In working to further our mission to help clinicians stay up-to-date on the latest education within cardiometabolic health, we have partnered with American Society of Endocrine Physician Assistants (ASEPA) to present the following blog to highlight a new and valuable clinical option in the practice of diabetes management.
Diabetes is a chronic illness that affects approximately 30.3 million people or 9.4% of the US population, and is associated with increased morbidity, mortality, and healthcare costs.
Adherence to a healthy lifestyle, including regular exercise, beneficial dietary changes, and weight loss, along with diabetes medications, is the cornerstone of diabetes management. In terms of medication, insulin therapy is an essential component for the management of individuals with type 1 diabetes. Due to the progressive nature of the disease, many type 2 diabetes patients may require insulin. Several insulins with different pharmacological profiles are approved in the US, such as ultra-rapid-acting insulin, rapid-acting insulin, regular or short-acting insulin, intermediate-acting insulin, long-acting insulin, and ultra-long-acting insulin.
However, many eligible patients do not use insulin, and increasing cost is one of the barriers that limit patient access to this drug class.3 It is imperative to have alternatives that confer the advantages of similar efficacy at a lower cost due to the high prevalence of diabetes. To that end – the development of “follow-on” or “biosimilar” insulin has been introduced in the market to drive down insulin cost, with the potential to increase its accessibility among patients with diabetes.4 In addition, recently the FDA has stated to continue efforts “to bring competition to the insulin market to lower prices and expand access”, with biosimilar insulins taking centerstage.5
As the concept of biosimilars is still novel, most clinicians are not familiar with the efficacy and safety of biosimilar insulins, and how they compare to their reference products. Biosimilar insulins are highly similar in terms of structure and have equivalent efficacy and safety compared to an already FDA-approved insulin biologic.6 Biologic drugs are a class of pharmaceuticals that are derived from living systems and are developed using advanced manufacturing technologies.4 These include the many available rapid-acting or basal insulin analogs currently in the market and manufactured using recombinant DNA technology.6 Due to the complex structure of insulin biologics, it is not possible to produce a chemically identical version to an existing biologic.6 Thus, unlike small-molecule drugs that can be easily replicated into generic versions, only “highly similar” versions of insulin biologics can be created, which are termed as “biosimilars” or “follow-on” products.6 Thus, biosimilar insulins should not be categorized as “generic,” as there are significant differences in product characteristics, production, development, regulation of “biosimilars” when compared with “generic” products.7
Numerous clinical trials are ongoing to assess the efficacy and safety of these biosimilar products as compared to the already established FDA approved products. On a safety level, the formation of antibodies against insulin is a potential concern with any insulin biologics, which can affect glucose control, insulin dose, and cause potential adverse events.4 Therefore, primarily, these trials are testing the immunogenicity profile as well as their hypoglycemic and drug-related adverse effects. Some of those trials are discussed here.
One of the latest developments in insulin therapy is the FDA-approval of 2 ‘follow-on’ or biosimilar insulins- insulin glargine and insulin lispro under the 505 (b) (2) pathway.8. Follow-on insulin glargine (LY2963016) was evaluated in the phase III ELEMENT 2 trial to determine its efficacy and safety compared to its reference product in patients with T2DM9. It was shown to be non-inferior to the reference product, leading to similar and significant decreases in HbA1c, with a similar safety profile (based on the rate of hypoglycemia and drug-related adverse events).9 Additional follow-up analyses of the ELEMENT-2 study have also suggested that LY2963016 and reference insulin glargine have similar immunogenicity profiles, as well as similar efficacy and safety in older adults (≥ 65 years of age) with T2DM.10, 11
Follow-on insulin lispro (SAR342434) was evaluated in the phase III SORELLA 2 study, which enrolled T2DM patients using basal insulin glargine and needing additional shorter-acting insulin to control blood glucose levels.12 The study indicated that insulin lispro was effective as it was non-inferior to that of reference insulin lispro. The biosimilar similarly decreases HbA1c and fasting plasma glucose after 26 weeks of treatment were observed, as well as similar seven-point self-monitored plasma glucose (SMPG) profiles.11 In addition, important safety components (hypoglycemic events, immunogenicity, and adverse events) were similar between the two groups.12
An additional follow-on insulin glargine product, MYL-1501D, is currently in clinical development. , iIt was evaluated in the phase III INSTRIDE 2 study in patients with T2DM who were insulin-naïve or on reference insulin glargine for at least three months before randomization and on ≥2 oral antihyperglycemic medications.12,14 Results from this study demonstrated that MYL-1501D was safe and effective as compared to reference insulin glargine.12 INSTRIDE 1 phase III was evaluatingevaluated its effect on T1DM patients and found similar results as INSTRIDE 2.15 MK-1293, another follow-on insulin glargine, was shown to be non-inferior to reference insulin glargine in T1DM and T2DM patients16,17, but its clinical development was recently discontinued from the manufacturer due to cost and manufacturing concerns.
Furthermore, a recent meta-analysis that evaluated the efficacy and safety of the three follow-on insulin glargine agents (LY2963016, MK-1293, and MYL-1501D) and the follow-on insulin lispro (SAR342434) reported that no significant differences were found between these agents and their reference products.186
Insulin therapy is an essential component of diabetes management, and the approval of follow-on insulins represents one of the latest advancements in this field, giving clinicians additional options to individualize diabetes care and improve patient access. Recently, several regulatory policies to guide the approval of these agents have been released by the FDA, and several recent studies have evaluated their efficacy and safety compared to the reference products in patients with diabetes. Thus, it is important for clinicians to be aware of the regulatory landscape, different nomenclatures, and the latest evidence-based data for the follow-on insulins in order to incorporate them as a viable treatment option.
- Centers for Disease Control and Prevention. “National diabetes statistics report, 2017.” Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services(2017).
- American Diabetes Association. “Standards of medical care in diabetes—2019 abridged for primary care providers.” Clinical Diabetes37.1 (2019): 11-34.
- Federal Trade Commission. Biologic drugs, biosimilars, and barriers to entry [homepage on the Internet]. [cited 2018 Jul 4]. Available from: https://www.ftc.gov/system/files/documents/public_comments/2014/02/00034-88736.pdf
- Llano, Andrea, Miles Fisher, and Gerry McKay. “Biosimilar insulin: the current landscape.” Practical Diabetes34.2 (2017): 51-54
- Statement from FDA Commissioner Scott Gottlieb, MD, on the agency’s continued efforts to bring competition to insulin market to lower prices and expand access [news release]. Silver Spring, MD: FDA; April 2, 2019. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm634999.htm. Accessed April 14, 2019
- Fonseca, Vivian A., et al. “AACE/ACE position statement on the use of follow-on biologics and biosimilars for endocrine diseases.” Endocrine Practice23.11 (2017): 1345-1349.
- Heinemann, Lutz, and Marcus Hompesch. “Biosimilar insulins: basic considerations.” Journal of diabetes science and technology8.1 (2014): 6-13.
- Dolinar, Richard O., et al. “Impact of biosimilar insulins on clinical practice: meeting report.” Journal of diabetes science and technology8.1 (2014): 179-185
- Rosenstock, J., et al. “Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin‐naïve or previously treated with insulin glargine: a randomized, double‐blind controlled trial (the ELEMENT 2 study).” Diabetes, Obesity and Metabolism17.8 (2015): 734-741.
- Ilag, L. L., et al. “Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus.” Diabetes, Obesity and Metabolism18.2 (2016): 159-168.
- Pollom, Robyn K., et al. “Similar Efficacy and Safety of LY2963016 Insulin Glargine and Insulin Glargine (Lantus®) in Patients with T2D in Age Groups (< 65,≥ 65 Years).” Canadian Journal of Diabetes40.5 (2016): S40.
- Derwahl, Karl-Michael, et al. “Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study.” Diabetes technology & therapeutics20.1 (2018): 49-58.
- Blevins, Thomas C., et al. “Efficacy and Safety of MYL-1501D (Mylan’s Insulin Glargine) Compared with Lantus (R)(Sanofi’s Insulin Glargine) in Patients with Type 2 Diabetes after 24 Weeks: The INSTRIDE 2 Study.” DIABETES. Vol. 66. 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA: AMER DIABETES ASSOC, 2017.
- Blevins, Thomas C., et al. “Efficacy and safety of MYL‐1501D versus insulin glargine in patients with type 2 diabetes after 24 weeks: Results of the phase III INSTRIDE 2 study.” Diabetes, Obesity and Metabolism21.1 (2019): 129-135.
- Blevins, Thomas C., et al. “Efficacy and safety of MYL‐1501D vs insulin glargine in patients with type 1 diabetes after 52 weeks: Results of the INSTRIDE 1 phase III study.” Diabetes, Obesity and Metabolism20.8 (2018): 1944-1950.
- Hollander, Priscilla A., et al. “Efficacy and safety of MK‐1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: A randomized, open‐label clinical trial.” Diabetes, Obesity and Metabolism20.9 (2018): 2229-2237.
- Home, Philip D., et al. “Efficacy and safety of MK‐1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: A randomized, open‐label clinical trial.” Diabetes, Obesity and Metabolism20.9 (2018): 2220-2228.
- Yamada, Tomohide, et al. “Biosimilar Versus Originator Insulins: Systematic review and meta‐analysis.” Diabetes, Obesity and Metabolism(2018).