Inhaled Insulin Plus Degludec an Option for Type 1 Diabetes

ORLANDO, Fla. — The inhaled insulin Afrezza combined with a long-acting basal analog offers a non-inferior insulin treatment option for people with type 1 diabetes, new phase 4 data suggest. 

Afrezza Inhalation Powder is a rapid-acting orally inhaled human insulin, approved by the US Food and Drug Administration in 2014 for treating adults with type 1 or type 2 diabetes. People with type 1 diabetes who use it also need basal insulin, most often taken as a long-acting injected insulin analog such as degludec (Tresiba). Afrezza is taken before or shortly after a meal. 

Here at the American Diabetes Association 84th Scientific Sessions, investigators presented 17-week results from the phase 4 INHALE-3 randomized trial of Afrezza plus degludec vs usual care — either automated insulin delivery systems (AIDs), multiple daily injections, or pumps without automation — in 123 adults with type 1 diabetes, of whom 115 completed the study. 

The primary endpoint of A1c at 17 weeks didn’t change from baseline in either group. Both groups started at 7.6%. At 17 weeks, A1c levels were 7.6% and 7.5% with Afrezza and usual care, respectively. 

However, “this really doesn’t tell the whole story. In fact, it doesn’t tell the story at all, even though this was not a statistically significant difference,” said lead investigator Irl B. Hirsch, MD, medical director of the Diabetes Care Center at the University of Washington, Seattle, summarizing the findings during a press briefing. 

The story, he explained, is told in the secondary endpoints. The proportions of study participants who achieved A1c levels below the recommended 7% were 30% with Afrezza vs just 17% with usual care. And, 21% of those on Afrezza had A1c improvements of 0.5% or greater vs just 5% on usual care. 

However, “we also had people who got worse,” he reported. A significant 26% of participants experienced at least a 0.5% worsening with Afrezza, compared with just 3% of the usual care group. 

Similarly, among those with baseline A1c levels above 7.0%, 21% in the Afrezza group achieved levels below 7.0% at 17 weeks vs none in the usual care group. And improvements of at least 0.5% occurred in 28% of the Afrezza group and in 7% of the usual care group, although 21% and 2%, respectively, got worse. 

The reason for the worsening, discussed extensively during the 90-minute symposium, had to do with Afrezza’s very rapid action and rapid clearance from the body. Extra boluses in addition to premeal dosing are often needed, particularly at bedtime. 

The participants whose glycemia worsened were the ones who tended to bolus less often, Hirsch explained during the briefing. 

“Inhaled insulin may be good for patients who are especially engaged in their diabetes, self-management,” he said. 

Because it’s so short acting, participants needed to dose 1 to 3 hours after meals, especially at bedtime. Not everybody was good at that, said Hirsch. If their levels were high at bedtime and they didn’t dose, their levels stayed high. 

“If they did dose at bedtime, they did great,” he said, adding that “it is important for the clinical care team to understand how patients can get their best results from this therapy.”

This aligns with the clinical experience of Viral Shah, MD, professor of medicine and director of diabetes clinical research at the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis. 

“The key to using Afrezza, which we know from previous studies as well, is that dosing properly and frequently are necessary to really have optimal outcomes,” Shah told Medscape Medical News. 

It’s ingrained in our patients that if you take insulin before a meal you don’t take it again for the next 2 to 3 hours in order to avoid insulin ‘stacking,’ ” he said. 

It’s the reverse with Afrezza, said Shah. “You want to dose as frequently as possible. So patients have to not be afraid to dose again in 1 hour or one and a half hours, rather than waiting 3 hours.”

People who have managed their diabetes the traditional way for a long time are the ones who would do worse with Afrezza, he added, “because they’re afraid to dose it fully or frequently enough.”

Asked to comment on the study in general, Shah said the fact that there was no difference in A1c shows that people are able to use Afrezza properly. “It was a non-inferiority trial. For people who don’t want to wear a pump, that’s an encouraging result.”

Dosing: More Afrezza Needed Than Previously Thought

Also discussed at length during the meeting symposium was the discovery, as the study progressed, that higher doses of Afrezza were needed than the label suggests in order to convert from injected short-acting insulin. 

Afrezza comes in cartridges of 4, 8, and 12 units. But the units differ from injected insulin, said Hirsch. For example, 8 units of Afrezza equals 5-8 units of injected insulin, and 12 units of Afrezza is the equivalent of 9-12 units of injected insulin. In the trial, patients often needed 2.5 to 3 times higher doses than they had been injecting or infusing. 

Giving someone 24 units of insulin “sounds high,” but it’s not, Hirsch told Medscape Medical News. Patients and clinicians have to keep in mind that a unit of Afrezza is not a unit of injected insulin. 

It’s a hard concept to grasp, said Shah, who has seen this issue before. “People who are accustomed to taking 2 units are afraid to take the full 4 units.” 

“To be honest,” he added, “I would be biased toward erring on the side of a higher dose in general because I think we’re seeing that higher doses are associated with better outcomes without hypoglycemia, because it’s cleared so rapidly.”

Shah noted that Afrezza’s manufacturer MannKind now offers BluHale, a Bluetooth-connected accessory that attaches to the Afrezza inhaler and conveys real-time information about inhalation effort and insulin dose. 

Hopefully, that will give patients an idea of how much they should dose, he said. 

Some Chose to Give Up Their Pumps 

Despite the challenges, 53% of the overall study group said they wanted to stay on the inhaled insulin after the 17-week trial period, including 60% of those originally on multiple daily injections and on non-automated pumps. 

But the “amazing part,” said Hirsch, is that 43% of those who had been on AIDs also wanted to keep using Afrezza plus injected basal insulin. 

“The point is, people really liked it,” for a lot of reasons, he said. They wanted to get rid of the pump, for one. Afrezza is easier for traveling and for exercise. 

Even in people who did not have an improvement in time in range of A1c found they could exercise without watching their sensor going down or eating carbs, he added. They don’t have to do that with Afrezza, “and they love it.”

Bottom line, according to Shah: “The beauty of Afrezza is that it has a quick onset. But then the downside of that beauty is that it’s short-lasting. So, the product has pros and cons.”

Indeed, Hirsch said, “Inhaled insulin is not for everybody, but I think most clinicians should be comfortable with it.”

The study was funded by MannKind. Hirsch is a consultant for Abbott, Roche, Hagar, Vertex, and Embecta, and receives research support from Dexcom and Tandem. Shah has received honoraria from Dexcom, Insulet, Tandem Diabetes Care, Embecta, Sanofi, Novo Nordisk, Genomelink, and LumosFit for consulting, speaking, or advising. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker. 

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