Afrezza Inhaled Insulin for Adults with Type 1 Diabetes: What Have We Learned?

What if you could manage mealtime blood sugar with inhaled insulin, instead of injecting rapid acting insulin multiple times each day? Managing mealtime blood sugar is no easy feat, especially when you have to remember to bolus well in advance of eating.

Indeed, a 2019 study by leading experts found that mealtime glucose is the key challenge preventing about 80% of people with type 1 diabetes from achieving their A1C goals.  

MannKind’s Afrezza launched in 2015 as the first and only ultra rapid-acting inhaled insulin. Although Afrezza has been available for nearly a decade, not all people with diabetes or healthcare providers may be familiar with this insulin option. 

Experts at the 2024 American Diabetes Association (ADA) Scientific Sessions characterized Afrezza as a “rapid on, rapid off” insulin that can be helpful for some people with diabetes. 

Whereas most injectable rapid-acting insulins take about 15 to 20 minutes to start working, Afrezza starts lowering blood sugars in about 12 minutes. Afrezza’s glucose-lowering effects also fade a lot quicker than traditional mealtime insulins. 

The INHALE-3 trial investigated Afrezza for mealtime glucose levels in adults with type 1 diabetes. Overall, Afrezza delivered similar reductions in A1C compared to usual diabetes care. Afrezza also led to better reductions in post-meal blood sugar compared to injected rapid-acting insulin. 

More participants in the Afrezza group showed substantial improvements in A1C and time in range, but more Afrezza users also showed substantial worsening in glycemic control. In the words of Dr. Carol Levy, endocrinologist and professor of medicine at Mount Sinai Health System, “One size did not fit all.” 

Experts took a deeper look at the results from INHALE-3 to reveal key considerations when taking Afrezza – read on for more. 

How did the trial work? 

INHALE-3 lasted for 17 weeks and included 123 adults with type 1 diabetes. About half of the participants were using automated insulin delivery (AID) systems, while the others were on multiple daily injections or using an insulin pump. 

Participants were randomly assigned to use the basal insulin Tresiba (degludec) with Afrezza, or to continue with their usual diabetes care. All participants wore a CGM. On average, participants were 45 years old and had lived with diabetes for 23 years. Approximately half of participants were female, and the vast majority were White. 

What were the key findings? 

Participants taking Afrezza achieved the same A1C as those receiving usual care: average A1C was 7.6% in both groups. However, this overall finding doesn’t tell the full story. 

While 28% of participants taking Afrezza improved their A1C by at least 0.5%, 21% of those taking Afrezza saw their A1C worsen by at least 0.5%. 

Similarly, 25% of participants taking Afrezza improved their time in range by 10% or more, but 31% of participants on Afrezza saw a decrease in time in range of 10% or more. 

These findings underscore that Afrezza works really well for some people, and not so well for others. 

“This is where it really gets interesting,” Levy said. “All of us [who] provide care to people with diabetes [know that] the treatment regimen that works for one person might not work for another.” 

Among participants with a starting A1C above 7%, about one in five of those taking Afrezza achieved an A1C less than 7%. Dr. Irl Hirsch, professor at the University of Washington School of Medicine, pointed out that nobody in the usual care group achieved an A1C below 7%. 

Safety wise, there was a low amount of CGM-measured hypoglycemia (low blood sugar)  in both groups, regardless of AID or MDI use. 

Adverse events were generally lung-related, with 23% of participants in the Afrezza group reporting a cough. Coughs tended to occur right around the time of inhalation and usually resolved with a sip of water, Levy said. 

Dose conversion is important

In a standardized meal challenge in INHALE-3, Afrezza was more effective at lowering post-meal glucose spikes compared to rapid-acting insulin analogs. To be successful with Afrezza, however, it’s important to optimize the dose. 

“We can really mitigate the postprandial meal spikes once we learn how much insulin we need,” Hirsch said. 

Through the trial, experts came to realize that the dosing listed on the Afrezza packaging wasn’t quite right. 

The packaging states that one dose of Afrezza is equivalent to about the same amount of injected rapid-acting insulin. Dr. Thomas Blevins, an endocrinologist at Texas Diabetes & Endocrinology, noted that one dose of Afrezza is actually equivalent to about 2.5 to 3 times the dose of injected rapid-acting insulin. 

“A starting dose of two times [the injected insulin] still underdoses, while an optimized dose of 2.5 to 3 times the rapid acting insulin analog is safe and effective,” Hirsch explained.

As a result, you may need to inhale more than one cartridge to get the full dose, Blevins said. 

Consider dose timing

Because Afrezza acts so fast, it’s important to time doses appropriately. 

If you’re eating out at a restaurant, Hirsch advised waiting to take Afrezza until you know your food is arriving – as you would for any rapid-acting insulin. This advice also applies to other situations when you don’t know when your food will be ready, such as meals on airplanes. 

As with most rapid-acting insulins, you can adjust the dose of Afrezza at the time of your meal. For instance, if you end up eating more or less than expected, or if you need to correct elevated glucose. 

It’s also important to consider the timing of physical activity when taking Afrezza. While it may be difficult to exercise 30 to 60 minutes after taking inhaled insulin, Hirsch said Afrezza is less problematic than injected rapid acting insulin if you wait longer after dosing before you exercise. 

“This was a major reason why some of my patients wanted to stay on Afrezza – they could exercise easier without treating hypoglycemia,” he said. 

Know when to take a correction dose

Correction doses are a key part of diabetes management with inhaled insulin. 

Many meals may require post-meal correction doses, Blevins noted, and these doses in between meals are very effective. You may need to dose one to three hours after eating, especially if the meal is high in protein or fat. 

Hirsch said that some people find it useful to set an alarm for 140 or 160 mg/dL on their CGM so they know when to take another dose.

Taking a correction dose before going to sleep is extremely important to avoid high blood sugar at night.  

“We need to emphasize the importance of taking post-bolus correction doses – called a ‘booster’ – and especially the bedtime correction dose,” said Dr. Grazia Aleppo, professor of medicine at Northwestern University Feinberg School of Medicine. 

Managing hypoglycemia 

Afrezza’s nature as a ultra-rapid acting insulin can bring challenges for low blood sugar management. 

Because Afrezza is “rapid on, rapid off,” Hirsch said it’s important to avoid over-treating hypoglycemia. If you experience low blood sugar while taking Afrezza, it’s likely you may not need the full 15 grams of carbohydrates recommended to treat hypoglycemia, he noted. 

Similarly, it’s important not to overreact to falling glucose when correcting high blood sugar levels with Afrezza, Hirsch said. 

“When correcting high blood glucose and you see two down arrows, people freak out,” he noted. In reality, he explained, “Afrezza stops working so fast that the glucose becomes flat relatively quickly.” 

Affording Afrezza

While some raised questions about the cost of Afrezza, Hirsch was quick to respond that most people are able to access the inhaled insulin without paying thousands of dollars each month. Indeed, according to the Afrezza website, most people do not pay the list price for Afrezza (about $500 to $1,500 per month).  

Thanks to the Inflation Reduction Act, people on Medicare can access Afrezza for a copay of no more than $35 per month, if Afrezza is covered by their health plan. Note that this does require a prior authorization or appeal – extra steps to get approval from your health insurance to pay for the medication. 

The Afrezza Savings Card allows eligible people with commercial insurance to pay as little as $35 per month for their supply of inhaled insulin. 

Finally, if your insurance doesn’t cover Afrezza, you may be eligible for a direct purchase program that provides Afrezza for as little as $99 per month. Learn more about accessing Afrezza here. 

The bottom line

Experts emphasized that Afrezza can be a compelling option, though it is not a one size fits all answer for everyone with diabetes. 

“Afrezza is not for everyone,” Hirsch said, “but for some, it is an important option.” He pointed to people who are engaged in their diabetes self-management and want to further reduce hyperglycemia as good candidates for inhaled insulin. 

Afrezza could also be helpful for people who want an alternative to an insulin pump or those who want a discreet, needle-less option. Pump users with frequent infusion set failures or people with skin challenges like severe lipohypertrophy or atrophy may also benefit.

Of course, there is also the simple fact that Afrezza can be taken right at mealtimes, instead of in advance of eating. 

“Do you know how hard it is to wait 15 or 20 minutes before you eat?” Levy said. “It’s not easy.” 

Afrezza is only approved for adults with diabetes, though researchers are looking to change that. The INHALE-1 study is investigating Afrezza in children with type 1 or type 2 diabetes ages 4 to 18 and is likely to complete soon. 

In the future, experts hope to see trials investigating the use of Afrezza with GLP-1 receptor agonists, with AID, and in gestational diabetes. 

Learn more about new insulins: 

• Once-Weekly Insulins For Type 1 Diabetes: Latest Research Update
• FDA Propels Insulin Affordability with Semglee
• Civica to Make California's own Insulin Brand

Image credit: MannKind