Counterpoint: No time to inhale: arguments against inhaled insulin in 2007.

M uch of the storied history of insulin has revolved around attempts to make its administration easier for patients who have to inject it to survive. The search for alternative routes of administration began almost immediately after its discovery—insulin was administered by inhalation, with modest effectiveness , and then within several years of its first administration by subcutaneous injection (1). The now almost unimaginable use of 20-gauge needles, sharpened by hand, and glass syringes that had to be sterilized regularly made the development of less painful and more convenient injections highly desirable. Moreover, before the development of intermediate-and long-acting formulations of insulin in the 1930s, four to five daily injections of the available rapid-acting formulation were required if patients wanted to avoid hyperglycemia and accompanying poly-uria and polydipsia. The introduction of " protamine insu-linate " in 1936 (2), followed by prota-mine zinc insulin, NPH, and the lente series of insulins, made it possible to maintain generally asymptomatic levels of glucose control, based on the longer-acting profile of the formulations, with only two injections per day. Although more convenient for patients with type 1 diabetes, the intermediate-acting insu-lins, and long-acting insulins that followed , had the unintended consequence of distracting attention from the more physiologic administration of insulin by multiple injections (3). When the glyco-hemoglobin assay became widely available in the early 1980s (4), it was clear that the chronic glycemic control achieved with these nonphysiologic, al-beit convenient, regimens was far from normal. More importantly, the elevated levels of chronic glycemia were strongly associated with all of the long-term complications of diabetes that resulted in severe morbidity and premature mortality (5). It took almost 60 years after the introduction of intermediate-acting insulins to establish the long-term benefits of intensive therapy. As defined in the Diabetes Control and Complications Trial (DCCT), intensive therapy included at least three injections per day or continuous subcutaneous insulin administration with an external pump (6). The need to frequently administer rapid-or very-rapid–acting insulin in order to achieve near-normal glucose control and delay or prevent the long-term complications once again placed a major burden on patients with type 1 diabetes. However, this time the burden was not owing to limited insulin formulations; rather, the demands of therapy arose from strong evidence that individuals with type 1 diabetes could live a healthier and longer life if they injected more frequently. The development of a whole range of insulin formulations …