Q&A: Increased awareness may boost uptake of inhaled insulin
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Key takeaways:
- Inhaled insulin uptake has been slow since its FDA approval due in part to a lack of awareness among adults with diabetes.
- The ongoing INHALE-1 study may help inhaled insulin earn FDA approval for children.
A form of inhaled insulin has been available for adults with type 1 and type 2 diabetes for nearly a decade, but providers say many people are not aware that it may be a treatment option for them.
In June 2014, the FDA approved a rapid-acting inhaled insulin (Afrezza, MannKind Pharma) for adults with type 1 and type 2 diabetes. The following year, two studies were published that found inhaled insulin was a therapeutic option for adults with diabetes. In the Affinity 1 trial, adults with type 1 diabetes had a noninferior reduction in HbA1c and fewer hypoglycemic events with inhaled insulin compared with subcutaneous insulin aspart. Similar findings were observed in the Affinity 2 study, in which adults with type 2 diabetes who used inhaled insulin plus an oral antidiabetes agent had a greater reduction in HbA1c than those using placebo plus an oral agent.
Thomas Blevins, MD, FACE, a clinical endocrinologist at Texas Diabetes and Endocrinology in Austin, Texas, said one of the biggest advantages inhaled insulin offers over subcutaneous forms is how much quicker it works.
“It depends on the dose, but time to first measurable effect is about 12 minutes, so people can take it right when they start to eat,” Blevins told Healio. “The time to peak is 35 minutes. That's quick, that's significantly faster than the fastest of the analogs, so people get that quick response to insulin to cover their meal carbs.”
Despite the FDA approval and the Affinity trial findings, uptake of inhaled insulin has been low, according to Blevins and Michael J. Haller, MD, professor and chief of pediatric endocrinology at the University of Florida. Some people, particularly those with pulmonary conditions, are unable to use the agent. A lack of awareness among patients is another issue. A third barrier is that inhaled insulin is not FDA approved for children. The ongoing INHALE-1 trial is assessing whether inhaled insulin is noninferior for children aged 8 to 17 years compared with their usual rapid-acting insulin. Findings from that trial could pave the way for FDA approval for children.
“A pivotal point for the drug’s success will be obtaining FDA approval for use in kids,” Haller, who is a principal investigator on INHALE-1, told Healio. “I think you'll start seeing people offering it at diagnosis. It's a very different paradigm — you take somebody who's new to needing insulin and you say that I can offer you [inhaled insulin] for all your meals and explain why it's so much better physiologically than injected insulin. I just think the uptake will be far greater in that kind of a population.”
Blevins and Haller spoke with Healio about the benefits of inhaled insulin, limitations associated with the agent and why inhaled insulin is not used more often in practice.
Healio: How does inhaled insulin differ from other types of insulin delivery?
Blevins: Inhaled insulin is human regular insulin that is complexed with technosphere microparticles. It carries the human regular insulin into the lungs where it can be absorbed. It gets in rapidly and crosses the lung alveolar membranes. Afrezza particles separate from the technosphere, and they're into the bloodstream promptly. That rate of absorption makes it the fastest insulin absorption out there. There's just no rival.
Haller: The key is the unique drug delivery. The insulin being absorbed through the lung alveolar membrane all at once allows insulin to go right into bloodstream, whereas when you give it subcutaneously, it's bound up with lots of other particles. It has to get absorbed through the microvascular system, then into the larger vessels and then get circulated. Inhaled insulin is the closest thing to physiologic insulin that we're going to have anytime soon.
Healio: What are some of the advantages of using inhaled insulin?
Blevins: [Inhaled insulin] is quick in and it’s also quick out. The time to return to baseline, depending on the dose, is anywhere from 90 minutes up to 3 hours. It’s really hard to “stack.” Doses can be taken 60 to 90 minutes apart to lower the glucose and the rapid offset makes hypoglycemia less likely. Subcutaneous rapid insulins take that close together will likely “stack” and cause hypoglycemia. Inhaled insulin gets in and out quickly, which is a big advantage.
Haller: One of the biggest issues in pediatrics is kids not getting adequate doses because they bolus late. It’s hard to count carbs and it’s hard to give pre-meal insulin with kids because you’re not sure how much they’re going to eat. Being able to give insulin as kids are eating or right before is a big advantage.
Blevins: Another advantage is there’s no need for an insulin pen or syringe. The delivery system is very small, and the insulin cartridges can be carried around. This is very portable and very simple. That's an advantage for the needle phobic and for people that don't want to be seen in public given injections.
Healio: What are some of the limitations with inhaled insulin?
Haller: The main one is not having it approved for pediatrics. We're trying to overcome that issue with the INHALE-1 study. INHALE-1 is a study that’s open right now to try and get FDA approval for pediatric use for children and adolescents aged 8 to 17 years who are on multiple daily injections,. Both type 1 and type 2 diabetes patients are eligible. The study is set up as a noninferiority study, it’s comparing the rapid-acting analog they would otherwise be using to Afrezza as a replacement for that insulin.
Patients are randomly assigned to Afrezza or to continue on their current rapid insulin for the first 6 months of the trial. The second 6 months of the trial, they switch to the other arm, although those who got Afrezza are offered the option to continue on after the study. It's a long study, but it's what we have to do to satisfy the federal agencies.
The study is doing well in terms of recruitment; there's over 230 patients already enrolled. But we do need more to get it to the finish line. The hope is to finish enrolling in early 2024, which would give us endpoint data right the end of 2024 into early 2025.
Another disadvantage [to inhaled insulin] is that it's a paradigm shift, and people don't like change. It's just a different way of thinking about insulin. The units of insulin on the cartridges are often two to three times what people need when they inject. Even though those aren't equitable units, people get very tied up in what they're used to doing. People are used to giving 10 units for a meal, and now they suddenly need to take 24 units of inhaled insulin because of the cartridge sizes. That can be hard to get people to accept at first, and that results in people underdosing and not getting an optimal dose.
Blevins: [Inhaled insulin] only comes in three cartridges sizes: 4 units, 8 units and 12 units. The FDA requires that they put the accurate number of units that's in these cartridges, but we know only half of that gets into the lungs and gets absorbed. I've had people with diabetes who are very insulin sensitive say 4 units is too much, but it's not really 4 units, it is equivalent to approximately 2 units. I tell patients that Afrezza 4 units is about 2 units of active insulin, Afrezza 8 units is about 4 doses of active insulin and Afrezza 12 units is about 6 units of active insulin. Sometimes, people have a higher dose, and then they have to take a few cartridges.
Haller: While it's not a huge percentage of people, folks who have a primary pulmonary issue can't take this insulin. If you have chronic asthma or you have some other primary lung disease, this is not the way to deliver insulin for you.
Healio: Why isn't inhaled insulin being used more in practice?
Haller: I think it's a marketing issue. People aren’t all that excited about a change, even though giving insulin is not something people particularly like doing. It's such a different shift that, frankly, doctors and patients haven't fully recognized the advantages that Afrezza gives, so they haven't been prescribing as much. It is a bit of a niche insulin, but one that I think should be used more often, because it has significant offerings and advantages.
Blevins:. There's definitely a lack of awareness among patients, and providers have let it sit in the background for various reasons. When patients talk to each other about it, they’re big advocates. From what I've seen with patients, with some exceptions, to know it is to like it. Some patients aren't going to go with it. Some get a cough they don't want, and some can't or shouldn't take it because of their pulmonary history. But most people like the quick onset, the feeling of increased glucose control and the portability of the dosing inhaler and cartridges. As long as it is getting reimbursed, they're quite eager to use it.
Healio: What further research needs to be conducted on inhaled insulin?
Blevins: I was an investigator on the ABC trial that looked at converting people to Afrezza for their bolus along with their automated insulin delivery system. It wasn’t superior, but it worked as well as the automated delivery system with boluses given through the pump. There was no difference with the HbA1c outcomes, but there was a significant difference when it came to the meal test with Afrezza being given pre-meal vs. analog insulin given by the automated insulin device. Afrezza given before the meal test led to considerably lower glucoses at 45, 60, 90 and 120 minutes than pre-meal analog insulin boluses given with the automated insulin-delivery pump. The ABC trial was small, there was a modest number of patients in that trial, we had a total of 26 participants at about three or four sites.
There’s another study we’re participating in here in Austin called INHALE-3. It’s going to take people with type 1 diabetes and convert them to insulin degludec (Tresiba, Novo Nordisk) plus Afrezza vs. staying on their usual care. That study is ongoing, stay tuned.
For more information:
Thomas Blevins, MD, FACE, can be reached at tblevins@texasdiabetes.com.
Michael J. Haller, MD, can be reached at hallemj@peds.ufl.edu.
Reference:
Bode BW, et al. Diabetes Care. 2015;doi:10.2337/dc15-0075.
Kaiserman K, et al. Diabetes. 2023;doi:10.2337/db23-1805-PUB.
Rosenstock J, et al. Diabetes Care. 2015;doi:10.2337/dc15-0629.
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