor to select an appropriate rapid or short-acting insulin for use during mealtimes, such as human insulin (HUMULIN), insulin lispro (HUMALOG) or insulin aspart (NOVOLOG).[28],[29]

If you have Type 2 diabetes, you should not take mealtime insulin unless you already are using a longer-acting basal insulin, such as insulin glargine (LANTUS),[30] and your blood sugar remains difficult to control.[31]

Work with your doctor or a dietician to create a diet plan that is rich in fruits, vegetables and whole grains, focusing on foods that are high in nutrition and fiber and low in fat and calories.[32] Aim to get 30 minutes of aerobic exercise, such as walking or biking, each day.[33]

For more advice on drug treatment for diabetes, see "Type 2 Diabetes: A Guide to Prevention and Treatment" in the May 2014 issue of Worst Pills, Best Pills News.[34]

References

[1] National Library of Medicine. DailyMed drug label: AFREZZA – insulin human powder, metered. Updated July 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=76fb46f1-82db-40da-ba19-b3a7b0bd78ff. Accessed September 19, 2015.

[2] American Diabetes Association. Insulin basics. http://www.diabetes.org/living-with-diabetes/treatment-and-care/medication/insulin/insulin-basics.html#sthash.ClIGJbTk.dpuf. Accessed September 19, 2015.

[3] Guettier J. Summary review: AFREZZA (NDA: 22-472). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000SumR.pdf. Accessed September 19, 2015.

[4] Mayo Clinic. Diabetes treatment: Using insulin to manage blood sugar. August 7, 2013. http://www.mayoclinic.org/diseases-conditions/diabetes/in-depth/diabetes-treatment/art-20044084.

[5] Mayo Clinic. Diabetes: Treatments and drugs. July 31, 2014. http://www.mayoclinic.org/diseases-conditions/diabetes/basics/treatment/con-20033091. Accessed September 19, 2015.

[6] Guettier J. Summary review: AFREZZA (NDA: 22-472). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000SumR.pdf. Accessed September 19, 2015.

[7] Ibid.

[8] Ibid.

[9] American Diabetes Association. Insulin basics. http://www.diabetes.org/living-with-diabetes/treatment-and-care/medication/insulin/insulin-basics.html#sthash.ClIGJbTk.dpuf. Accessed September 19, 2015.

[10] Nathan DM, Holman RR, Buse JB, et al. Management of hyperglycemia in Type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006;29(8):1963-1972.

[11] Guettier J. Summary review: AFREZZA (NDA: 22-472). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000SumR.pdf. Accessed September 19, 2015.

[12] Ibid.

[13] Ibid.

[14] Ibid.

[15] Ibid.

[16] Ibid.

[17] Ibid.

[18] National Library of Medicine. DailyMed Drug Label: AFREZZA – insulin human powder, metered. Updated July 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=76fb46f1-82db-40da-ba19-b3a7b0bd78ff. Accessed September 19, 2015.

[19] Ibid.

[20] Yanoff SA. Cross disciplinary review: Afrezza (insulin human inhalation powder). NDA#: 22472. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000CrossR.pdf.

[21] Straus DS. Effects of insulin on cellular growth and proliferation. Life Sciences. 1981;29(21):2131-2139.

[22] Guettier J. Summary Review: AFREZZA (NDA: 22-472). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000SumR.pdf. Accessed September 19, 2015.

[23] Ibid.

[24] FDA Center for Drug Evaluation and Research. Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting minutes. April 1, 2014. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM397049.pdf.
[25] Guettier J. Summary review: AFREZZA (NDA: 22-472). Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000SumR.pdf. Accessed September 19, 2015.

[26] Letter from the Food and Drug Administration to MannKind Corporation, June 27, 2014. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/022472Orig1s000ltr.pdf.

[27] Ibid.

[28] Mayo Clinic. Insulin: Compare common options for insulin therapy. July 30, 2013. http://www.mayoclinic.org/diseases-conditions/diabetes/in-depth/insulin/art-20050970. Accessed September 19, 2015.

[29] American Diabetes Association. Insulin basics. Last edited July 16, 2015. http://www.diabetes.org/living-with-diabetes/treatment-and-care/medication/insulin/insulin-basics.html. Accessed September 19, 2015.

[30] Mayo Clinic. Insulin: Compare common options for insulin therapy. July 30, 2013. http://www.mayoclinic.org/diseases-conditions/diabetes/in-depth/insulin/art-20050970. Accessed September 19, 2015.

[31] Nathan DM, Holman RR, Buse JB, et al. Management of hyperglycemia in Type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006;29(8):1963-1972.

[32] Mayo Clinic. Diabetes: Treatments and drugs. July 31, 2014. http://www.mayoclinic.org/diseases-conditions/diabetes/basics/treatment/con-20033091. Accessed September 19, 2015.

[33] Ibid.

[34] Type 2 Diabetes: A Guide to Prevention and Treatment. Worst Pills, Best Pills News. May 2014. /newsletters/view/901. Accessed October 2, 2015.