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Afrezza: Treating Diabetes in a Physiologic Manner

R. Keith Campbell, RPh, FAADE, FASHP, FAPhA, CDE,
Distinguished Professor Emeritus in Diabetes Care/Pharmacotherapy,
Washington State University College of Pharmacy

The health care crisis created by the explosion of diabetes worldwide is one of society’s greatest challenges.

The IDF projects that the prevalence of diabetes by 2030 will be over 550 million patients worldwide. When one adds in the patients with “Prediabetes,”who presently are not often treated, the impact on health care becomes frightening. Diabetes is a family of diseases that have in common hyperglycemia. Glucose, the main fuel of the body is needed by all cells all of the time. Glucose is supplied to the entire body during meals from ingested food and between meals from glucagon stored in the liver. Insulin is supplied from the beta cells in the pancreas to utilize the glucose for the cells as the glucose levels become elevated. In a healthy person it is provided in two waves, the phase 1 at the first ingestion of carbohydrates and phase 2 to manage the extended glucose level from the meal. In type 1 diabetes the immune system destroys the beta cells and insulin is no longer secreted. In type 2 diabetes, the first phase release is blunted and the patient becomes resistant to the effect of the insulin. Also in type 2 patients, more glucose is released by the liver, incretin (gut) hormones are diminished, the kidney reabsorbs more glucose and glucose levels spike in response to the meal. Excess glucose via several changes in normal physiology create diabetes complications including retinopathy (eye), neuropathy (nerve), nephropathy (kidney) and blood coagulation disorders. Excess glucose combined with hypertension and lipid disorders result in the enhancement of heart disease and a financial burden on health care systems.

When a person without diabetes consumes food, the first phase spike of insulin reaches an early peak in the blood in about 10 minutes. That first phase starts the glucose metabolism process. The second phase release of insulin responds to the quantity and timing of the food. Non-diabetics also have a basal release of insulin that occurs continually to support fueling the body between meals. In type 1 diabetes patients, both the first and second phases of insulin release and also the basal release do not occur. In type 2 patients who make up well over 90% of patients diagnosed with diabetes, the first abnormal physiologic problem occurs is the lack of the first phase of insulin release. In diabetes patients exogenous insulin is needed to replace the insulin release that would be provided in a non-diabetic person. Diabetes results when insulin is either not released (type 1) or is not normally released and the person is resistant to the effect of the insulin (type 2). The average healthy adult person releases about 1 unit of insulin each hour as basal insulin and approximately 1 unit of insulin is released for each 10 to 15 grams of carbohydrate consumed.

Treating Diabetes

When a state of insufficient pancreatic insulin occurs, exogenous injected insulin products are available to replace the deficiency. THE PROBLEM is that current available products are not adequate, they are far from being able to replace the deficiency in a natural physiologic manner. The pharmacokinetic/dynamic profile of prandial (mealtime) insulins are much too slow, their activity does not become effective quickly enough and they persist far longer than is needed to control mealtime glucose. The current rapid acting insulin analogs (RAAs), which are the best of the current prandial products, do not reach a peak in the blood for close to an hour and persist for as long as 5-7 hours. To reasonably control the increase of glucose from the meal, the dose of such an insulin should be inconveniently injected about 15 or even 30 minutes before starting to eat. Of even greater concern, the slow activity produces a late excessive postprandial hyperinsulinemia which is the primary cause of dangerous hypoglycemia in today’s insulin therapy. That late persistence is one of the most significant problems with insulin therapy that clinicians and patients face today.


MannKind Corporation recognized the problems with current mealtime insulins and has developed a technology for drug stabilization. That technology was able to stabilize insulin monomers and the development was successful, creating a powder formulation called Technosphere Insulin that could effectively and efficiently be administered by oral inhalation that ELIMINATED subcutaneous prandial injections. This very rapid-acting insulin called Afrezza enters the blood very quickly, peaking in about 12-15 minutes and is eliminated from the body in a couple of hours. This pharmacokinetic/dynamic profile mimics what happens with insulin released in a person without diabetes and the result is significantly less hypoglycemia. It is even difficult to envision how there could be any hypoglycemia generated from properly timed Afrezza dosing. Much of the reduced level of hypoglycemia during the clinical trials was probably caused by the basal insulin or sulfonylureas (in type 2). The Figure below shows the comparison between Afrezza and Bi-phasic Endogenous Insulin:


Although the dynamic response of Afrezza in the blood compares incredibly well to the total insulin response of a healthy person to an average short term meal, that is very different from the response of current prandial insulin products. The dynamic effects of the very-rapid-acting insulin and of the current prandial insulins are shown in the following Figure:


Current prandial insulins start far too slowly and last far too long. In my opinion, when one evaluates the pathophysiology of both type 1 and type 2 diabetes the pharmacokinetic/dynamic profile of Afrezza, an insulin that has now been approved by the FDA, it is seen that it creates an ideal profile to prevent the spikes in blood glucose levels after meals for both type 1 and type 2 patients. In type 2 patients, the first insulin problem is the loss of the first phase insulin release, so inhaling Afrezza should be a great treatment to overcome that physiologic defect in early type 2. For those with more advanced type 2, taking a basal insulin like Lantus or Levemir, adding Afrezza would greatly improve after meal elevations. For type 1 patients, a once daily shot of a basal insulin with inhalation of Afrezza for meals would much more likely simulate the normal physiologic release of insulin. Insulin pump patients could use Afrezza with each meal and take 1 shot of a basal insulin and greatly reduce the cost of treatment plus supplies. Afrezza does not cause a SHARPS problem and that is another major advantage. It could also be used for the many diabetes patients who have gastroparesis and those of us who have taken insulin over many years and have developed much scarring and thus unpredictable absorption of insulin. Also, Afrezza could be used by patients for correction doses when blood glucose levels are elevated. It is an especially good insulin for the many patients worldwide who detest insulin injections. When one considers the explosion of diabetes in China, India, Japan, Pakistan and the Arab nations, the demand for Afrezza could certainly be substantial.

Afrezza was approved by the FDA in late June of 2014 for use in both type 1 and type 2 diabetes patients as a prandial insulin. It has not yet been approved for use in children and it is a Category C product for use during pregnancy. It is contraindicated in patients who have asthma, Chronic Obstructive Pulmonary Disorder, Lung cancer or are smokers. The design of the inhaler device is simply great. It is the size of a small whistle and is called the Dreamboat. It is very easy to teach to health care providers and patients (in less than 2 minutes) unlike the previously approved inhalation insulin that took much unreimbursed time (30 minutes) to teach to patients or clinicians. Some people worry that Afrezza might be like Exubera and sales will be small. That is total baloney because it is like comparing Edison’s first light bulb to a laser.

Afrezza cartridges should be refrigerated until use and the cartridges and Dreamboat (see picture) should be kept at room temperature for 10 minutes before use. The cartridges will initially be available in 4 unit and 8 unit strengths; higher doses are planned. It is recommended that patients have a pulmonary function test done before beginning treatment with Afrezza. Although the risk of hypoglycemia is low, anyone taking insulin should be cautioned and be instructed as to how to treat hypoglycemia. Afrezza does cause a dry cough initially in about 20+ % of patients starting it but in most patients the cough goes away in a few weeks. Patients who had been in clinical trials with Afrezza have loved it and many of the people who testified before the FDA were patients who had used it in the clinical trials.

Afrezza is a major addition to the tool chest of meds and especially of insulins available to treat a wide spectrum of diabetes patients. Afrezza provides a much more physiologic prandial insulin. Now there must be an effort to create a better basal insulin so that together diabetics would have a much more physiologic replacement for today’s exogenous insulin products.


R. Keith Campbell, RPh, FASHP, FAPhA, FAADE, CDE, MBA, is Distinguished Professor Emeritus in Diabetes Care/Pharmacotherapy, Washington State University College of Pharmacy. He is also on the Diabetes In Control Advisory Board.