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Introduction
Afrezza®, a dry-powder formulation of recombinant human regular insulin, was recently approved by the US Food and Drug Administration.[1] Afrezza is indicated for use in adults ≥ 18 years of age with type 1 or type 2 diabetes mellitus (T1DM or T2DM); however, in those with T1DM, Afrezza must be used in combination with long-acting insulin.[2] Afrezza is not indicated for use in children, women who are pregnant or breastfeeding, or patients with diabetic ketoacidosis.[2]
After inhalation, Technosphere® insulin (TI) particles will reach the lung and dissolve on contact, with subsequent rapid absorption into systemic circulation.[2,3] Per the manufacturer, the amount of insulin delivered to the lung depends on individual patient factors. It is considered an ultra-rapid-acting insulin because the onset of action is 12-15 minutes, with a peak of about 60 minutes and duration of activity of about 2.5-3 hours.[2]
Efficacy and Tolerability
In an abstract presented at the 44th General Assembly of the European Association for the Study of Diabetes, Kapsner and colleagues[4] reported outcomes from a 52-week study of patients with T1DM (baseline A1c > 7.0% and ≤ 11.0%) who were randomly assigned to receive basal insulin glargine plus a prandial rapid-acting analogue (RAA) (n = 288) or prandial TI (n = 301). The dose of TI and dose titration protocols for basal, RAA, or TI were not provided.
At study end, a reduction in A1c was reported in the TI/glargine and the RAA/glargine groups (-0.17% vs -0.47%, respectively). Changes in fasting plasma glucose (FPG) and weight were favorable for those receiving TI compared with RAA (-45 mg/dL vs -23.4 mg/dL; P = .0052 and -0.5 kg vs +1.4 kg; P < .0001, respectively). Postprandial glucose (PPG) at 1 hour was 165.6 mg/dL in patients receiving TI vs 201.6 mg/dL in patients receiving RAA (P = .0203). However, data from 2-hour PPG were not provided. Mild to moderate hypoglycemia occurred less frequently in those receiving TI vs RAA (85.67% vs 92.65%, respectively; P = .0091), but severe hypoglycemia occurred similarly between the groups (32.76% vs 37.50%, respectively).[4]
In an open-label, 52-week study, 677 patients with T2DM (baseline A1c, 8.7%) were randomly assigned to receive prandial TI plus bedtime insulin glargine vs twice-daily premixed aspart 70/30.[5] Standardized meal challenge was done to assess PPG response, with administration of preprandial TI within 90 seconds of ingesting the meal or premixed aspart insulin 15 minutes before the meal.
Study dosing for glargine plus TI:
Basal insulin: 50% of the total daily dose
TI insulin: 50% of the total daily dose distributed across main meals and individually adjusted in 15-unit increments (maximum, 90 units per meal) on the basis of self-monitoring of blood glucose. Cartridges of 15 units and 30 units were provided to patients (15 units of TI is about 3.8 units of subcutaneous [SC] rapid-acting insulin, based on bioequivalence of 24%-28%)
Study dosing for premixed aspart 70/30: dose adjusted on target FPG and predinner plasma glucose values of 79-110 mg/dL
By study end, patients assigned to TI were receiving 198 ± 74 units per day. The mean daily dose of glargine was 47 ± 25 units. Those assigned to premixed aspart 70/30 received 88 ± 48 international units per day. Patients in both groups had a statistically significant reduction in A1c (-0.59% with TI/glargine vs -0.71% with premixed aspart 70/30) and FPG (-32 mg/dL TI/glargine vs -18.4 mg/dL premixed aspart 70/30) vs baseline, and the difference in FPG was in favor of TI/glargine (P = .0029) Although the TI/glargine group also experienced a significant reduction in 1-hour PPG, it took almost 6 hours for PPG to reach preprandial levels. In comparison, PPG in the premixed aspart 70/30 group reached the preprandial level in 4 hours.[5]
Weight gain occurred in both groups (+0.9 kg with TI/glargine vs +2.5 kg with premixed aspart 70/30), but was greater for those on premixed aspart 70/30 (difference between groups, -1.6 ± 0.4 kg; 95% confidence interval (CI), -2.4 to -0.7; P = .0002). Cough was reported more frequently in those receiving inhaled insulin (33% vs 6%); it occurred most frequently during the first 10 minutes of inhalation, usually during the first week of therapy, and was typically nonproductive. However, withdrawal owing to any adverse events was more likely among patients receiving TI/glargine than those receiving premixed aspart (9% vs 4%, respectively), with cough as the main reason for discontinuation.[5]
Hypoglycemia of any severity was most likely to occur with premixed aspart 70/30 vs TI/glargine (odds ratio, 0.417; 95% CI, 0.303-0.573), and the occurrence of severe hypoglycemic events at any time of day was higher with premixed aspart 70/30.[5]
Patients were included in the study if the forced expiratory volume in 1 second (FEV1) and diffusing lung capacity for carbon monoxide (DLCO) were ≥ 70% of predicted values and total lung capacity was ≥ 80% of predicted values. At study end, there was a nonsignificant reduction in FEV1, DLCO, and forced vital capacity in both treatment groups.[5]
How Is Afrezza Supplied?
Afrezza is available in 2 strengths: 4 units (blue cartridge) and 8 units (green cartridge), both dispensed in foil packages:
• Each package contains 2 blister cards, with 15 cartridges per blister card (total of 30 cartridges). Patients will tear along a perforation, remove a strip (3 cartridges per strip), press on the individual cartridge to remove it from the strip, and insert the cartridge into the inhaler for use.
• If a patient requires mealtime insulin before 3 meals per day, then 1 strip will be used per day; however, if a patient uses fewer than 3 cartridges per day, any cartridge left on an open strip must be used within 3 days.
Alternatively, if the prescribed dose is greater than 8 units per meal, then the patient will need more than 1 cartridge. For example, if a patient requires 12 units before a meal, then 1 blue cartridge plus 1 green cartridge, with the same inhaler, will be used.
All cartridges (whether in blister packs or those on the strip being used for that day) should be kept refrigerated. However, cartridges and the inhaler should be at room temperature for 10 minutes before use.
Patients do have the option of keeping sealed blister cards and strips at room temperature; however, all of the cartridges must then be used within 10 days.
The Afrezza inhaler can be kept refrigerated or at room temperature in a clean, dry place but should be replaced after 15 days of use (use a calendar to keep track). The outside of the inhaler can be wiped with a clean, dry cloth if needed, but should not be washed for any reason.
Dosing
Afrezza is administered via oral inhalation using the Afrezza inhaler, as a single inhalation at the beginning of a meal. If a meal is skipped, then the dose is skipped.
Insulin-naive patients: 4 units before each meal
Prandial SC insulin users: convert 1:1
Up to 4 units: one 4-unit cartridge
5-8 units: one 8-unit cartridge
9-12 units: one 4-unit and one 8-unit cartridge
13-16 units: two 8-unit cartridges
17-20 units: one 4-unit and two 8-unit cartridges
21-24 units: three 8-unit cartridges
For doses > 24 units, combinations of different multiple cartridges can be used.
Premixed SC insulin users
Determine the mealtime injected dose by dividing one half of the total daily injected premixed insulin dose equally among 3 meals of the day. For example, if a patient injects a premixed insulin at 25 units SC twice daily (total daily dose, 50 units), divide 25 units by 3, to equal 8 units before each meal. This patient can then use one 8-unit green cartridge of Afrezza before to each meal. One half of the total daily injected premixed dose is administered as an injected basal dose.
Calculating the insulin-to-carbohydrate ratios of each meal can help guide motivated patients with how much rapid-acting insulin to administer before a meal. Because Afrezza is an ultra-rapid-acting insulin with early PPG control, patients initially may benefit from performing self-monitoring of blood glucose at 90-120 minutes to see whether another inhalation might be needed.[7]
Selected Warnings and Precautions
Several key warnings should be emphasized[2]:
Afrezza is contraindicated in persons with chronic lung disease (eg, asthma, chronic obstructive pulmonary disease) because acute bronchospasm has been reported in these patients. Spirometry to determine FEV1 and thus identify possible lung disease is recommended at baseline, 6 months, and 12 months and then yearly. If FEV1 drops ≥ 20% from baseline, consider discontinuation. If a patient experiences persistent shortness of breath, wheezing, or excessive coughing, consider more frequent pulmonary function monitoring. If symptoms continue, discontinue Afrezza.
Avoid use in patients with active lung cancer, a history of lung cancer, or those at risk for lung cancer.
Afrezza is not recommended for current smokers or those who have recently stopped smoking.
Afrezza is pregnancy category C and should not be used during pregnancy unless potential the benefit justifies the potential risk to the fetus.
Conclusion
Afrezza is an ultra-rapid-acting inhalation insulin that is administered right before a meal and is effective at improving glycemic control. Patients should be counseled on possible adverse events, including cough, weight gain, and hypoglycemia. In addition, patients should be told to report any persistent pulmonary symptoms for further evaluation.
Afrezza is not yet available in pharmacies, and the cost is unknown. Additional randomized, active-comparator studies in adults and children with T1DM or T2DM, smokers, and those with reduced lung function will further clarify the efficacy and safety profile of insulin inhalation powder.