Can Inhaled Insulin Be Used for the Treatment of Diabetes Mellitus?
Can Inhaled Insulin Be Used for the Treatment of Diabetes Mellitus?
Reluctance to start and adequately titrate subcutaneous insulin are major reasons why many patients with diabetes mellitus are insufficiently metabolically controlled. Pulmonary insulin administration has the advantage over subcutaneous insulin in that it is noninvasive, seems better accepted by the diabetic population and exerts equal efficacy in terms of glycemic control. As such, inhaled insulin has the potential to increase the diabetic (Type 2) patient's willingness to commence and adhere to insulin therapy. Inhaled insulin's short duration of action makes it suitable for prandial administration provided that basal insulin requirements are met by residual β-cell function, or by supplemental long-acting subcutaneous insulin. In clinical trials, inhaled insulin is comparable to short-acting subcutaneous insulin with regard to efficacy and hypoglycemic risk. Adverse effects associated with inhaled insulin include dry cough, which tends to diminish over time, a slight drop in pulmonary function that does not progress and is reversible in most patients if treatment is discontinued, and increased insulin antibody formation, albeit without clinical sequelae. Long-term safety remains an issue for a product intended to be used chronically for many years. Exubera® was thus far the only inhaled insulin product to receive approval in the USA and Europe for use in adults with Type 1 or Type 2 diabetes, but was recently withdrawn from the market. At present it is unclear how this decision will affect programs from other companies with inhaled insulin products under development.
The discovery of therapeutic insulin in the early 1920s and its subsequent worldwide distribution has transformed Type 1 diabetes from an acutely debilitating disease leading to a certain (sub)acute death into a chronic condition, yet at high risk of vascular complications and pre-mature cardiovascular death. At present, the importance of maintaining glucose levels as close to normal to prevent or delay micro- and macrovascular complications has been firmly established for both Type 1 and 2 diabetes. Due to the necessity for good glycemic control, and the rising prevalence of Type 2 diabetes in particular, ever increasing numbers of patients (ultimately) require insulin therapy.
Advances in the development of the bio-chemical structure of insulin and insulin analogues, glucose monitoring devices and insulin delivery systems have provided the conditions for the potential optimization of glycemic control, which and enables patients to self-manage their condition. A wide range of injectable insulin products are currently available, including short- and immediate-acting agents, intermediate- and prolonged-acting agents, and premixed formulations, combinations of which can be used to optimize glycemic management. In spite of all this, however, optimal glycemic control (i.e., hemoglobin [Hb] A1c ≤ 7%) has shown to be achieved by a minority of patients on insulin. A major reason for this failure is the limitation of subcutaneous insulin in replicating the physiological pattern of endogenous insulin secretion, so that euglycemia can be maintained over prolonged periods of time. In addition, despite advances in the development of smaller needles and patient-friendly pen-injector devices to allow for better tolerability of subcutaneous administration, the injection of insulin is still viewed as a complicated and painful procedure. The burden of daily insulin injections may lead to an avoidance to self-inject, even in the absence of overt needle phobia, and to the postponement of the initiation of insulin therapy in Type 2 diabetic patients who fail on oral therapy.
Attempts to develop noninvasive routes for insulin administration emerged soon after the introduction of insulin. Degradation by the acidic environment of the stomach or by peptidases in the upper gastrointestinal tract, active mucociliary clearance and the presence of proteolytic enzymes in the nasal cavity, and the relative impermeability of the skin all complicate successful delivery by oral, intestinal, intranasal, and transdermal routes. None of these obstacles apply to pulmonary drug delivery and attempts to use the lungs for insulin administration date back to the beginning of insulin treatment. In 1971, it was first shown that inhalation of insulin resulted in a prompt increase of plasma immunoreactive insulin and reduction of blood glucose levels in healthy and diabetic subjects. Better understanding of aerosol dynamics and particle properties has laid the foundation that has allowed for the development of an inhaled insulin product. This review aims to provide an overview of pulmonary insulin preparations in development, to discuss the pharmacokinetics and safety of inhaled insulin, and to critically evaluate the results of clinical trials performed with inhaled insulin.
Abstract and Introduction
Abstract
Reluctance to start and adequately titrate subcutaneous insulin are major reasons why many patients with diabetes mellitus are insufficiently metabolically controlled. Pulmonary insulin administration has the advantage over subcutaneous insulin in that it is noninvasive, seems better accepted by the diabetic population and exerts equal efficacy in terms of glycemic control. As such, inhaled insulin has the potential to increase the diabetic (Type 2) patient's willingness to commence and adhere to insulin therapy. Inhaled insulin's short duration of action makes it suitable for prandial administration provided that basal insulin requirements are met by residual β-cell function, or by supplemental long-acting subcutaneous insulin. In clinical trials, inhaled insulin is comparable to short-acting subcutaneous insulin with regard to efficacy and hypoglycemic risk. Adverse effects associated with inhaled insulin include dry cough, which tends to diminish over time, a slight drop in pulmonary function that does not progress and is reversible in most patients if treatment is discontinued, and increased insulin antibody formation, albeit without clinical sequelae. Long-term safety remains an issue for a product intended to be used chronically for many years. Exubera® was thus far the only inhaled insulin product to receive approval in the USA and Europe for use in adults with Type 1 or Type 2 diabetes, but was recently withdrawn from the market. At present it is unclear how this decision will affect programs from other companies with inhaled insulin products under development.
Introduction
The discovery of therapeutic insulin in the early 1920s and its subsequent worldwide distribution has transformed Type 1 diabetes from an acutely debilitating disease leading to a certain (sub)acute death into a chronic condition, yet at high risk of vascular complications and pre-mature cardiovascular death. At present, the importance of maintaining glucose levels as close to normal to prevent or delay micro- and macrovascular complications has been firmly established for both Type 1 and 2 diabetes. Due to the necessity for good glycemic control, and the rising prevalence of Type 2 diabetes in particular, ever increasing numbers of patients (ultimately) require insulin therapy.
Advances in the development of the bio-chemical structure of insulin and insulin analogues, glucose monitoring devices and insulin delivery systems have provided the conditions for the potential optimization of glycemic control, which and enables patients to self-manage their condition. A wide range of injectable insulin products are currently available, including short- and immediate-acting agents, intermediate- and prolonged-acting agents, and premixed formulations, combinations of which can be used to optimize glycemic management. In spite of all this, however, optimal glycemic control (i.e., hemoglobin [Hb] A1c ≤ 7%) has shown to be achieved by a minority of patients on insulin. A major reason for this failure is the limitation of subcutaneous insulin in replicating the physiological pattern of endogenous insulin secretion, so that euglycemia can be maintained over prolonged periods of time. In addition, despite advances in the development of smaller needles and patient-friendly pen-injector devices to allow for better tolerability of subcutaneous administration, the injection of insulin is still viewed as a complicated and painful procedure. The burden of daily insulin injections may lead to an avoidance to self-inject, even in the absence of overt needle phobia, and to the postponement of the initiation of insulin therapy in Type 2 diabetic patients who fail on oral therapy.
Attempts to develop noninvasive routes for insulin administration emerged soon after the introduction of insulin. Degradation by the acidic environment of the stomach or by peptidases in the upper gastrointestinal tract, active mucociliary clearance and the presence of proteolytic enzymes in the nasal cavity, and the relative impermeability of the skin all complicate successful delivery by oral, intestinal, intranasal, and transdermal routes. None of these obstacles apply to pulmonary drug delivery and attempts to use the lungs for insulin administration date back to the beginning of insulin treatment. In 1971, it was first shown that inhalation of insulin resulted in a prompt increase of plasma immunoreactive insulin and reduction of blood glucose levels in healthy and diabetic subjects. Better understanding of aerosol dynamics and particle properties has laid the foundation that has allowed for the development of an inhaled insulin product. This review aims to provide an overview of pulmonary insulin preparations in development, to discuss the pharmacokinetics and safety of inhaled insulin, and to critically evaluate the results of clinical trials performed with inhaled insulin.