Technosphere Inhaled Insulin: Is Faster Better?

Pulmonary-delivered insulin is again a reality (1). The failure of the first inhaled insulin in 2007 showed that being radically different from what health care providers are used to, even when injections are avoided, can be problematic. The current product Technosphere inhaled insulin has addressed many of the prior concernsda more convenient delivery device that is dosed in insulin units. Also, fear of lung toxicity or tumor development has been lessened somewhat by in vitro cytotoxic (2) and in vivo clearance (3) studies, plus a 2-year clinical trial showed no differences in pulmonary imaging or function in Technospheretreated and untreated subjects with diabetes (4). In addition, aerosolized medicines that have effective absorption into the bloodstream are well established (5), with numerous agents having been tried including glucagonlike peptide 1 (6). A highly touted feature of pulmonarydelivered insulin is its rapid absorptiond peak absorption by 10–15 min and fully cleared by 2–3 h versus a peak of 45–60 min and clearance of 5–6 h for injected analog prandial insulins (1,7) (Fig. 1). The potential importance of an ultrafast “on response” relates to the phasic nature of endogenously secreted insulin. An intravenous glucose infusion in humans without diabetes elicits a distinct first phase of insulin secretion over the first 10 min that is followed by a short lull and then a sustained second phase for the duration of the hyperglycemia. Actually, the diverse nutrient makeup of meals and their oral delivery initiate a more broad-based insulin response that does not separate into distinct phases. Still, the early insulin that is secreted into the portal vein serves a key role to rapidly turn off hepatic glucose production (8) and likely contributes to the fall in glucagon and controlled rise and fall in circulating free fatty acids that collectively characterize normal prandial metabolism. A defining feature of type 2 diabetes is a near-total absence of the early insulin response, while the later phase is present and often exaggerated because of the hyperglycemia, i.e., mealtime insulin is delayed (9,10). Restoring early insulin with a shortterm insulin infusion in type 2 diabetes markedly improved prandial glycemia and lipemia (11). Hence, a reasonable conclusion is the earliest secreted insulin is a necessary element of the normal mealtime insulin response, and consequently optimal exogenous prandial insulin needs a rapid “on response.” And Technosphere insulin is the best we have. However, a question that needs to be answered is whether that difference provides any meaningful clinical advantage over the injected prandial insulins. Two studies in this issue of Diabetes Careprovided insight into how this insulin performs. Bode et al. (12) performed a 24-week noninferiority open-label study of subjects with type 1 diabetes that received injected basal and aspart insulins (basal-bolus) or injected basal and inhaled Technosphere insulin at meals. The main finding was noninferiority with the attained A1C values falling within the agreed-upon study criteria of within 0.4%. The basal-bolus group fell from 7.9% after basal insulin optimization to 7.5% at the end of the study versus 7.9% to 7.7% in the inhaled insulin group. However, the percent of subjects attaining A1C #7% was superior in the injection group (31% vs. 18%), and the 7-point glucose profiles showed better control in the injected insulin group at all times except fasting. Otherwise, there were no major surprises or concerns over the use or safety of inhaled insulin. Thus, for type 1 diabetes, the fact that inhaled insulin was not more effective than prandial injections and probably less effective (despite meeting the noninferiority criteria) seems predictable as the rapid insulin profile likely runs out too soon on the background of complete insulin deficiency. However, features of inhaled insulin raise novel possibilities that might allow for creative ways to take advantage of its unique action profile. Importantly, Bode et al. found the faster “off time” of inhaled insulin lowered the risk of hypoglycemia 2–5 h