Inhaled Insulin: Is it Safe, Does it Work?

Many people are surprised to learn that insulin can be inhaled. Afrezza is a dry powder formulation of Technosphere microparticles (link to 1^st article). The particles are absorbed into the lungs and dissolved into the bloodstream¹. It is considered an ultra-rapid-acting insulin, which works faster than any of the injectable insulins (lispro, aspart, etc). Therefore, it may allow more flexibility for dosing without the need to take it 15 minutes before eating. It also may bring down above-range blood glucose more quickly.

How Well Does Inhaled Insulin Work?

All drugs need to show they are effective in order to gain FDA approval. Therefore, Afrezza inhaled insulin has been studied in a wide range of clinical trials for people with type 1 and type 2 diabetes.

For example, Afrezza was studied in the AFFINITY-1 trial, which included 174 people with type 1. The average A1C decreased from 7.92% to 7.73%, by 0.21, which was found to be similar to insulin aspart, the comparator². This demonstrates that Afrezza can work just as well as the typical rapid-acting insulins used. In another trial of 20 people with type 2, A1C decreased from 9.0% to 7.4%, a 1.6 A1C reduction³ demonstrating its ability to also work well in people with type 2.

A1C has limitations, as it tells nothing about glucose variability. Afrezza was compared to rapid-acting insulin aspart in the STAT study, which included 60 people with type 1. All wore a real-time CGM. The two groups achieved comparable time in range, but those taking Afrezza had less time in hypoglycemia (glucose <60mg/dL and <50mg/dL). The group taking Afrezza was encouraged to take additional doses 1 or 2 hours after eating if glucose remained above target. Those who followed those directions had greater time in range (62.5% vs. 53.8%) and less time in hyperglycemia (glucose over 180mg/dL) compared to the aspart group. This is important because injectable insulins aren’t generally safe to dose 1 or 2 hours after eating due to the risk of hypoglycemia since they last longer in the body. This trial demonstrated that it is safe to dose with Afrezza 1 or 2 hours after meals. There was also weight loss with Afrezza compared to weight gain with aspart despite higher doses⁴. In general, across clinical trials, Afrezza has been associated with neutral weight, whereas insulin aspart and insulin lispro have been associated with weight gain⁵.

Is Inhaled Insulin Safe?

Some people feel uneasy about inhaling medication. Will it damage the lungs? Or cause other side effects? All insulin can cause hypoglycemia or low blood glucose. Since inhaled insulin is out of the system more quickly, there is actually a lower risk of hypoglycemia. The most common side effects of inhaled insulin are cough and throat pain or irritation. A cough is usually a dry cough that occurs within 10 minutes of inhalation and generally gets better after continued use. Some tips to help with cough are to keep Afrezza at room temperature and have a sip of water before inhaling⁶. Only about 3% of people in clinical trials discontinued due to cough, and no persistent safety concerns related to the lungs were identified⁷.

Monitoring Lung Function with Inhaled Insulin

Because it is inhaled, it’s not recommended for use in people with asthma or chronic obstructive pulmonary disease (COPD) or people who smoke. In clinical trials, there was a 1% change in lung function compared to those not taking the drug, although this difference didn’t increase through the duration of taking Afrezza and went away once the drug was discontinued.

To be cautious, checking lung function while taking inhaled insulin is recommended, and this is done through an FEV1 test. These kits are often in doctor’s offices, or a kit can be mailed to you to test at home. The test checks to ensure the lungs are working properly and no unknown lung disease exists. It is performed by blowing into a small device as hard as possible and is typically done three times. This test is fast, usually about 2 minutes. The test should be done before starting the drug, after six months, and then annually. Often, insurance plans request this information for the drug to be approved.

Real-World Uses of Inhaled Insulin

Inhaled insulin can be used to replace all rapid-acting insulin for anyone who requires mealtime insulin. It does not replace long-acting or basal insulin, so it’s important to continue to take that. Inhaled insulin works especially well for a high glycemic index food, one that will spike glucose quickly, like soda, juice, candy, or desserts. One of the great things is that if blood glucose remains above range after eating, more inhaled insulin can be given just an hour after the meal. This is so different from other insulins, with the recommendation to wait 3 to 4 hours between doses to avoid stacking insulin and going too low. The best way to monitor this is to wear a continuous glucose monitor (CGM). The diabetes guidelines advocate that everyone taking insulin should have access to a CGM for glucose monitoring. While it can be done with blood glucose meters, the information provided by a CGM can help with decisions on adjusting doses based on how rapidly glucose is rising or falling.

Dosing Inhaled Insulin: An Art

Say goodbye to strict carbohydrate counting. Yes, knowing which foods have carbohydrates is still important, but with inhaled insulin, you can usually start with a dose and then add more as needed. Even if carbohydrate counting isn’t perfect, it can be easier to manage blood glucose levels.

Using Inhaled Insulin with an Insulin Pump

It is considered off-label to use inhaled insulin with an insulin pump, however, prescribers can use their judgment on use in different clinical situations. For example, some may use it with a manual insulin pump, which does not directly communicate with a CGM. In this scenario, inhaled insulin would be used to give boluses and correction doses while the insulin pump provides the background insulin. In Automated Insulin Delivery systems, inhaled insulin will work better with some over others. Some systems like Medtronic 780G and Omnipod 5 rely on total daily insulin dose for insulin adjustments. If insulin is taken outside of the system and the system isn’t aware of it, that can mess with the algorithm. The iLet can also be problematic because of the automatic correction doses and the need to be made aware of the inhaled insulin. Other systems like Control IQ and Tidepool Loop can more readily be used to supplement bolus doses, and in fact, they are being studied for this purpose, so stay tuned. But it’s important to keep in mind when using it in an insulin pump, the pump won’t know that there is extra insulin on board. And if the pump is not working well to bring down glucose, you should check your infusion set and ensure there is no occlusion or leaking insulin at the site. If there is, a dose of inhaled insulin could be taken, and the pump site should be changed out.

Inhaled Insulin for Women: Special Considerations

Many women experience changes in their glucose around their menstrual cycle. They often may experience higher insulin requirements. This can be hard to plan for, depending on how regular their cycle is or how in tune they are. Inhaled insulin could be nice to have on hand when additional insulin is needed since it will work more quickly with a lower risk of hypoglycemia versus changing long-acting and rapid-acting insulin doses. Of note is that inhaled insulin is not FDA-approved for use in pregnancy. Although it’s simply regular insulin known to be safe, a couple of additional ingredients need to be studied further to evaluate safety and gain FDA approval.

So Why Isn’t Inhaled Insulin Used More?

The biggest reason it’s probably not used more is that people don’t know about it. Many people with diabetes are not aware that there is an inhaled option available to them. Unfortunately, many healthcare providers also don’t know about it. The second reason may be misconceptions about side effects and monitoring. Although the FEV1 test is required for prescription, it’s super-fast and easy, and any healthcare provider’s office can request the device. The clinical trials show that inhaled insulin works to lower A1C, helps to reduce post-meal spikes, and reduces instances of low glucose with its quick onset and how quickly it leaves the body.

Future Outlook of Inhaled Insulin

It’s great to have options when it comes to medications and technologies to treat diabetes. With its numerous benefits, inhaled insulin is likely to be used more in clinical practice as more people learn about it and indications expand. It’s being studied for a wide variety of new indications, like children and pregnancy, and in combination with insulin pumps. It is the most physiologic type of insulin, being the most similar to insulin’s action time in a person who doesn’t have diabetes. Additionally, this isn’t the only medication administered through the airway. We have nasal glucagon, Narcan, and now epinephrine. Although these go through the nose instead of mouth, it’s a similar idea of medications being absorbed through the lungs instead of the usual oral route, where they can be degraded more quickly. Consider asking your healthcare team to learn more about it.

Interested in learning more about inhaled insulin?

Join us for two exciting upcoming events! Sign up for a webinar with Diana Isaacs, PharmD, BCPS, BC-ADM, CDCES: Discover the benefits and practical tips for using inhaled insulin.

And join us for a workshop with Ginger Vieira, diabetes expert and advocate: Dive deeper into how inhaled insulin can fit into your diabetes management plan. Attend either at 12:00 PM ET or 7:00 PM ET.

Don’t miss these opportunities to get valuable insights and have your questions answered!

References

1. Wilson LM, Castle JR. Recent Advances in Insulin Therapy. Diabetes Technol Ther. 2020 Dec;22(12):929-936. doi: 10.1089/dia.2020.0065. Epub 2020 May 12. PMID: 32310681; PMCID: PMC7864088
2. . Bode BW, McGill JB, Lorber DL, Gross JL, Chang PC, Bregman DB. Inhaled Technosphere insulin compared with injected prandial insulin in type 1 diabetes: a randomized 24-week trial. Diabetes Care. 2015;38(12):2266-2273
3. Levin P, Hoogwerf BJ, Snell-Bergeon J, Vigers T, Pyle L, Bromberger L. Ultra rapid-acting inhaled insulin improves glucose control in patients with type 2 diabetes mellitus. Endocr Pract. 2021;27(5):449-454 4
4. Akturk HK, Snell-Bergeon JK, Rewers A, et al. Improved postprandial glucose with inhaled Technosphere insulin compared with insulin aspart in patients with type 1 diabetes on multiple daily injections: the STAT study. Diabetes Technol Ther. 2018;20(10):639-647
5. Afrezzahcp.com/efficacy
6. . McGill JB, Peters A, Buse JB, et al. Clin Drug Investig. 2020;40(10):973-983
7. Afrezza prescriber information

Image from Mannkind.