A Clinical Review of Concentrated Insulins for Type 1 and Type 2 Diabetes Mellitus

Main Article Content

Jennifer N. Clements

Abstract

Insulin therapy is cornerstone treatment for the management of type 1 diabetes mellitus and often, is initiated for patients with type 2 diabetes inadequately controlled with oral antidiabetic medications or with severe hyperglycemia.  Concentrated insulin products are available to address the volume concerns with high doses of insulin U-100 (100 units per milliliter) due to poor or unpredictable absorption.  Humulin R U-500 has been available for 20 years, but have been underutilized in clinical practice due to conversions into a U-100 syringe or tuberculin syringe with the vial.  Now, its use may increase as a pre-filled pen and U-500 syringe has recently become available.  In addition, two additional concentrated insulin were approved in 2015 - insulin glargine U-300 (300 units per milliliter) and insulin degludec U-200 (200 units per milliliter).  These specific products are alternative insulin options for type 1 or type 2 diabetes, especially among patients with high doses of insulin therapy and high risk of hypoglycemia.  Insulin glargine U-300 and insulin degludec U-200 have similar A1c reduction to active comparators, but have a lower risk of hypoglycemia and nocturnal hypoglycemia.  This article evaluates and summarizes the indications, dosing, recent clinical evidence and role of insulin regular U-500, insulin glargine U-300 and insulin degludec U-200 for type 1 and type 2 diabetes mellitus.

Article Details

How to Cite
CLEMENTS, Jennifer N.. A Clinical Review of Concentrated Insulins for Type 1 and Type 2 Diabetes Mellitus. Medical Research Archives, [S.l.], v. 5, n. 2, feb. 2017. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/1029>. Date accessed: 20 sep. 2021.
Keywords
insulin glargine U-300; insulin degludec; insulin U-500; concentrated insulin; type 1 diabetes; type 2 diabetes; diabetes mellitus
Section
Review Articles

References

Pharmacists’ knowledge and skills to provide diabetes services and educate patients about insulin. In: Practice Insights, American Pharmacists Association. Washington, DC; December 2016.

Becker RH, Dahmen R, Bergmann K, et al. New insulin glargine 300 units/mL provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 units/mL. Diabetes Care. 2015;38:637–43.

Becker RH, Nowotny I, Teichert L, et al. Low within- and between-day variability in exposure to new insulin glargine 300 U/ml. Diabetes Obes Metab. 2015;17:261–7.

Biester T, Blaesig S, Remus K, et al. Insulin degludec’s ultra-long pharmacokinetic properties observed in adults are retained in children and adolescents with type 1 diabetes: insulin degludec in children/adolescents. Pediatr Diabetes. 2014;15:27–33.

Bliss M. The Discovery of Insulin. University of Chicago Press; Chicago, IL; 1982.

Bolli GB, Riddle MC, Bergenstal RM et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering
drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab. 2015;17:386-94.

Centers for Disease Control and Prevention (CDC), National Center for Health Statistics, Division of Health Interview Statistics, data from the National Health Interview Survey. Retrived from https://www.cdc.gov/diabetes/statistics/meduse/fig2.htm.

Cochran E, Musso C, Gorden P. The use of U-500 in patients with extreme insulin resistance. Diabetes Care. 2005;28(5):1240-1244.

Cochran E, Gorden P. Use of U-500 insulin in the treatment of severe insulin resistance. Insulin. 2008;3(4):211-218.

DeFronzo RA. Current issues in the treatment of type 2 diabetes. Overview of newer agents: where treatment is going. Am J Med 2010 Mar;123(3 Suppl):S38-48. doi: 10.1016/j.amjmed.2009.12.008.

Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal–Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379:1498–1507. doi: 10.1016/S0140-6736(12)60205-0.

Garg R, Johnston V, McNally PG, et al. U-500 insulin: why, when and how to use in clinical practice. Diabetes Metab Res Rev. 2006;23(4):265-268.

Gough SC, Bhargava A, Jain R, et al. Low-Volume Insulin Degludec 200 Units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naive patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: The BEGIN Low Volume trial. Diabetes Care. 2013;36:2536–2542. doi: 10.2337/dc12-2329.

Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet. 2014;53:787–800.

Heller S, Buse J, Fisher M, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal–Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379:1489–1497. doi: 10.1016/S0140-6736(12)60204-9.

Home PD, Bergenstal RM, Bolli GB et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 1 diabetes: a randomized, Phase 3A, open-label clinical trial (EDITION 4). Diabetes Care. 2015;38:2217-25.

Hood RC, Arakaki RF, Wysham C, et al. Two treatment approaches for human regular U-500 insulin in patients with type 2 diabetes not achieving adequate glycemic control on high-dose U-100 insulin therapy with or without oral agents: A randomized, titration-o-treat clinical trial. Endocr Pract 2015 Jul;21(7):782-93. doi: 10.4158/EP15612.OR. Epub 2015 Mar 26.

Humulin N [package insert]. Indianapolis, IN; Eli Lilly, USA, LLC, 2015.

Humulin R U-500 [package insert]. Indianapolis, IN; Eli Lilly, USA, LLC, 2016.

Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2015;38:140–9.

Korsatko S, Deller S, Mader JK, et al. Ultra-long pharmacokinetic properties of insulin degludec are comparable in elderly subjects and younger adults with type 1 diabetes mellitus. Drugs Aging. 2014;31:47–53.

Lamos EM, YounkLM, Davis SN. Concentrated insulins: the new basal insulins. Ther Clin Risk Manag 2016 Mar 9;12:389-400. doi: 10.2147/TCRM.S99855.

Lane WS, Cochran EK, Jackson JA, et al. High dose insulin therapy: is it time for U-500 insulin? Endocr Pract. 2009;15(1):71-79.

Lantus [package insert]. Bridgewater, NJ; Sanofi-Aventis, Inc., 2015.

Levemir [package insert]. Plainsboro, NJ; Novo Nordisk, Inc., 2015.

Marso SP, McGuire DK, Zinman B, et al. Design of DEVOTE (Trial comparing cardiovascular safety of insulin degludec vs insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events) - DEVOTE 1. Am Heart J 2016 Sep;179:175-83. doi: 10.1016/j.ahj.2016.06.004. Epub 2016 Jun 18.

Mathieu C, Hollander P, Miranda-Palma B, et al. Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol Metab. 2013;98:1154–1162. doi: 10.1210/jc.2012-3249.

Meneghini L, Atkin SL, Gough SC, et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in people with type 2 diabetes. Diabetes Care. 2013;36:858–864. doi: 10.2337/dc12-1668.

Neal JM. Analysis of effectiveness of human U-500 insulin in patients unresponsive to conventional insulin therapy. Endocr Pract. 2005;11(5):305-307.

Novolin N [package insert]. Plainsboro, NJ; Novo Nordisk, Inc., 2016.

Onishi Y, Iwamoto Y, Yoo SJ, Clauson P, Tamer SC, Park S. Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: a 26-week, randomized, controlled, Pan-Asian, treat-to-target trial. J Diabetes Invest. 2013;4:605–612. doi: 10.1111/jdi.12102.

Owens DR. Clinical evidence for the earlier initiation of insulin therapy in type 2 diabetes. Diabetes Technol Ther 2013 Sep;15(9):776-85. doi: 10.1089/dia.2013.0081. Epub 2013 Jun 20.

Philis-Tsimikas A, Del Prato S, Satman I, et al. Effect of insulin degludec versus sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabetic agents. Diabetes Obes Metab. 2013;15:760–766. doi: 10.1111/dom.12115.

Riddle MC, Bolli GB, Zieman M, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose
control and hypoglycemia in a 6-month randomized, controlled trial (EDITION 1). Diabetes Care. 2014;37:2755-62.

Riddle MC, Yki-Jarvinen H, Bolli GB, et al. One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin: the EDITION 1 12-month randomized trial, including 6-month extension. Diabetes Obes Metab. 2015;17:835-42.

Ritzel R, Roussel R, Bolli GB et al. Patient-level meta-analysis of the EDITION 1, 2, and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab. 2015;17:859-67.

Segal AR, Brunner JE, Burch FT, et al. Use of concentrated insulin human regular for patients with diabetes. Am J Health Syst Pharm. 2010;67(18):1526-1535.

Shiramoto M, Eto T, Irie S, et al. Single-dose new insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes. Diabetes Obes Metab. 2015;17:254–60.

Thuillier P, Alavi Z, Kerlan V. (2015). Long-term safety and efficacy of insulin degludec in the management of type 2 diabetes. Diabetes, Metabolic Syndrome and Obesity 2015;8:483–493. http://doi.org/10.2147/DMSO.S54953.

Toujeo [package insert]. Bridgewater, NJ; Sanofi-Aventis, Inc., 2015.

Tresiba [package insert]. Plainsboro, NJ; Novo Nordisk, Inc., 2016.

Vora J, Christensen T, Rana A, Bain SC. Insulin degludec versus insulin glargine in type 1 and type 2 diabetes mellitus: A meta-analysis of endpoints in Phase 3a trials. Diabetes Ther 2014 Dec;5(2):435-46. doi: 10.1007/s13300-014-0076-9. Epub 2014 Aug 1.

Yki-Jarvinen H, Bergenstal R, Ziemen M et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin:
glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care. 2014;37:3235-43.

Yki-Jarvinen H, Vergenstal RM, Bolli GB et al. Glycaemic control and hypoglycaemia with new insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 2
diabetes using basal insulin and oral antihyperglycaemic drugs (EDITION 2 randomized 12-month trial including 6-month extension). Diabetes Obes Metab. 2015; 17:1142-9.

Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long) Diabetes Care. 2012;35:2464–2471. doi: 10.2337/dc12-1205.