Inhaled insulin therapy in diabetes mellitus
INTRODUCTION
Therapy with insulin is effective at lowering blood glucose in patients with diabetes, but there is resistance to its use by patients and health care providers because of its need to be injected subcutaneously and because of concern regarding interference with patients’ lifestyle, risk of hypoglycemia, and perception that people treated with insulin are "sicker". Consequently, patients with type 1 diabetes may hesitate to embrace multiple-dose injection regimens while patients with type 2 diabetes may defer initiating insulin therapy, resulting in inadequate glycemic control and increased risk for complications. Therefore, alternative, less invasive options for insulin therapy are desirable.
An inhaled form of rapid-acting insulin (Exubera) was available for a short time (August 2006 to October 2007) before it was discontinued by the manufacturer as the new technology failed to gain acceptance by patients or clinicians. Since then, most companies have abandoned their development programs on inhaled insulin. Currently, one formulation of inhaled insulin (Afrezza) has received approval by the US Food and Drug Administration (FDA) and is expected to become available for clinical use in early 2015 .
Inhaled insulin represents a paradigm shift for insulin delivery, as it differs not only in route of administration, but also dosing units, patient eligibility (precautions and exclusions related to lung disease and smoking), and need for periodic testing for safety. This topic reviews the efficacy, safety, and patient acceptability of inhaled insulin therapy. Since most of the publicly available data on inhaled insulin are for Exubera, the topic primarily reflects the experience with this formulation, but more recent data from the Afrezza formulation are included. An overview of pharmacologic therapy for type 1 and type 2 diabetes including insulin therapy is presented separately.
MECHANISM OF ACTION
Most polypeptides used for therapy require parenteral delivery, as oral administration results in loss of biopotency, owing to breakdown in the stomach. Several non-oral routes of insulin administration have been studied, including transdermal, buccal, nasal, and inhaled delivery. Specifically, the lung provides an attractive option for therapeutic administration of polypeptides, given its accessibility and large alveolar-capillary network for drug absorption.
Delivery system — For insulin to be delivered through the lungs, inhalation devices that provide dose accuracy and consistency are critical. Due to its inefficient absorption, higher doses of inhaled insulin compared to subcutaneous must be administered to achieve an equivalent therapeutic response. The first inhaled insulin delivery system (Exubera), which is no longer available, involved use of a bulky device to dispense human insulin as a dry-powdered formulation with little dosing flexibility. A different inhaled insulin formulation with a more convenient delivery system will become available in 2015 . This new formulation (Afrezza) uses the Technosphere platform that contains recombinant human insulin dissolved in dry powder. Once inhaled, insulin is rapidly absorbed upon contact with the lung surface . Both the insulin and the powder are nearly completely cleared from the lungs of healthy individuals within 12 hours of inhalation; only 0.3 percent of the insulin and 0.4 percent of the powder concentration remain after 12 hours. In contrast, with the Exubera formulation, about 8 to 9 percent of the inhaled dose remained in the lungs 12 hours later.
