Insulin has a key role in the regulation of glucose metabolism, and defects in either insulin production and/or resistance to its action underlie all types of diabetes mellitus. For type 1 diabetes, which involves loss of the insulin-producing 
-cells in the pancreas, injections of insulin are the primary therapy1. Insulin injections also have an important role in optimal treatment regimes for type 2 diabetes, which is characterized by both peripheral insulin resistance and defective insulin production1.
It is well-established that tight control of the hyperglycaemia associated with type 1 and type 2 diabetes is crucial in attenuating the microvascular and macrovascular complications of the disease, which include nerve damage, renal failure, blindness and the acceleration of cardiovascular disease1, 2. There have been many improvements in diabetes therapy to help achieve this goal since the first use of injectable insulins more than 80 years ago, including the introduction of various drugs for the management of hyperglycaemia, such as metformin, sulphonylureas and glitazones. Insulin therapy has also undergone major developments. Various 'rapid-acting' insulin analogues have improved postprandial glucose control, and 'long-acting' insulin analogues have improved on 'conventional' basal insulin suspensions by having an absorption profile that better simulates the basal insulin secretion of normal individuals. In parallel, the delivery of insulin has been made easier with 'pen' devices, and implantable pumps for constant infusion of insulin with meal-time adjustment.
Nevertheless, the burden of multiple daily insulin injections needed to achieve optimal dosing in patients with type 1 diabetes, and a reluctance to initiate insulin therapy and a lack of acceptance of injections in patients with type 2 diabetes, are key barriers to achieving optimal glycaemic control. Recognition of this problem has stimulated efforts to investigate alternatives routes of insulin administration1, 2.
Basis of discovery
The advantages of pulmonary delivery include the large surface area available for absorption, and rapid absorption through the alveolar epithelium2, 3. Indeed, attempts to deliver insulin as an inhaled aerosol began in the 1920s, but it was not until the 1990s that major progress was made as a result of advances in the understanding of the relevance of aerosol dynamics to effective delivery2. Factors now known to affect the amount and site of deposition of inhaled, aerosolized insulin include particle size, surface morphology, charge, solubility and hygroscopicity2. In addition to developing a suitable insulin formulation for pulmonary delivery, the development of an inhalation device that can be easily and reliably operated by patients is a key challenge in providing consistent efficient pulmonary delivery2, 3.
Drug properties
Exubera consists of blisters that contain recombinant human insulin formulated as a dry powder with excipients that help stabilize the insulin during the spray-drying production process and allow room-temperature storage2, 3. Blisters of Exubera, which contain either 1 mg or 3 mg of insulin to facilitate dosing flexibility, are administered by the patient using the Exubera inhaler2, 3.
Clinical data
In patients with type 1 diabetes, the inhaled insulin Exubera, administered three times daily prior to meals and a single night-time injection of a long-acting insulin (Humulin U Ultralente), has been compared with a conventional subcutaneous insulin regime (involving regular human insulin administered twice daily with NPH human insulin adminis-tered twice daily) in 24-week randomized, open-label trials4, 5. The primary efficacy parameter was glycaemic control, as measured by the reduction from baseline in haemoglobin A1c (HbA1c). In these trials, the reduction in HbA1c and the rates of hypoglycaemia were comparable in the two treatment groups4, 5.
Inhaled insulin administered three times daily prior to meals has also been evaluated in several randomized open-label trials involving patients with type 2 diabetes5, 6, 7. A 12-week trial involving patients with type 2 diabetes not optimally controlled with diet and exercise compared inhaled insulin before meals with the oral hypoglycaemic drug rosiglitazone twice daily6. Significantly more patients receiving inhaled insulin achieved HbA1c <8.0% than those receiving rosiglitazone (83% versus 58%, respectively)6. The frequency of hypoglycaemic episodes was higher in the inhaled insulin group (0.7 versus 0.05 episodes per subject-month, respectively)6. In a 24-week trial in patients with type 2 diabetes who were being previously treated with subcutaneous insulin injections, changes in HbA1c from baseline to the end of study were similar in patients receiving inhaled insulin and a single night-time injection of Humulin U Ultralente and patients receiving a standard subcutaneous insulin regime involving regular human insulin and NPH human insulin twice daily7. Treatment satisfaction was greater in the inhaled insulin group7.
Small, non-progressive declines in pulmonary function relative to comparator treatments have been seen in trials of inhaled insulin, and pulmonary function tests are recommended prior to initiating therapy, and periodically after treatment initiation5. The use of inhaled insulin is contraindicated in patients who smoke or who have discontinued smoking less than 6 months prior to starting therapy, and is also contraindicated in patients with unstable or poorly controlled lung disease5.
Indications
In the United States, Exubera is approved by the FDA for the treatment of adult patients with diabetes mellitus for the control of hyperglycaemia5. In patients with type 1 diabetes, it should be used in regimens that include a longer-acting insulin5. In patients with type 2 diabetes, it can be used as monotherapy or in combination with oral agents or longer-acting insulins5.
In Europe, Exubera is approved by the EMEA for the treatment of adult patients with type 2 diabetes mellitus not adequately controlled with oral hypoglycaemic agents and requiring insulin therapy8. It is also approved for the treatment of adult patients with type 1 diabetes mellitus, in addition to long- or intermediate-acting subcutaneous insulin, for whom the potential benefits of adding inhaled insulin outweigh the potential safety concerns8.
Insulin therapies
Analysing clinical issues related to novel insulins is David Owens CBE, M.D., Professor and Consultant Diabetologist at Cardiff University, School of Medicine, Cardiff, UK.
The evidence for the importance of strict glycaemic control in retarding micro- and macrovascular complications of diabetes, such as blindness, renal failure and neuropathy, is overwhelming in both type 1 and type 2 diabetes (for example, see Refs 9, 10). Unfortunately, this is rarely achieved in the majority of patients. Insulin therapy is a necessity in the management of type 1 diabetes; however, inadequate insulin dose titration and/or poor compliance contributes to both short-term (diabetic ketacidosis and hypoglycaemia) and long-term consequences of poor glycaemic control11. Insulin therapy becomes a key requirement in type 2 diabetes inadequately controlled by lifestyle changes and a variety of oral hypoglycaemic agents. Recent evidence indicates that the excess glycaemic burden to which patients with type 2 diabetes are exposed reflects both a delay in the introduction and dose-adjustment of oral therapies to meet the increasing requirements, and also a delay in the initiation of insulin therapy12.
The main obstacles to optimising insulin therapy include patients' fear and anxiety surrounding injections, hypoglycaemia and weight gain, and inconveniences such as the need for frequent blood-glucose monitoring. These concerns are often shared and amplified by physicians, who frequently delay prescribing insulin therapy in patients with type 2 diabetes13. Patients with type 2 diabetes are therefore unnecessarily burdened by prolonged excessive glycaemic exposure, which is a prelude to vascular complications.
Exubera will offer the chance to reduce the need for several daily insulin injections in patients with type 1 diabetes troubled by injections. It should also help people with type 2 diabetes accept insulin earlier if they are unwilling to consider insulin injections when failing to reach glycaemic targets on a variety of oral hypoglycaemic agents. Inhaled insulin provides a practical alternative to 'short-acting' insulin from subcutaneous injections, achieving comparable glycaemic control without increased risk of hypoglycaemia, and no serious adverse events have been seen so far. Inhaled insulin also seems to be well tolerated and consistently preferred over subcutaneous insulin injections, resulting in improved treatment satisfaction and quality of life, although it remains to be seen whether this will be sustained in the long-term, and studies reported so far did not use an insulin pen delivery device, which might have reduced patient preference for inhaled insulin. There are also no results available from studies comparing inhaled insulin with the rapid-acting insulin analogues or with insulin infusion pumps.
Nevertheless, the greater patient satisfaction with inhaled insulin is encouraging, as it has been suggested that increased patient satisfaction, possibly due to better compliance, translates into improvements in glycaemic control14. The question remains as to what impact this new mode of insulin delivery will have on the potentially devastating long-term diabetes-related complications. Now that the efficacy and safety of inhaled insulin (Exubera) has been proven, the economic viability of this route of insulin administration will also be important in establishing its clinical role. See Box.
