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Evidence-Based Diabetes Management September 2016

Afrezza: Treating Diabetes in a Physiologic Manner

R. Keith Campbell, MBA, BPharm, CDE
Professor R. Keith Campbell, MBA, BPharm, CDE, now retired from Washington State University College of Pharmacy, highlights the clinical advantages of Afrezza based on the evidence as well as his personal perspective.
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. 

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