Abstract
I
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. 2 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. 3,4 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. 5 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 user-friendly 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. 6 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. 7
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. 8 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. 9 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 safety of the biosimilar preparations but also the reliability and ease of use of the delivery devices. To that effect, the article by Heinemann et al., 10 in this issue of the journal, addresses some of the potential concerns that follow the introduction of biosimilar insulins and their delivery technologies, both within the United States and Europe, as well as in less regulated markets around the world. It has been shown that the frequency of adverse events associated with biosimilar product use (not necessarily insulin) in highly regulated markets has not increased; however, there is limited evidence to support equivalency of use regarding a biosimilar product's delivery device. 9 The authors make some valid points that bring into discussion the robustness of local regulations for approval of biosimilar and related delivery devices, and some of the more user friendly and safety features that have been developed for pens to date, such as the end-of-content feature and injection force. They also question the accuracy and variability of delivered doses from biosimilar devices, patient comfort level and preferences for specific insulin pens and features, and potential adherence to therapy.
Although it might be challenging to support or refute their assertions in certain markets around the world, the same might not be true for the recently FDA- and EMA-approved biosimilar glargine U100. For one, Basaglar™ (or Abasaglar™ as it is known in Europe) has undergone clinical evaluation to assess its pharmacokinetic and pharmacodynamics profile, its safety and immunogenicity profile, and its efficacy compared with the originator glargine U100 preparation. 11 –15 Based on these studies, there does not appear to be any difference in the efficacy or safety of the biosimilar compound compared with the originator molecule. With regard to accuracy and dose variability from devices used with biosimilar insulins, the authors discuss the higher dose variability seen with some of the other devices used for administering glargine biosimilars in other parts of the world, such as Glaritus® and Basalin®, compared with the ClickSTAR® and SoloSTAR® pens. 16 Although all of the pens met the DIN EN ISO 11608–1:2000 requirements, the coefficient of variation at the lowest dosage level (5 U) was higher in the devices used for the biosimilar products, although close to the range seen in other studies comparing state-of-the-art insulin delivery devices. 17 And although some studies have demonstrated better results for patients using pens versus traditional insulin vials and syringes with regard to metabolic outcomes and treatment persistence, 18 no such benefit has been shown in comparing pen devices among themselves. Use of Kwikpen® for delivery of the glargine biosimilar should allay most concerns regarding accuracy, safety, and ease of use of Basaglar™ 19 ; the same might not be true of other locally developed devices in other markets.
Patient and healthcare professional preference for insulin pen delivery methods has been extensively documented. 20 –28 Insulin pens are easier to use, more accurate, more portable, and less intrusive than vial and syringe options, and are becoming the preferred method for subcutaneous insulin delivery in the United States (they are well established as the preferred delivery method in Europe). As Heinemann et al. point out, there have been considerable improvements in pen delivery technology that have made their use more facile and safe for patients (see discussions on injection force and end-of-content features). As such, it would be ideal for devices that are to be used to deliver biosimilar products, to incorporate similar advances in technology. Although for some products this might be the case, for others it is not. 10 Clearly, this will require appropriate instruction and education of patients who might initiate or switch to biosimilar insulin and related pen devices. Although this might represent a departure from the patient's comfort level with, and preference for, their current insulin and pen device, switching between products is often driven in clinical practice by periodic changes in formularies, over which patients and providers have little control. In addition, if the switch to option comes at a lower cost to the patient, this might be a sufficient incentive for adoption. Reductions in biosimilar insulin prices in the United States are estimated to be 20%–40% compared with originator preparations, thus making this technology more affordable to more patients. 9,29 For example, a patient survey (N = 3214) conducted by a market research company to better understand patient perspectives on emerging biosimilar insulins identified that the majority of respondents would switch to a hypothetically less expensive biosimilar if their provider prescribed it. 30 Reported patient concerns included the potential effectiveness and safety (side effect profile) of the biosimilar, and the design of the administration device.
The drive to develop more physiological insulin preparations and more user-friendly delivery technology has considerably bettered the lives of people with diabetes over the past couple of decades. Unfortunately, many of these incremental improvements have come at an increasingly unaffordable expense for many patients, translating into increased copays and out-of-pocket expenses. 31,32 The promise of more affordable options for insulin replacement in the form of biosimilar insulins is a long-awaited respite for patients and healthcare professionals, as well as insurers. Let us hope that for the end users, this promise materializes instead of evaporating like a mirage in the desert.