https://www.ajmc.com/journals/evidence-based-diabetes-management/2016/september-2016/afrezza-treating-diabetes-in-a-physiologic-manner
Afrezza: Treating Diabetes in a Physiologic Manner

R. Keith Campbell, MBA, BPharm, CDE

In the many years that I have had type 1 diabetes (T1D), I have been treated with insulin using syringes and needles, as well as insulin pumps. Until recently, none of the available subcutaneous (SC) insulins came even close to being absorbed, metabolized, and excreted like physiologic insulin. Regular insulin took a long time to work and remained in the body for many hours; analog insulins were an improvement, but still took too long to work and displayed similar delayed metabolism. In addition, all of the forms of insulin needed to be injected, and all resulted in weight gain and many episodes of low blood glucose levels (hypoglycemia). I started on 22-gauge, 1-inch long needles that I inserted only halfway.

Today, an inhalable, very rapid-acting insulin—Afrezza, from MannKind—has been developed, is available to patients, is cost-effective, and has a physiologic profile close to the insulin that our body secretes when consuming food.1

Afrezza is the most rapidly absorbed rapid-acting insulin on the market. The insulin concentration from Afrezza peaks at Tmax in approximately 12 to 15 minutes and returns to near baseline in about 3 hours (FIGURE 1a).2,3 In contrast, the concentration of SC rapid-acting insulin analog (SC RAA) peaks at Tmax in about 45 to 60 minutes and can remain elevated for more than 5 hours. The difference in pharmacokinetics (PK) translates into a difference in pharmacodynamics (PD): Afrezza’s glucose-lowering effect begins sooner and has a shorter duration than SC RAA.3 In the Affinity 1 trial, Afrezza demonstrated clinical noninferiority to SC RAA with significantly lower incidence of hypoglycemia,4 a clinically significant benefit for patients. Because Afrezza does its work early and then “gets out of the way,” the risk of late hypoglycemia (2 to 5 hours after the start of a meal) was markedly reduced, while postmeal glucose excursions were diminished.

Patients who are motivated to manage their blood glucose levels through frequent monitoring—and who understand the effect of different doses of Afrezza—do extremely well when using it. Once a patient understands his or her individual dose response (eg, “a 4-unit cartridge reduces my glucose by 30 mg/dL in 90 minutes”), frequent blood glucose monitoring or continuous glucose monitoring provides data that can be acted upon quickly with little risk of “insulin stacking.” Several patients on pump therapy, who achieved glycated hemoglobin (A1C) of 7.5% to 8%, gave up the pump, switched to basal insulin injections and prandial (mealtime) Afrezza, and reached their A1C goal for the first time in years. The payoff for these patients is so great, both in terms of treatment success and the freedom from having to think about diabetes all the time, that they have become the biggest champions of Afrezza.

Afrezza delivers insulin in a manner that makes it an ideal choice for treating type 2 diabetes (T2D). The loss of early first phase insulin release, a hallmark of T2D,5 leads to inadequate suppression of endogenous glucose production (EGP) and early postprandial hyperglycemia.6,7 For patients early in the progression of T2D, when A1C is less than 7.3%, postprandial glucose excursions are the major component of overall hyperglycemia.Not only can Afrezza, with its rapid absorption, complement the patient’s late-phase insulin release, but it also has been shown to suppress EGP earlier than SC lispro.9 Thus, there might be a therapeutic advantage to using Afrezza as the initial treatment early in T2D, particularly for patients whose insulin timing is faulty (ie, patients who have diminished early insulin response but retain some beta cell function).

As with all insulins, dosing adjustments must be individualized. Afrezza’s extremely rapid absorption and short duration of action are different from SC RAA, so it is not surprising that a simple unit-for-unit switch is not the most effective dosing strategy. Rapidly absorbed insulin (an intravenous bolus) actually lowers glucose less than the slowly absorbed SC lispro.10 The same phenomenon at work with Afrezza, which exhibits a more rapid onset and shorter duration than SC RAA (FIGURE 1).3 The implication for dosing is that the starting dose of Afrezza may be too low and could require up-titration to achieve glucose control. The need to increase the dose was reported in MannKind’s Affinity 1 trialwhere the average Afrezza dose was increased from 30 units/day to approximately 43 units/day over a 12-week titration period. Subsequent simulation work11 suggests an additional increase of 30% would have provided better glucose control with no significant increase in the risk of hypoglycemia. The need for higher doses of Afrezza versus SC RAA is a natural consequence of the difference in PK/PD profiles.

The use of Afrezza has lagged despite its advantageous PK/PD properties, at least in part due to barriers, both real and perceived. 

Afrezza Is Impressively Effective

Afrezza is human insulin, and insulin is known to lower blood glucose levels when used appropriately. Like all insulins, Afrezza requires individualization and adequate dosing. A consequence of its PK/PD profile is that the dose of Afrezza required to control glucose will probably be numerically higher than SC RAA. If the healthcare provider and patient do not titrate the dose to an adequate blood glucose control, they might believe it does not work.

Lung Issue Perspective

The delivery of Afrezza via the lungs has raised concerns about administration of medications via this route. Years of study and delivery of medications into the lungs has generally shown positive risk benefit. However, in clinical trials with Afrezza, although there were no cases of lung cancer reported in the comparator group, the Afrezza group had 4 (2 cases while on study and 2 cases reported spontaneously 2 years after the end of the trial). The observed incidence was 0.73 cases per 1000 patient-years compared with an expected rate of 1 or 2 cases per 1000 patient-years in patients with diabetes (among smokers plus nonsmokers). These numbers are insufficient to draw conclusions about an association between Afrezza and cancer. A 5-year randomized controlled safety study is planned as part of postmarketing requirements.

Spirometry. There is a risk of bronchospasm when any dry powder is inhaled by persons with hyper-reactive airways. Spirometry is required by the FDA to screen out patients with underlying lung disease prior to starting treatment in order to avoid the risk of bronchospasm. Follow-up testing (at 6 months and annually thereafter) is to confirm the absence of obstructive lung disease. A pulmonary substudy is included as part of the 5-year safety study.1

Cough. After hypoglycemia, cough was the most common adverse event in phase 3 studies of Afrezza. The cough was generally mild and dry, occurred within 10 minutes of inhalation, was transient, and declined with continued use. In phase 2 and 3 studies, 27% of patients treated with Afrezza reported cough; 2.8% discontinued treatment due to cough.2

Accessibility and Cost

Afrezza is an FDA-approved medication and is being marketed by MannKind Corporation through its salesforce. Available throughout the country, and generally covered by national payers for commercially insured lives, Afrezza has a unique cost-benefit profile because of its PK/PD profile and resultant less severe hypoglycemia. It enables patients to have real-time flexibility to correct their elevated sugars and does not require an insulin pump. Patients on Afrezza have the potential of saving themselves from multiple co-pays for their needles and other accessories associated with insulin pumps and pens. In addition, patients do not have to manage sharps hazards and disposal for their mealtime insulin. The price of injectable insulin has been increasing, at a compounded annual rate of more than 20%, for the last several years to an average price point of about $19 per day, while alternatives, such as Afrezza with a fixed price per cartridge, may range from $9 to $18 per day.13 A prior authorization is often required to help patients get started, but unfortunately, this is likely causing many patients to forego the benefit of this novel treatment option if their doctors don’t go the extra step to get it approved.

The majority of patients with diabetes are not at their ideal treatment goals, which creates opportunity for health plans, doctors, and patients to manage the postprandial impact insulin can have. Although there are some unknowns to the long-term use of Afrezza, the known risks and complications that patients with diabetes face with elevated sugars are well established. Afrezza has been studied up to 4 years in clinical trials in over 8000 patients, and the future trials that are planned will continue to articulate the PK/PD profile to demonstrate real-time disease control.
 
The PD effect of SC therapy is much like a super tanker: once launched, it can change course only very slowly. Patients have no choice but to adapt their schedules to meet the demands of insulin. Afrezza is more like a speedboat: its shorter duration of action permits navigation between the risks of hyperglycemia and the consequences of hypoglycemia. 
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