Is Inhaled Insulin a 'Game Changer'?
Matthew L. Mintz, MDDisclosures
July 23, 2014
A new formulation of insulin that is delivered via inhaler promises the elimination of needles for patients with diabetes. So why hasn't there been more fanfare over the anticipated arrival of Afrezza® (MannKind; Valencia, California)?
Many clinicians are skeptical about the inhaled insulin product, despite its approval last month by the US Food and Drug Administration (FDA). They may remember an earlier version of inhaled insulin called Exubera, which was produced by Pfizer back in 2006. Manufacturing of that drug was discontinued 1 year later -- not because it was ineffective or for safety concerns, but simply because too few clinicians were prescribing it.
Will this new inhaled insulin product fare any differently? Several arguments can be made for why Afrezza could be a true game changer in diabetes management, whereas other reasons suggest that it may not.
Pros
1. Insulin without injections is still something that patients want.
Despite the failure of Exubera, patients really like the concept of inhaled insulin. Although pens have made insulin injections significantly easier, they are still inconvenient, can be expensive, and, of course, can be painful. In fact, a fear of needles can be a major barrier to initiating insulin in some patients who need it. In addition, some patients have a negative perception of self-injections, associating it with the idea that "I must be really sick." Given that inhalers are used for common conditions, such as asthma or other chronic pulmonary diseases, inhaled insulin may be substantially preferable to injectable insulin. This could ease the process of initiating insulin and could improve patient adherence.
2. The new device is substantially better than the previous one.
One of the main problems with Exubera was that the device was enormous and difficult to use. MannKind's original device for Afrezza looked similar to an asthma peak flow meter, and it was a substantial improvement. However, mid-way through the development process, the company created an even smaller device that some have described as looking like a whistle. This design change delayed the approval process (because the FDA wanted to see data on the new device), but the final design is compact and reportedly simple to use.
3. The dosing issue has been resolved.
Both clinicians and patients struggled with the dosing of Exubera. Because inhaled insulin comes in a powder, the FDA requires dosing by weight, not by unit. This was incredibly confusing, because other forms of insulin are dosed in units. In addition, Exubera was available in 1-mg and 3-mg cartridges, yet the contents of 3 of the 1-mg cartridges did not exactly equal the contents of the 3-mg cartridge. With Afrezza, the dosing is in units, with a 4-unit cartridge and an 8-unit cartridge, and the conversion is essentially unit to unit. The Afrezza package insert contains a fairly simple dosing chart that suggests comparable dosing for patients who are converting from mealtime insulin injections to the inhaled product.
4. The barrier of lung function testing may be slightly diminished.
The Exubera prescribing information carried a significant warning about lung function, and prescribers were advised to get baseline spirometry levels before initiating the drug. But many clinicians do not have spirometers in their offices, which created a substantial barrier to prescribing Exubera. However, long-term studies of Exubera showed that lung function diminished only slightly after the first few months and remained stable after 2 years of use. Lung function returned to baseline when Exubera was discontinued, and the declines were deemed clinically insignificant. Similar results were seen with Afrezza. Although clinicians are still advised to perform baseline spirometry for Afrezza, which also carries a boxed warning, the context of the warning is for acute bronchospasm in patients with lung disease. This is quite different from a warning about an unknown lung function effect for all.
The Exubera label stated, "Because of the effect of EXUBERA on pulmonary function, all patients should have pulmonary function assessed prior to initiating therapy with EXUBERA." Contrast that with the warning for Afrezza: "Acute bronchospasm has been observed in patients with asthma and COPD using AFREZZA. AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD. Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients."
In other words, baseline spirometry is still recommended before initiating Afrezza (as well as follow-up at 6 months and yearly thereafter). However, because the likelihood is fairly low that asymptomatic nonsmokers have lung disease, clinicians may view this advisory more liberally if spirometry is not readily available in their office.
5. Weight gain and hypoglycemia risks are lower with Afrezza than with other insulin formulations.
Type 2 diabetes is essentially a combination of glucose overproduction, insulin resistance, and beta-cell dysfunction with diminished insulin production. All therapies for diabetes work on one or more of these mechanisms. The problem with exogenous insulin and agents that increase insulin production (primarily sulfonylureas) is that they also lead to weight gain and bouts of hypoglycemia. The latter is particularly concerning, because severe hypoglycemia can lead to hospitalization and even death. Although Afrezza is associated with some weight gain and hypoglycemia risk, these risks are substantially lower than those associated with sulfonylureas and injectable insulin. In a study comparing Afrezza with insulin aspart, patients receiving Afrezza had almost one half the number of severe hypoglycemia episodes, and they actually lost weight compared with the insulin aspart recipients, who gained weight.
Cons
Despite the positives of this new inhaled insulin product, there are still 2 main reasons why Afrezza might not overcome the resistance among clinicians and patients that Exubera encountered.
1. Cost
Afrezza will probably be expensive, and insurance companies are restricting coverage of such new agents more than ever. Even if the manufacturer provides coupons to reduce patients' out-of-pocket costs, insurance companies may require proof that patients' disease cannot be controlled on injectable insulin.
2. Inertia
Many endocrinologists believe that injectable insulin works quite well, so it may be difficult to convince them to prescribe the inhaled product. And primary care physicians may be reluctant to try something new, especially when they are already pressed for time when seeing complex diabetic patients in a 15-minute visit.
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