Role of Devices in Insulin Delivery.

Insulin therapy remains a lifesaving drug for individuals with complete beta cell deficiency, and an important therapy for those with type 2 diabetes and waning insulin secretion. Both the purity, safety, and pharmacodynamics of insulin preparations and the tools used for their administration have considerably evolved since their introduction in the early 1920s. Insulin preparations first became available from animal sources, and manipulation of the excipients in insulin preparations allowed changes in absorption after subcutaneous administration, which have delayed and prolonged the pharmacodynamics of insulin preparations such as Neutral Protamine Hagedorn (NPH) or the Lente family of insulins introduced in the late 1940s and early 1950s, respectively. This allowed patients to reduce the frequency of daily injections and/or experience better coverage of insulin needs over a 24-h period. In the early 1980s, human recombinant technology allowed for the mass production of ‘‘human’’ insulin preparations with amino acid structure identical to that of the native protein, and presumably lower immunogenicity than the corresponding animal preparations. Although insulin replacement is lifesaving for patients with type 1 diabetes, seminal studies such as the Diabetes Control and Complications Trial underscored the importance of glycemic control through intensive insulin therapy in reducing the complications associated with the disease. Despite these advances, insulin therapy, especially with multiple daily insulin injections, remained a considerable challenge and burden to effectively implement for patients with advanced insulin deficiency. The quest for more ‘‘physiologic’’ insulin preparations, which might more closely mimic the pharmacodynamics of normal prandial and basal insulin secretion, led to the introduction of insulin analogs in the form of lispro insulin in 1996, followed by aspart and glargine insulin in 2000. Manipulation of the amino acids on the insulin molecule, reformulations of insulin excipients, and attachment of fatty acid moieties to the insulin structure have resulted in rapid-acting insulin analogs that can be injected closer to the meals and have a faster onset and peak of biological action, as well as delayed/prolonged acting basal insulin preparations that provide more consistent biological activity over a 24-h period. These newer insulin analogs have allowed more userfriendly administration of insulin replacement, an important consideration to patients, and better safety profiles, through the reduction in frequency, and at times severity, of hypoglycemia. For example, the landmark treat-to-target study by Riddle et al. in 2003 established once daily insulin glargine as the gold standard for basal insulin replacement in diabetes, not because it was more effective at lowering glycemia than once daily NPH insulin but because it was associated with less hypoglycemia. Today, both insulin degludec and glargine U300 promise even safer biological profiles than glargine U100 insulin, through further reduction of hypoglycemia risk. Another very important development for both the end user and the prescriber of insulin has been the introduction of better and more user-friendly technologies for the delivery of insulin. For patients on multiple daily insulin doses, the use of portable, simple, accurate, and unobtrusive insulin pen technology has greatly facilitated insulin administration in their day-to-day lives; for health providers, pen technologies have streamlined and simplified both the discussions surrounding insulin use and the effort and time needed to teach patients how to properly administer insulin. Insulin pumps have also substantially evolved over the past several decades, making the life of the person with insulin-dependent diabetes considerably more tolerable. The recent introduction of a hybrid closed loop insulin system, which combines sensing technology that partially directs the continuous infusion from an insulin pump, is the harbinger for the revolution in insulin replacement systems long awaited by patients and providers alike. Currently, we are also entering the era of ‘‘biosimilar’’ insulin, also referred to as ‘‘follow-on biologic,’’ ‘‘me too biologic,’’ and ‘‘nonoriginator,’’ to list a few. Because insulin preparations are biological products, characterized by large protein complexes produced through recombinant DNA technology in living cells, they cannot be labeled as ‘‘generics,’’ which are small, chemically synthesized copies of nonbiological preparations. The inability to manufacture a biological product exactly will lead to inherent differences in the biosimilar and thus may illicit a different immunological response than the originator. The first biosimilar insulin to be introduced in the United States, after the expiration of the patent on Lantus insulin in 2015, is Basaglar , which is a biosimilar glargine U100, produced by Eli Lilly and Company, to be delivered through the Kwikpen prefilled device. As with most modern insulin preparations, patients and providers need to be confident of not only the efficacy and