Original Research

Clinical Impact of Initiation of U-500 Insulin vs Continuation of U-100 Insulin in Subjects With Diabetes

Fed Pract. 2021 November;38(4):e15 | 10.12788/fp.0105

Author(s):

Alejandro Ramirez, MD

Natalia Weare-Regales, MD

Anthony Domingo, MD

Arnaldo Villafranca, MD

Krystal A. Valdez, MD

C. Marcela Velez, MD, PhD

Philip Foulis, MD, MPH

Joaquin Gomez-Daspet, MD

Background: The prevalence of obesity and diabetes mellitus (DM ) has each increased drastically according to the Centers for Disease Control and Prevention. Growth of severe insulin-resistant DM is predicted. U-500 insulin is highly concentrated and can replace less concentrated formulations in patients that need high insulin dosages. The aim of this study was to compare clinical outcomes of U-500 and U-100 insulin regimens in veterans with obesity and insulin-resistance.

Methods: A single-site retrospective chart analysis of adult subjects was conducted from July 2002 to June 2011. Data for repeated measures spanned a period from 3 months before the intervention (baseline) through 12 months afterward. The main outcome was the variation in hemoglobin A1C (Hb A1C). Other outcomes included incidence of severe hypoglycemia, weight changes, cardiovascular events, and number of injections.

Results: A total of 142 subjects (68 taking U-500 and 74 taking U-100) were included. Baseline characteristics were similar between groups, except for weight, which was higher among U-500 subjects. Mean Hb A1C was reduced by 0.84% and 0.56% in U-500 and U-100, respectively (P = .003). Severe hypoglycemia occurred in 5 subjects in U-500 and 1 in U-100 ( P = .08). No significant difference was noted in the number of CV events. Mean number of daily injections was 2 in the U-500 group, and 4 in the U-100 group (P < .001).

Conclusions: U-500 insulin compared with U-100 insulin regimens led to a statistically significant reduction in Hb A1C and number of insulin injections. Additional research is necessary to assess the risk of severe hypoglycemia in U-500 users. Neither regimen was associated with increased cardiovascular risk.

References

1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among adults and youth: United States, 2015–2016. NCHS data brief no. 288. Published October 2017. Accessed January 29, 2021. https://www.cdc.gov/nchs/products/databriefs/db288.htm

3. Cochran E, Gorden P. Use of U-500 insulin in the treatment of severe insulin resistance. Insulin. 2008;3(4):211-218 [Published correction appears in Insulin. 2009;4(1):81]. doi:10.1016/S1557-0843(08)80049-8

4. Shrestha RT, Kumar AF, Taddese A, et al. Duration and onset of action of high dose U-500 regular insulin in severely insulin resistant subjects with type 2 diabetes. Endocrinol Diabetes Metab. 2018;1(4):e00041. Published 2018 Sep 10. doi:10.1002/edm2.41

5. Dailey AM, Tannock LR. Extreme insulin resistance: indications and approaches to the use of U-500 insulin in type 2 diabetes mellitus. Curr Diab Rep. 2011;11(2):77-82. doi:10.1007/s11892-010-0167-6

6. de la Peña A, Riddle M, Morrow LA, et al. Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects [published correction appears in Diabetes Care. 2014 Aug;37(8):2414]. Diabetes Care. 2011;34(12):2496-2501. doi:10.2337/dc11-0721

7. Brusko C, Jackson JA, de la Peña A. Comparative properties of U-500 and U-100 regular human insulin. Am J Health Syst Pharm. 2013;70(15):1283-1284. doi:10.2146/130117

8. Dailey AM, Williams S, Taneja D, Tannock LR. Clinical efficacy and patient satisfaction with U-500 insulin use. Diabetes Res Clin Pract. 2010;88(3):259-264. doi:10.1016/j.diabres.2010.02.012

9. Wysham C, Hood RC, Warren ML, Wang T, Morwick TM, Jackson JA. Effect of total daily dose on efficacy, dosing, and safety of 2 dose titration regimens of human regular U-500 insulin in severely insulin-resistant patients with type 2 diabetes. Endocr Pract. 2010;22(6):653-665. doi:10.4158/EP15959.OR

10. Gagnon-Auger M, du Souich P, Baillargeon JP, et al. Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study. Diabetes Care. 2010;33(12):2502-2507. doi:10.2337/dc10-1126

11. Schloot NC, Hood RC, Corrigan SM, Panek RL, Heise T. Concentrated insulins in current clinical practice. Diabetes Res Clin Pract. 2019;148:93-101. doi:10.1016/j.diabres.2018.12.007

12. 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. doi:10.4158/EP.15.1.71

13. Boldo A, Comi RJ. Clinical experience with U500 insulin: risks and benefits. Endocr Pract. 2012;18(1):56-61. doi:10.4158/EP11163.OR

14. Granata JA, Nawarskas AD, Resch ND, Vigil JM. Evaluating the effect of u-500 insulin therapy on glycemic control in veterans with type 2 diabetes. Clin Diabetes. 2015;33(1):14-19. doi:10.2337/diaclin.33.1.14

15. Eby EL, Zagar AJ, Wang P, et al. Healthcare costs and adherence associated with human regular U-500 versus high-dose U-100 insulin in patients with diabetes. Endocr Pract. 2014;20(7):663-670. doi:10.4158/EP13407.OR

16. Eby EL, Curtis BH, Gelwicks SC, et al. Initiation of human regular U-500 insulin use is associated with improved glycemic control: a real-world US cohort study. BMJ Open Diabetes Res Care. 2015;3(1):e000074. Published 2015 Apr 30. doi:10.1136/bmjdrc-2014-000074

17. Jones P, Idris I. The use of U-500 regular insulin in the management of patients with obesity and insulin resistance. Diabetes Obes Metab. 2013;15(10):882-887. doi:10.1111/dom.12094

18. Hood RC, Arakaki RF, Wysham C, Li YG, Settles JA, Jackson JA. 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-to-target clinical trial. Endocr Pract. 2015;21(7):782-793. doi: 10.4158/EP15612.OR

19. Ballani P, Tran MT, Navar MD, Davidson MB. Clinical experience with U-500 regular insulin in obese, markedly insulin-resistant type 2 diabetic patients [published correction appears in Diabetes Care. 2007 Feb;30(2):455]. Diabetes Care. 2006;29(11):2504-2505. doi:10.2337/dc06-1478

20. Davidson MB, Navar MD, Echeverry D, Duran P. U-500 regular insulin: clinical experience and pharmacokinetics in obese, severely insulin-resistant type 2 diabetic patients. Diabetes Care. 2010;33(2):281-283. doi:10.2337/dc09-1490

21. Bulchandani DG, Konrady T, Hamburg MS. Clinical efficacy and patient satisfaction with U-500 insulin pump therapy in patients with type 2 diabetes. Endocr Pract. 2007;13(7):721-725. doi:10.4158/EP.13.7.721

22. Lane WS, Weinrib SL, Rappaport JM, Przestrzelski T. A prospective trial of U500 insulin delivered by Omnipod in patients with type 2 diabetes mellitus and severe insulin resistance [published correction appears in Endocr Pract. 2010 Nov-Dec;16(6):1082]. Endocr Pract. 2010;16(5):778-784. doi:10.4158/EP10014.OR

23. Martin C, Perez-Molinar D, Shah M, Billington C. U500 Disposable Patch Insulin Pump: Results and Discussion of a Veterans Affairs Pilot Study. J Endocr Soc. 2018;2(11):1275-1283. Published 2018 Sep 17. doi:10.1210/js.2018-00198

24. Ziesmer AE, Kelly KC, Guerra PA, George KG, Dunn FL. U500 regular insulin use in insulin-resistant type 2 diabetic veteran patients. Endocr Pract. 2012;18(1):34-38. doi:10.4158/EP11043.OR

25. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S61-S70. doi:10.2337/dc19-S006

More than 70% of Americans are overweight or obese and 1 in 10 has type 2 diabetes mellitus (T2DM). In the last 20 years, the prevalence of obesity and DM has each increased drastically according to the Centers for Disease Control and Prevention.^1,2 Thus, an increase in severe insulin-resistant DM is predicted. Severe insulin resistance occurs when insulin doses exceed 200 units per day or 2 units/kg per day.^3-5 Treating this condition demands large volumes of U-100 insulin and a high frequency of injections (usually 4-7 per day), which can lead to reduced patient adherence.^8-10 Likewise, large injected volumes are more painful and can lead to altered absorption.^3,9-11

U-500 insulin (500 units/mL) is 5 times more concentrated than U-100 insulin and has advantages in the management of severe insulin-resistant DM.^11-13 Its pharmacokinetic profile is unique, for the clinical effect can last for up to 24 hours.^4-6 U-500 can replace basal-bolus and other complex insulin regimens, offering convenient, effective glycemic control with 2 or 3 injections per day.^11,14-20 U-500 can also improve the quality of life and adherence compared with formulations that require more frequent injections.^7,14,21 Historically, only exceptional or “special” cases were treated with U-500, but demand for concentrated insulins has increased in the last decade as clinicians adjust their care for this growing patient population.¹⁷

The purpose of this study was to determine whether a population of subjects with severe insulin-resistant T2DM would benefit from the use of U-500 vs U-100 insulin regimens. The hypothesis was that this population would obtain equal or better glycemic control while achieving improved adherence. Other studies have demonstrated that U-500 yields improvements in glycemic control but also potentially increases hypoglycemic episodes.^15-18,22-24 To our knowledge, this study is the first to evaluate the clinical outcomes of subjects with severe insulin-resistant T2DM who changed from U-100 to U-500 vs subjects who remained on high-dose U-100 insulin.

Methods

This was a single-site, retrospective chart review of subjects with T2DM who attended the endocrinology specialty clinic at the James A. Haley Veterans’ Hospital (JAHVA) in Tampa, Florida, between July 2002 and June 2011. The study included a group of subjects using U-500 insulin and a comparison group using U-100 insulin. The study was approved by the JAHVA Research & Development Committee and by the University of South Florida Institutional Review Board.

Inclusion criteria included diagnosis of T2DM, body mass index (BMI) of more than 30, use of U-500 insulin, or > 200 units daily of U-100 insulin. Exclusion criteria included hypoglycemia unawareness, type 1 DM, and use of an insulin pump. A total of 142 subjects met the inclusion criteria (68 in the U-500 group and 74 in the U-100 group).

All study subjects had at least 1 DM education session. U-500 subjects used insulin vials and 1-mL volumetric hypodermal syringes. All U-500 prescriptions were issued electronically in units and volume (U-500 insulin was available exclusively in vials during the time frame from which data were collected). Subjects in the U-100 group used insulin vials or pen devices. Laboratory studies were processed in house by the institution using high-pressure liquid chromatography to determine hemoglobin A_1C (Hb A_1C) levels. All study subjects required at least 2 Hb A_1C measurements over the observed 12 months for inclusion.

Transition to U-500 Insulin

U-500 transition was considered routinely and presented as an option for patients requiring > 200 units of insulin daily. The transition criteria included adherence to medications, follow-up appointments, and glucose monitoring recommendations, and ability to learn and apply insulin self-adjustment instructions. All subjects were given an additional U-500 insulin education session before transition. The endocrinologist calculated all starting doses by reducing the total daily dose by 20%.

References

2. Centers for Disease Control and Prevention. Diabetes and prediabetes: CDC works to prevent type 2 diabetes and improve the health of all people with diabetes. Updated November 30, 2020. Accessed February 17, 2021. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm

3. Cochran E, Gorden P. Use of U-500 insulin in the treatment of severe insulin resistance. Insulin. 2008;3(4):211-218 [Published correction appears in Insulin. 2009;4(1):81]. doi:10.1016/S1557-0843(08)80049-8

4. Shrestha RT, Kumar AF, Taddese A, et al. Duration and onset of action of high dose U-500 regular insulin in severely insulin resistant subjects with type 2 diabetes. Endocrinol Diabetes Metab. 2018;1(4):e00041. Published 2018 Sep 10. doi:10.1002/edm2.41

5. Dailey AM, Tannock LR. Extreme insulin resistance: indications and approaches to the use of U-500 insulin in type 2 diabetes mellitus. Curr Diab Rep. 2011;11(2):77-82. doi:10.1007/s11892-010-0167-6

6. de la Peña A, Riddle M, Morrow LA, et al. Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects [published correction appears in Diabetes Care. 2014 Aug;37(8):2414]. Diabetes Care. 2011;34(12):2496-2501. doi:10.2337/dc11-0721

7. Brusko C, Jackson JA, de la Peña A. Comparative properties of U-500 and U-100 regular human insulin. Am J Health Syst Pharm. 2013;70(15):1283-1284. doi:10.2146/130117

8. Dailey AM, Williams S, Taneja D, Tannock LR. Clinical efficacy and patient satisfaction with U-500 insulin use. Diabetes Res Clin Pract. 2010;88(3):259-264. doi:10.1016/j.diabres.2010.02.012

9. Wysham C, Hood RC, Warren ML, Wang T, Morwick TM, Jackson JA. Effect of total daily dose on efficacy, dosing, and safety of 2 dose titration regimens of human regular U-500 insulin in severely insulin-resistant patients with type 2 diabetes. Endocr Pract. 2010;22(6):653-665. doi:10.4158/EP15959.OR

10. Gagnon-Auger M, du Souich P, Baillargeon JP, et al. Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study. Diabetes Care. 2010;33(12):2502-2507. doi:10.2337/dc10-1126

11. Schloot NC, Hood RC, Corrigan SM, Panek RL, Heise T. Concentrated insulins in current clinical practice. Diabetes Res Clin Pract. 2019;148:93-101. doi:10.1016/j.diabres.2018.12.007

12. 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. doi:10.4158/EP.15.1.71

13. Boldo A, Comi RJ. Clinical experience with U500 insulin: risks and benefits. Endocr Pract. 2012;18(1):56-61. doi:10.4158/EP11163.OR

14. Granata JA, Nawarskas AD, Resch ND, Vigil JM. Evaluating the effect of u-500 insulin therapy on glycemic control in veterans with type 2 diabetes. Clin Diabetes. 2015;33(1):14-19. doi:10.2337/diaclin.33.1.14

15. Eby EL, Zagar AJ, Wang P, et al. Healthcare costs and adherence associated with human regular U-500 versus high-dose U-100 insulin in patients with diabetes. Endocr Pract. 2014;20(7):663-670. doi:10.4158/EP13407.OR

16. Eby EL, Curtis BH, Gelwicks SC, et al. Initiation of human regular U-500 insulin use is associated with improved glycemic control: a real-world US cohort study. BMJ Open Diabetes Res Care. 2015;3(1):e000074. Published 2015 Apr 30. doi:10.1136/bmjdrc-2014-000074

17. Jones P, Idris I. The use of U-500 regular insulin in the management of patients with obesity and insulin resistance. Diabetes Obes Metab. 2013;15(10):882-887. doi:10.1111/dom.12094

18. Hood RC, Arakaki RF, Wysham C, Li YG, Settles JA, Jackson JA. 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-to-target clinical trial. Endocr Pract. 2015;21(7):782-793. doi: 10.4158/EP15612.OR

19. Ballani P, Tran MT, Navar MD, Davidson MB. Clinical experience with U-500 regular insulin in obese, markedly insulin-resistant type 2 diabetic patients [published correction appears in Diabetes Care. 2007 Feb;30(2):455]. Diabetes Care. 2006;29(11):2504-2505. doi:10.2337/dc06-1478

20. Davidson MB, Navar MD, Echeverry D, Duran P. U-500 regular insulin: clinical experience and pharmacokinetics in obese, severely insulin-resistant type 2 diabetic patients. Diabetes Care. 2010;33(2):281-283. doi:10.2337/dc09-1490

21. Bulchandani DG, Konrady T, Hamburg MS. Clinical efficacy and patient satisfaction with U-500 insulin pump therapy in patients with type 2 diabetes. Endocr Pract. 2007;13(7):721-725. doi:10.4158/EP.13.7.721

22. Lane WS, Weinrib SL, Rappaport JM, Przestrzelski T. A prospective trial of U500 insulin delivered by Omnipod in patients with type 2 diabetes mellitus and severe insulin resistance [published correction appears in Endocr Pract. 2010 Nov-Dec;16(6):1082]. Endocr Pract. 2010;16(5):778-784. doi:10.4158/EP10014.OR

23. Martin C, Perez-Molinar D, Shah M, Billington C. U500 Disposable Patch Insulin Pump: Results and Discussion of a Veterans Affairs Pilot Study. J Endocr Soc. 2018;2(11):1275-1283. Published 2018 Sep 17. doi:10.1210/js.2018-00198

24. Ziesmer AE, Kelly KC, Guerra PA, George KG, Dunn FL. U500 regular insulin use in insulin-resistant type 2 diabetic veteran patients. Endocr Pract. 2012;18(1):34-38. doi:10.4158/EP11043.OR

25. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S61-S70. doi:10.2337/dc19-S006

Clinical Impact of Initiation of U-500 Insulin vs Continuation of U-100 Insulin in Subjects With Diabetes

References

Methods

Transition to U-500 Insulin

Pages

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