Inhaled Insulin Afrezza – The Fastest acting FDA-Approved Insulin

Inhaled Insulin Afrezza

Afrezza is an inhaled insulin. It is a rapid-acting insulin that is used as bolus insulin before meals or with meals. It is administered via oral inhalation at the beginning of each meal.

It is the fastest-acting insulin. The onset of action of Inhaled Insulin Afrezza is shorter than the rapid and ultra-rapid acting insulins including FiAsp and Insulin Lyumjev.

Inhaled Insulin Afrezza has an onset of action of about 12 minutes. Compared to the injectable ultra-rapid-acting insulin, FiAsp (faster-acting Aspart), and Insulin Lyumjev, the onset of action of Inhaled Insulin Afrezza is three to five minutes more rapid.

The onset of action of Inhaled Insulin Afrezza is 15 to 20 minutes more rapid than the rapid-acting insulins (Insulin Lispro, Aspart, and Glulisine).

inhaled insulin afrezza compared with rapid acting and ultra rapid acting insulin
Inhaled Insulin Afrezza compared with rapid-acting and ultra-rapid-acting insulin

Inhaled Insulin Afrezza vs Injectable Rapid-acting and Ultra-rapid-acting Insulin:

Inhaled Insulin Afrezza is the fastest-acting insulin and has the shortest duration of action. It is best for people who are prone to develop hypoglycemia such as patients with kidney impairment and liver disease.

Its onset of action is even more rapid than the ultra-rapid acting insulins i.e. Insulin FiAsp and Insulin Lyumjev. The duration of action of Inhaled Insulin Afrezza is about three hours i.e. one to two hours less than the ultra-rapid-acting and the rapid-acting insulins.

comparing rapid acting insulin and ultra-rapid acting insulin with inhaled insulin afrezza
Comparing rapid-acting insulin and ultra-rapid-acting insulin with Inhaled Insulin Afrezza.

It takes a minute for the Inhaled Insulin Afrezza to enter the bloodstream after it is absorbed from the alveolar epithelium. The rapid-acting insulins are present in the bloodstream for 1 to 3 minutes after they are administered subcutaneously.

The efficacy of insulin Afrezza is dependent on the dose administered. It is also important to note that Inhaled insulin does not totally diminish the use of injections.

It has to be administered with basal insulin such as Insulin Glargine (Lantus), Insulin Detemir (Levemir), or Insulin Degludec (Tresiba).

How effective is Inhaled Insulin Afrezza?

Inhaled Insulin Afrezza was studied in both type 1 diabetes patients as well as type 2 diabetes patients.

  • Inhaled Insulin Afrezza in T1DM patients:

It was compared with Insulin Aspart in a 24 weeks trial in patients with T1DM. Patients were divided into two groups.

One group of patients received insulin Aspart and a basal while the other group of patients received Inhaled Insulin Afrezza and basal insulin.

More patients in the Aspart + basal insulin group achieved the target glycated hemoglobin after 24 weeks than in the Afrezza + basal insulin.

The results were statistically significant. Afrezza + basal insulin, though, achieved the non-inferiority difference of 0.4%. [Ref]

  • Inhaled Insulin Afrezza in T2DM patients:

In patients with T2DM, Inhaled Insulin Afrezza was compared with a Placebo medicine. All patients who had uncontrolled diabetes despite oral antidiabetic treatment were divided into two groups.

One group of patients received a placebo inhalational medicine plus oral antidiabetic treatment. The other group received Inhaled Insulin Afrezza plus oral antidiabetic treatment.

At week 24, a greater percentage of patients achieved the target glycated hemoglobin.

There was a 0.4% statistically significant difference in the reduction of glycated hemoglobin in the Afrezza + Oral antidiabetic medicines compared to Placebo + Oral antidiabetic medicines. [Ref]

How safe is Inhaled Insulin Afrezza?

Inhaled Insulin Afrezza is considered as safe as other insulin formulations. However, lung-related adverse drug reactions are more common in patients who are using inhaled insulin.

  • Hypoglycemia:

The most common adverse event that occurred in patients using Inhaled Insulin Afrezza, as expected, was hypoglycemia.

Hypoglycemia including severe hypoglycemia requiring urgent intervention was 5 times more frequent in patients using inhaled insulin.

This is illustrated in the bar charts below:

incidence of hypoglycemia in patients using Inhaled Insulin Afrezza
Incidence of hypoglycemia in patients using Inhaled Insulin Afrezza compared to placebo.
  • Cough and decline in pulmonary function tests:

Cough was the most common side effect in clinical trials. In fact, the most common reason for discontinuation of inhaled Insulin Afrezza was persistent intolerant cough (2.8%).

It was almost five times more common in patients taking another comparator medicine (27% in the Afrezza group vs 5.2% in the active comparator group).

A decline in pulmonary function of 15% or more occurred in 6% of the patients treated with Inhaled Insulin compared to 3% of the comparator-treated group.

In clinical trials, there was a 40 ml decline in the FEV1 that was seen three months after treatment initiation and persisted after 2 years [Ref].

  • Weight gain:

Weight gain is common with all insulins because of their anabolic effects. Weight gain of 0.49 kgs occurred in patients treated with inhaled insulin Afrezza compared to a weight loss of 1.13 kgs in the placebo group.

  • Antibody production:

Anti-insulin antibody formation was observed during clinical trials. Compared to other insulin analogs, more patients in the Afrezza group had anti-insulin antibody formation. However, this does not have a significant effect on the efficacy or safety of insulin.

How to use Afrezza Inhaled Insulin?

Afrezza Inhaled Insulin is administered via oral inhalation. Two types of Cartridges are used. They can be identified by color coding. Blue Colored Cartridge delivers 4 units of insulin while the green-colored cartridge delivers 8 units.

One wrapped packaged foil contains two cards. Each card contains 5 blisters (a total of ten blisters). Each blister cavity contains three cartridges. So a total of 30 cartridges are provided in a single packing.

The Inhaler device is separately packed that can be used for 15 days. The Cartridge is fitted into the inhaler device. The mouthpiece is kept upright. Once the cartridge has been placed, it is important not to shake or tilt the inhaler upside down.

The patient should keep the mouthpiece of the inhaler in the mouth, tilt the head backward, and release the inhaler.

Simultaneously, the patient should breathe in deeply until the cartridge is emptied and then take breaths normally. The cartridge should then be discarded.

Afrezza Inhaled Insulin Advantages and Disadvantages:

Switching from one type of Diabetes medicine to another or switching from one modality of treatment to another is considered by the patient only if there are significant advantages.

Similarly, a patient who opts for inhaled insulin expects to experience some of the benefits of this insulin or at least to avoid the bad experiences with the previous treatment.

Pros of Inhaled Insulin Afrezza

Cons of Inhaled Insulin Afrezza

Patients avoid needlesMay not cover a full meal because of the short duration of action
No waiting time to start a meal because of the rapid onset of actionAdditional long-acting injectable insulin is required
Fewer chances of hypoglycemiaGlycemic fluctuations are possible
More effectively and rapidly lower blood sugarsAwkward to use it in public
Easy to useAssociated with lung diseases
Cheaper than an insulin infusion pumpCostlier than insulin pen devices and syringes

The benefits (Advantages) of inhaled insulin Afrezza include:

  • The patient avoids needles:

    • This is one of the main reasons patients might opt for Inhaled Insulin. However, since Insulin Afrezza has a very short duration of action, patients still need at least one injection of basal insulin (Insulin Degludec, Levemir, or Insulin Glargine).
  • It has a rapid onset of action, so no waiting time:

    • Most mealtime bolus insulins need to be administered at least five to twenty minutes before a meal. The ultra-rapid-acting insulin, Insulin Lyumjev, and Insulin FiAsp can be administered with meals. Likewise, patients need not wait before the meal when using Inhaled Insulin Afrezza.
  • It has a shorter duration of action, so there are fewer chances of hypoglycemia:

    • The shorter the duration of action, the lesser the chances of hypoglycemia. Since inhaled insulin is used only to lower prandial hyperglycemia, it does not lower blood glucose levels after three to five hours.
    • This effect is especially required in patients who have kidney disease where the half-life of insulin is prolonged and the risk of hypoglycemia is increased.
  • It can lower very high blood sugars faster than most rapid-acting insulins:

    • In cases where the blood sugars are very high, it takes time to lower them with conventional insulin.
    • This causes anxiety. Inhaled insulin rapidly lowers blood glucose. because of its rapid onset of action and shorter duration.
  • It is comparatively easy to use:

    • Inhaler techniques, especially with the newer formulations of Afrezza are not cumbersome compared to an insulin infusion pump.
    • Although some people are more comfortable with using insulin injection pens, inhaler use is not difficult either.
  • It is cheaper than an Insulin Infusion pump:

    • Cost is a major issue in deciding the type of insulin a patient opts for. Compared to insulin infusion pumps, it is much cheaper and easy to use.

However, the fear of hazards associated with this insulin is one of the factors that has limited its use in diabetic patients.

The disadvantages of Inhaled Insulin Afrezza include:

  • Patients have to use long-acting insulin with it:

    • Although Inhaled insulin reduces the number of daily injections, it does not totally avoid it. Patients using inhaled insulin have to use basal insulin with it.
  • Because of its shorter duration of action, it might not cover a full meal in certain situations:

    • Inhaled insulin has a very short duration of action. This is considered a plus point, however, in patients with gastroparesis or after a fatty meal, this could result in hyperglycemia.
    • These patients (patients who ingest a fatty meal and those with gastroparesis where the stomach empties its contents very slowly) have a post meals hyperglycemia when using inhaled insulin Afrezza.
    • This is because the meal is so slowly absorbed that the insulin Afrezza duration of action times out. There is no more insulin in the systemic circulation to cover the meal that has been absorbed after three to five hours.
  • Patients need to adapt to the highs and lows during the initial periods:

    • Although, unlike injectable insulin, Inhaled insulin does not need to be precisely administered.
    • There is still a chance that the patient might observe marked variations in the plasma glucose after treatment initiation.
    • Furthermore, the absorption of inhaled insulin is dependent on the alveolar surface and blood flow to the lungs.
    • In patients with pneumonia, heart failure, or other lung-related conditions, the absorption of inhaled insulin is severely affected. Such patients may be put back on injectable insulin.
  • It may be awkward to use in public places:

    • The stigma of being diabetic is one factor, the use of inhaler devices adds to the stigma. Most people don’t feel comfortable using an inhaler in public places.
  • It is associated with serious lung conditions:

    • Serious lung conditions have been associated with inhaled insulin. The risk of fibrosis, bronchospasm, cough, and lung cancers has been associated with it. This is probably the major factor that people avoid inhaling insulin.

Has Afrezza been discontinued?

Insulin Afrezza has never been discontinued. Initially, Pfizer marketed an inhaled insulin by the brand name of “Exubera” which was discontinued after a year because of low sales and the cumbersome inhaler device.

After repeated submission by Mannkind, the Inhaled Insulin Afrezza manufacturers, the FDA finally approved it for the treatment of post meals hyperglycemia.

Afrezza manufacturers have signed an agreement with Sanofi Aventis regarding its distribution. It is likely to be available soon in many countries.

Afrezza Side effects:

The most common side effects apart from hypoglycemia, reported in clinical trials were cough and pain/ irritation in the throat.

Hypoglycemia was the most common side effect, however, compared with the active comparator drugs, the incidence of hypoglycemia was reduced by 20 – 65%.

In addition, Insulin Afrezza has been issued a “Black Box Warning” regarding its use in pulmonary conditions such as Asthma and COPD.

The FDA had concerns regarding the development of lung cancers in patients using Afrezza. In clinical trials, two heavy smokers developed lung cancers.

The incidence was equivalent to that of the general population. However, the FDA added lung malignancies as a possible adverse event associated with inhaled insulins.

There is no evidence to prove or disprove whether Afrezz Insulin could result in the growth of patients already diagnosed with lung cancer.

Other less common side effects of inhaled insulin include chest pain or discomfort, nasal bleeding, pharyngitis, dry oral cavity, shortness of breath, and an increase in the production of sputum.

Afrezza Assist Program:

Afrezza assist program has been launched by manufacturers and distributors to help diabetic patients who are uninsured or can not afford it.

To enroll in the Afrezza assist program, one has to register via the Mannkind Afrezza site. The program is not totally free. A person opting for the Afrezza Assist program has to pay a minimum of USD 15 per prescription.

Afrezza Dosing:

Afrezza dosing depends on whether the patient is naive to insulin or has been using insulin previously. All patients who are using Afrezza must be using basal insulin (Insulin Glargine, Levemir, or insulin Degludec).

Insulin Naive patients should start Insulin Afrezza in a dose of 4 units before each meal. Patients can increase their insulin dose by an increment of 4 units if required.

Patients already on prandial or premixed insulin can switch from subcutaneous insulin as per the following guidelines [Ref]:

Units of Pre-mixed or Prandial Insulin

Units of Inhaled Insulin

4 units or less injected dose per meal:4 units of inhaled insulin per meal
5 to 8 units per meal:8 units of inhaled insulin per meal
9 to 12 units per meal:12 units of inhaled insulin per meal
13 to 16 units per meal:16 units of inhaled insulin per meal
17 to 20 units per meal:20 units of inhaled insulin per meal
21 to 24 units per meal:24 units of inhaled insulin per meal

Details about Afrezza Prescribing Information and package Insert can be viewed here in PDF: Afrezza Package Insert

dose adjustment and switching from and to inhaled insulin afrezza
Dose adjustment and switching from and to inhaled insulin Afrezza

Afrezza reviews:

Afrezza has been rated 6 to 10 stars by patients. A review poll will be generated. Users can rate their experience using the following polls:

Afrezza storage:

Afrezza can be stored in the refrigerator at a temperature of 2 to 8 C (36 to 46F) until the expiry date.

Opened foil packages can be stored at room temperature for three to ten days. If the blister card has been opened but sealed, it can be stored at room temperature for ten days.  If the strips have been opened, they must be used within three days.

The inhaler and cartridges must be kept for ten minutes at room temperature each time before use.

Afrezza Insulin Inhaler Price [Ref]:

Every 4 units cost USD 4.72.

Each 4 & 8 & 12 units cost USD 9.44

Every 8 units Cost USD 9.44

Every 12 units Cost USD 14.16

Each 90 x 4 units & 90×8 units Cost USD 7.08

Each 90 x 8 units & 90×12 units Cost USD 11.80

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Written by Dr. Ahmed

I am Dr. Ahmed (MBBS; FCPS Medicine), an Internist and a practicing physician. I am in the medical field for over fifteen years working in one of the busiest hospitals and writing medical posts for over 5 years.

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