Inhaled, Dry Powder Insulin

US Pharm. 2007;32(10)(Diabetes suppl):3-8.


Diabetes mellitus (DM) currently affects an estimated 20.8 million people within the United States, with a current worldwide prevalence estimated at 180 million and which is expected to double by 2030.^1,2 Despite the many advances in the management of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in recent years, the average glycated hemo­ globin test (HbA1c) result of patients with diabetes increased from 7.7% to 7.9% between 1990 and 1999.³ Strong evidence exists demonstrating the benefits of tight glycemic control in T1DM and T2DM patients; however, glycemic goals are not adequately achieved for many patients.^4-6 While people with T1DM require insulin, many T2DM patients could improve their glycemic control by the initiation of insulin therapy, but they are either not prescribed insulin or have fear associated with the injection process.⁶

The advent of dry powdered insulin delivered by pulmonary inhalation provides an alternative mode of delivery for patients with perceived barriers to the use of insulin. One clinical trial looked at the acceptance of insulin therapy in 700 participants with T2DM and an HbA1c result greater than 8%. The subjects in this study were randomized to receive information regarding the risks and benefits of various treatment options.⁷ A treatment regimen that included insulin was opted for by 43.2% of patients in the group that had received information on inhaled, dry powder insulin (IDPI), compared with 15.5% of those offered information only on subcutaneous (SC)insulin therapy. Results from this trial suggest that availability of inhaled insulin may increase acceptance of insulin therapy in patients not currently using insulin. This review will discuss the clinical pharmacology, tolerability, contraindications and precautions, side effects, and special considerations of the currently marketed IDPI product Exubera.

IDPI Comparative Efficacy
Five phase II or III efficacy trials were conducted comparing HbA1c reduction in participants receiving bolus premeal inhaled insulin (Exubera) plus insulin isophane suspension (NPH), Ultralente, or insulin glargine for their basal insulin needs versus patients receiving bolus regular SC insulin plus NPH, Ultralente, or insulin glargine basal insulin. These trials enrolled a combined total of 1,354 participants with T1DM.^8-12 In these studies, IDPI and SC regular insulin achieved similar HbA1c reductions and percentage of patients achieving an HbA1c less than 7%. Additionally, eight comparative efficacy studies enrolled a total of 2,398 T2DM patients uncontrolled with diet and exercise, sulfonylurea monotherapy, metformin monotherapy, metformin plus a sulfonylurea, or an insulin secretagogue plus an insulin sensitizer and were randomized to receive either IDPI monotherapy or the addition of IDPI to their current regimen.^13-20 Results from these trials demonstrated that the addition of IDPI further reduced HbA1c levels and allowed more patients to achieve an HbA1c less than 7%. In both T1DM and T2DM, clinical trials show IDPI to have similar efficacy when compared to SC regular insulin, and in some instances superior efficacy, when compared to oral antidiabetic therapies.

Adverse Events
While IDPI therapy carries with it the same considerations and precautions as injectable insulin preparations (e.g., risk of hypoglycemia, weight gain), the delivery mechanism of IDPI involves a variety of additional factors for consideration by prescribers and pharmacists alike. A major consideration for determining the appropriateness and safety of inhaled insulin use in a given patient is assessment of pulmonary function. Patients with lung disease (e.g., asthma, chronic obstructive pulmonary disease [COPD], etc.) have potentially impaired inspiratory capabilities that may impede adequate delivery of insulin to the lung for absorption. Due to this possibility, the manufacturer recommends that all patients undergo spirometry testing (forced expiratory volume in one second [FEV₁]) prior to the initiation of IDPI therapy. Additionally, FEV₁ monitoring should be conducted six months after the initiation of IDPI therapy and every year thereafter to ensure that FEV ₁ changes have not occurred as a consequence of IDPI use. Likewise, respiratory adverse events (e.g., cough, dyspnea) should be monitored closely as with any inhaled medication.²¹

Cough, dyspnea, increased sputum, and epistaxis were the most frequently reported adverse respiratory events during clinical trials involving both T1DM and T2DM patients.²¹ The single most common respiratory adverse event during clinical trials was cough.^{8,13,16,18,19,22} Cough occurred in approximately 30% of patients with T1DM and in approximately 22% of subjects with T2DM during clinical trials.²¹ Mild-to-moderate nonproductive cough was most commonly observed. Cough frequently decreased over time, indicating that this adverse reaction often resolves or lessens with continued treatment, with a two-week median duration of increased cough in one study. ^{8,13,16,18,19,22} Another study reported a decrease in the incidence and prevalence of cough with continued treatment when the initial four weeks of treatment were compared directly to the incidence of cough witnessed during weeks 20 through 24.²²

Dyspnea was reported with a frequency of 4.4% [0.9% for SC insulin comparator] and 3.6% (2.5% and 1.4% for SC insulin and oral agent comparators, respectively) in IDPI-treated patients with T1DM and T2DM, respectively.²¹ Additionally, increased sputum production was noted in 3.9% of IDPI-treated patients with T1DM, compared to an incidence of 1.3% for the SC insulin comparator. In patients with T2DM treated with IDPI, 2.8% reported increased sputum, compared to 1.0% and 0.5% for the SC insulin and oral agent comparator groups, respectively.²¹ The incidence of epistaxis was also increased in patients receiving IDPI, with 1.3% incidence (0.4% for SC insulin comparator) for subjects with T1DM and 1.2% (0.4% and 0.8% for SC insulin and oral agent comparators, respectively) for patients with T2DM.²¹

As with the use of any pulmonary medication, adverse respiratory events related to pulmonary function is of clinical importance. Pulmonary function parameters were closely monitored during clinical trials to asses the safety of IDPI. Results from 12-week and 24-week trials showed small, comparable mean declines between inhaled insulin–treated subjects and comparator groups for a variety of respiratory parameters, including but not limited to FEV₁.^{8,10,13,16,18,20,22} It is important to note, however, that respiratory changes generally resolved following drug discontinuation. Further pulmonary data taken from 580 patients with T1DM and 620 patients with T2DM treated with IDPI or SC insulin are reported by the manufacturer in the IDPI package insert. ²¹ After two years of therapy, the mean difference in FEV₁ between the IDPI and comparator group was -0.04 L. Patients with lung function below 70% of predicted FEV₁ prior to initiation should not receive IDPI, and any patient experiencing a decline of lung function of 20% or more from baseline while using IDPI should discontinue use of the product.

Contraindications and Precautions
Because IDPI presents a novel delivery mode in comparison to other currently marketed insulin products (TABLE 1), its prudent use requires additional and unique considerations for both health care providers and consumers. Current smokers or those who have quit smoking for less than six months should not receive IDPI. Similarly, if a patient begins or resumes smoking while taking IDPI, this treatment should be discontinued immediately. Patients with asthma, COPD, or other lung diseases should not use IDPI. IDPI can be used during mild, intercurrent respiratory illnesses such as rhinitis, upper respiratory infection, and bronchitis; however, more vigilant monitoring of blood glucose should be practiced until the illness resolves and blood glucose levels have normalized.^21,23 The use of IDPI has been studied in clinical trials for the treatment of both T1DM and T2DM. When treating T1DM patients with IDPI, it is important that patients also receive a long-acting insulin for their basal insulin needs. For patients with T2DM, however, IDPI can be utilized in conjunction with lifestyle modifications (i.e., diet and exercise), basal insulin, or oral diabetes therapies.

Dosing and Administration
IDPI blisters come in 1-mg (equal to 3 units of regular insulin) and 3-mg (equal to 8 units of regular nsulin) strengths. TABLE 2 outlines approximate dose equivalencies between regular SC insulin and IDPI. It is important to note that three 1-mg blisters are therefore not equivalent to one 3-mg blister. For those patients initiated on IDPI therapy, without any previous insulin use from which to base dosing parameters, a patient's initial dose is calculated based on weight and rounded to the nearest milligram value using the following formula provided by the manufacturer: body weight (kg) x 0.05 mg/kg = premeal dose (mg). Following the initiation of IDPI therapy, the dose is titrated corresponding to clinical effectiveness and specific patient needs, as with any insulin product.²¹ Once a target dose is identified, patients should combine 1-mg and 3-mg blisters to achieve their target dose so that the least amount of blisters are used. If a patient is stabilized on a dosage regimen utilizing 3-mg blisters but 3-mg blisters are temporarily unavailable, two 1-mg blisters can be substituted for one 3-mg blister until 3-mg blisters are again available. If such a temporary substitution is made, patients should be instructed to monitor blood glucose concentrations closely.²¹

IDPI use is associated with a faster onset of action compared to traditional SC regular human insulin, requiring that it be dosed no more than 10 minutes prior to meals.²¹ The duration of action of IDPI, however, is approximately equal to that of SC regular insulin. Because IDPI is a fast-acting insulin, the manufacturer recommends that IDPI be used in combination with a long-acting insulin preparation in those with T1DM, and either as monotherapy or in combination with oral medications or long-acting insulin in patients with T2DM.²¹

IDPI blisters should be used only in conjunction with the inhaler. A fully assembled inhalation device consists of the inhaler base, an inhalation chamber, and an IDPI release unit as illustrated in FIGURE 1. Maintenance of the IDPI inhalation device should include regular cleaning weekly. The inhalation chamber should be cleaned with soap and water, while the inhaler unit should be wiped down with a wet cloth, avoiding the release unit and blister insertion point. The release unit should never be cleaned and should instead be replaced every two weeks. Likewise, the entire inhaler should be replaced annually.²¹ Unopened inhaler blister packs should be stored at controlled room temperature (59°F-86°F). Once opened, dose blisters should be protected from moisture and stored under the protective foil overwrap. Also, once the foil wrap is opened, blisters should be used within three months (TABLE 3).²¹

Conclusions
Exubera is the first dry powder, inhaled insulin available for the treatment of DM, and with the introduction of IDPI comes a hopeful future for future advancements in pulmonary insulin delivery. The inhaler can be used in T1DM patients in combination with basal insulin, and in T2DM patients in combination with basal insulin and/or oral therapies. The inhaler does have its limitations. The dosing can prove difficult for some patients because the use of multiple blisters requires multiple inhalations. Additionally, dosing can become confusing for some patients considering one 3-mg blister is not therapeutically equivalent to three 1-mg blisters. Despite these potential limitations, this novel delivery of rapid-acting regular insulin to the respiratory tract has the potential to revolutionize the treatment of diabetes by providing a more readily acceptable administration of insulin to patients who could benefit from insulin therapy, especially for those unable or unwilling to undergo frequent insulin injections.

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