Point: Pulmonary Inhalation of Insulin: Another “Brick in the Wall”

The latest innovation for advancing diabetes care is not a new pharmacologic class; it represents a new “twist” on one of the oldest pharmacologic agents known for treatment of diabetes. After >80 years of clinical use and after many years of research for alternative means of delivery (including dermal, nasal, and oral approaches), insulin delivered by pulmonary inhalation is finally a clinical reality. The availability of inhaled insulin could not have come at a better time. At a time when the prevalence of diabetes is increasing at alarming rates worldwide and when the majority of individuals with diabetes have not achieved the recommended glycemic goal, new insights into the disease itself are being revealed at a rapid pace and are allowing for the development of novel approaches to better manage the disease. As such, inhaled insulin now joins the glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase-IV inhibitors, and synthetic analogs of amylin as the latest tools available to the clinician. However, it is somewhat surprising that despite the promise that inhaled insulin could contribute to a paradigm shift in the clinical management of diabetes, considerable concern is openly expressed regarding its routine use.

There is no question about the need for insulin therapy in an individual with type 1 diabetes. The use of insulin in type 2 diabetes and, in particular, earlier in the course of management is supported by the natural history of the disease, which is characterized by progressive β-cell dysfunction. However, as a medical community, we need to do a much better job in advancing therapy in order to achieve glycemic control. Data from the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999–2000 suggested, if anything, a decrease in the percentage of individuals achieving glycemic targets (1). At the same time, the percentage of individuals treated with insulin, either as monotherapy or in combination with oral agents, remained essentially unchanged. Since these initial findings, additional data have suggested a slight improvement in glycemic control, but the majority of individuals with diabetes are still not at goal (2). Although new guidelines suggest continual titration of therapy over a period of months (which includes initiation of insulin) in order to achieve glycemic targets (3,4), the reality is that in many circumstances, providers fail to intensify management despite inadequate glycemic control on the current regimen, an observation referred to as “clinical inertia” (5). Therefore, providers who care for patients with type 2 diabetes appear to accept less than optimal control on combination oral therapy because of their concerns of using insulin or because of the concerns of the patients. This resistance to advance to insulin therapy is particularly disturbing given that insulin remains as the sole clinically available agent that allows the clinician to continuously titrate until the patient is at glycemic goal. An additional limitation of insulin therapy is that in order to optimize glucose control, the regimen may require multiple insulin injections that, in turn, may increase the complexity and effort required to comply with the regimen. Therefore, barriers to insulin use and intensification exist from both patients and physicians (6–8). Thus, it would appear that inhaled insulin, by overcoming some of the barriers to insulin use, would be well received and judged as a valuable addition to our treatment options based on the data suggesting need, efficacy, patient acceptability, and safety.

Based on the feasibility of delivering insulin via pulmonary inhalation, there are a number of devices and insulin formulations currently in development by pharmaceutical companies for pulmonary delivery and include the Pfizer/Nektar Exubera, Lilly/Alkermes AIR, Novo Nordisk/Aradigm AERx iDMS, and MannKind Technosphere pulmonary insulin delivery systems. The major differences in these systems currently in development include the insulin formulation used, e.g., dry powder versus liquid, and the specific mechanics of the devices. Despite the apparent differences of the insulin formulations and devices, a consistent observation is that inhaled insulin has a faster onset of action than subcutaneous regular insulin and an onset of action that is comparable to fast-acting analogs such as lispro insulin.

Inhaled insulin has demonstrated its efficacy in numerous clinical trials. Studies have been conducted in individuals with type 1 diabetes using the Pfizer/Nektar Exubera Pulmonary Insulin Delivery System and have compared preprandial inhaled insulin, with basal injection at night, with both conventional insulin and intensive insulin dosing (9,10). These studies, for the most part, demonstrate comparable glycemic control between subcutaneous insulin regimens and regimens incorporating premeal use of inhaled insulin. Similar findings were reported for the Lilly/Alkermes AIR system for individuals with type 1 diabetes. These findings included comparisons with regimens using fast-acting insulins, such as lispro (11). Regimens using preprandial inhaled insulin, along with one injection of basal insulin, were comparable with conventional insulin injection regimens (mixed-regular/NPH insulin) in subjects with type 2 diabetes (12). Patients with either type 1 or type 2 diabetes receiving inhaled insulin reported enhanced overall satisfaction, quality of life, and acceptance of intensive insulin therapy (9,12,13). However, the most important use of inhaled insulin may be in the treatment of individuals with type 2 diabetes who fail combination oral therapy. A phase 3 study (14) of 309 patients with type 2 diabetes suboptimally controlled on oral therapies revealed improved glycemic control (as assessed by A1C) in the patients taking inhaled insulin alone and in combination by 1.2 and 1.9%, respectively, compared with those receiving oral agents alone.

The argument most frequently used against the widespread use of inhaled insulin would be long-term safety. However, long-term safety would need to be definitively established for any new agent. Yet, the frequency and nature of adverse events such as hypoglycemia reported with inhaled insulins appear, in general, to be comparable with subcutaneous insulin, with the exception of cough (although it decreases in incidence and prevalence with continued use). Pulmonary function tests, including forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), total lung capacity (TLC), and carbon monoxide diffusing capacity (DL_CO) have been conducted for all inhaled insulin studies. Some of the earlier studies (9,10) reported differences in the more variable DL_CO relative to subcutaneous insulin. However, longer-term studies (15) have been conducted, and 2-year data are available. Treatment group differences in changes from baseline in FEV₁ and DL_CO were small, occurred early, remained stable, and were nonprogressive for up to 2 years of follow-up (15). Patients treated with inhaled insulin have been shown to develop increased serum insulin antibody levels (9,10,12,14). However, the increase in antibodies observed did not result in any apparent clinical change and were not related to changes in pulmonary function (16). In addition, extensive preclinical and clinical studies, which have included 2-year controlled studies utilizing high-resolution computerized tomography of the thorax, have not revealed evidence of inflammatory, fibrotic, or proliferative responses in the lung. Based on the efficacy of inhaled insulin, the safety data reported to date, the medical need, and the sponsor’s commitment to conduct a comprehensive postmarketing risk management plan, the Pfizer/Nektar Exubera insulin inhaler was given U.S. Food and Drug Administration approval in January 2006 and is currently the only insulin inhaler available for routine clinical use.

Because of the effects noted on pulmonary function, it is currently recommended that all patients have spirometry (FEV₁) assessed before initiating inhaled insulin, after the first 6 months of therapy, and yearly thereafter. It is important to understand that the studies that evaluated the safety and efficacy of inhaled insulin were not done in subjects for which the baseline FEV₁ was <70%. One major question would be whether adjustments in the dose of inhaled insulin should be considered in the face of respiratory infections. A retrospective analysis of pooled data from 14 controlled phase 2 and 3 clinical trials, ranging in duration from 3 to 24 months, revealed no apparent changes in glycemic control or hypoglycemic rates for inhaled insulin during intercurrent respiratory infections. As such, it was felt to be safe and efficacious even during these intercurrent respiratory illnesses (17). However, smoking has been shown to greatly alter the pharmacokinetics of inhaled insulin, and inhaled insulin should not be used in patients with diabetes who chose to continue smoking (18).

Although the new inhaler provides a means to deliver prandial insulin and appears to be comparable on glycemic control when compared with injections, two observations appear noteworthy. First, patients delivered insulin via pulmonary inhalation appear to have less of a tendency for weight gain as reported in a presented abstract (19) on retrospective data from a number of completed studies. Clearly, head-to-head comparisons will need to be made with analog insulins for both postprandial control and weight before marketing claims can be made. Second, studies have shown that use of insulin with the inhaler results in greater reductions in fasting blood glucose (15). The mechanisms behind the weight and fasting glucose effects are not yet known.

The availability of the insulin inhaler should not be viewed as the sole answer to the problem of compliance and inadequate glycemic control commonly seen in clinical practice today. However, inhaled insulin has been demonstrated to be an effective therapy compared with subcutaneous insulin regimens and appears superior when compared against failed oral therapies. Based on the efficacy and side-effect profile, the insulin inhaler should be considered as another viable therapeutic option available to the clinician and should be used as part of a comprehensive program with other new and established agents in an attempt to improve and maintain glycemic control. In this context, the new insulin inhaler can be considered as another “brick in the wall.”