A Clinical Review of Concentrated Insulins for Type 1 and Type 2 Diabetes Mellitus
Main Article Content
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: 21 dec. 2024.
Keywords
insulin glargine U-300; insulin degludec; insulin U-500; concentrated insulin; type 1 diabetes; type 2 diabetes; diabetes mellitus
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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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.
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.