PHARMACOLOGY UPDATE
Human Insulin Inhalation Powder (Afrezza®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A second inhalation rapid human insulin has been approved by the FDA. The first inhaled insulin (Exubera) was approved in 2006 and was withdrawn from the market by Pfizer due to low acceptance and poor sales after about 13 months on the market. The current approval is human insulin delivered as microparticles using the MannKind Corporation’s Technosphere technology and is marketed as Afrezza.
INDICATIONS
Inhaled insulin is indicated for use as a rapid-acting form to improve glycemic control in adult diabetic patients.1 In type 1 diabetics, it must be used with long-acting insulin. It is not recommended for use in patients who smoke.
DOSAGE
Inhaled insulin is administered at the beginning of a meal. For insulin-naïve patients, the initial dose is 4 units with meals. For those on insulin, the dose is individualized and is based on injected insulin dose. Inhaled insulin is available as single-use cartridges of 4 and 8 units.
POTENTIAL ADVANTAGES
Inhaled insulin is more rapidly absorbed and provides higher insulin levels than injected insulin with effects about 2 hours earlier.2,3 It more closely mimics normal postprandial endogenous insulin release. Due to its pharmacokinetics and pharmacodynamics, inhaled insulin provides improved early postprandial glycemic control. The inhaler fits in one’s palm and is much smaller and easier to use than the previous inhaled formulation (Exubera).
POTENTIAL DISADVANTAGES
Inhaled insulin may cause a decline in lung function.1 A decline in FEV1 of ≥ 15% occurred in 6% of those treated with inhaled insulin. This was noted within the first 3 months and continued for at least up to 2 years. It is contraindicated in patients with chronic lung disease. The drug comes with a boxed warning recommending spirometry in all patients prior to use. The package insert also recommends spirometry after 6 months of use and annually thereafter.1 Inhaled insulin is eliminated more rapidly than injected insulin and may have suboptimal late postprandial glycemic control.2 In the clinical trials, more patients experienced diabetic ketoacidosis with inhaled insulin than with injected insulin (0.43% vs 0.14%).1 Dose titration is less precise as inhaled insulin is available as 4-unit and 8-unit single-use cartridges.
COMMENTS
Insulin delivered in the proprietary Technosphere technology is rapidly absorbed from the lungs but is less bioavailable than injected insulin. Its efficacy and safety were evaluated in both type 1 and type 2 diabetic subjects in 24-week active-controlled studies.1 Type 1 diabetic subjects (n = 344) with a mean baseline HbA1c of approximately 7.93% were randomized to inhaled insulin or insulin aspart given at each meal. All subjects were on basal insulin. At week 24, change from baseline in HbA1c was -0.21% for inhaled insulin compared to -0.40% for insulin aspart (adjusted difference of 0.19; 95% CI; 0.02, 0.36). This met the preset non-inferiority margin of 0.4. Fewer subjects achieved HbA1c goal (7% or less) with inhaled insulin, 14% vs 27%. However, inhaled insulin produced lower fasting plasma glucose, -25 mg/dL vs 10 mg/dL from a baseline of 154 mg/dL and 152 mg/dL, respectively. In the study with type 2 diabetic patients, subjects with baseline HbA1c of about 8.26% and inadequately controlled on optimal or tolerable doses of metformin or two or more oral agents were randomized to inhaled insulin or placebo. Changes from baseline were -0.82% for inhaled insulin and -0.42% for placebo (adjusted difference of 0.4; 95% CI, -0.57, -0.23). Change from baseline fasting plasma glucose (175 mg/dL) was -11.2 mg/dL and -3.8 mg/dL, respectively. The most common adverse event was cough (25%).1 Other adverse events (throat pain/irritation, headache) were infrequent (3-4%). In a 52-week subgroup analysis in type 2 diabetics randomized to inhaled insulin and insulin glargine or twice daily mixture of 70% aspart protamine suspension and 30% insulin aspart, similar change in HbA1c were reported but with less weight gain and fewer mild-to-moderate and severe hypoglycemic episodes.4 Patient satisfaction and acceptance have been reported to be good.5 Postprandial glucose levels ([PPG] 2-hour postprandial) and PPG AUC (0-360 minutes) were similar. However, AUC (0-180) were lower with the inhaled insulin arm and AUC (180-360) were lower with injected insulin. The most common adverse event is cough (26%).1
CLINICAL IMPLICATIONS
Inhaled insulin appears to provide an effective delivery of postprandial insulin. Its long-term safety (particularly affecting the lungs) remains to be established. Acceptance on the patient and physician level is hard to predict. Although the inhalation system is easier to use than the previously marketed inhaled insulin (Exubera), it still does not obviate the need for long-acting insulin in type 1 patients. The need to monitor pulmonary function may also discourage use. Cost information is not yet available.
REFERENCES
- Afrezza Prescribing Information. Danbury, CT: MannKind Corporation; June 2014.
- Boss AH, et al. Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin. J Diabetes Sci Technol 2012;6:773-779.
- Rave K, et al. Pharmacokinetics and linear exposure of AFRESA compared with the subcutaneous injection of regular human insulin. Diabetes Obes Metab 2009;11:715-720.
- Rosenstock J, et al. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: A multicentre randomised trial. Lancet 2010;375:2244-2253.
- Neumiller JJ, et al. A review of inhaled technosphere insulin. Ann Pharmacother 2010;44:1231-1239.
