Patient Care

Concentrated Insulins: A Review and Recommendations

Fed Pract. 2017 October;34(suppl 8):S38-S42

References

1. Humalog [package insert]. Indianapolis, IN: Eli Lilly & Co; 2015.

2. de la Peña A, Seger M, Soon D, et al. Bioequivalence and comparative pharmacodynamics of insulin lispro 200 U/mL relative to insulin lispro (Humalog®) 100 U/mL. Clin Pharmacol Drug Dev. 2016;5(1):69-75.

3. VA Pharmacy Benefits Management Services, Medical Advisory Panel, VISN Phar macist Executives. Insulin Lispro 200units/mL (Humalog) KwikPen abbreviated review. https://www.pbm.va.gov/PBM/clinicalguidance/abbreviatedre views/Insu lin_Lispro_200units_per_mL_Abbreviated_Review.pdf. Published February 2016. Accessed August 22, 2017.

4. Painter NA, Sisson E. An overview of concentrated insulin products. Diabetes Spectr. 2016;29(3):136-140.

5. Korsatko S, Deller S, Koehler G, et al. A comparison of the steady-state pharmacokinetic and pharmacodynamic profiles of 100 and 200 U/mL formulations of ultra-long-acting insulin degludec. Clin Drug Investig. 2013;33(7):515-521.

6. Goldman-Levine JD, Patel DK, Schnee DM. Insulin degludec: a novel basal insulin analogue. Ann Pharmacother. 2013;47(2):269-277.

7. Meneghini L, Atkin SL, Gouch SC, et al; NN1250-3668 (BEGIN FLEX) Trial Investigators. 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 individuals with type 2 diabetes. Diabetes Care. 2013;36(4):858-864.

8. Rendell M. United States experience of insulin degludec alone or in combination for type 1 and type 2 diabetes. Drug Des Dev Ther. 2017;11:1209-1220.

9. Zinman B, Philis-Tsimikas A, Caropi B, et al; NN1250-3579 (BEGIN Once Long) Trial Investigators. 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(12):2464-2471.

10. Garber AJ, King AB, Del Prato S, et al; NN1250-3582 (BEGIN BB T2D) Trial Investigators. 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(9825):1498-1507.

11. Heller S, Buse J, Fisher M, et al; BEGIN Basal-Bolus Type 1 Trial Investigators. 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(9825):1489-1497.

12. Ratner RE, Gough SC, Mathieu C, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab. 2013;15(2):175-184.

13. Marso SP, McGuire DK, Zinman B, et al; DEVOTE Study Group. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377(8):723-732.

14. Lane W, Bailey TS, Gerety G, et al; Group Information; SWITCH 1. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes: the SWITCH 1 randomized clinical trial. JAMA. 2017;318(1):33-44.

15. Wysham C, Bhargava A, Chaykin L, et al. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 randomized clinical trial. JAMA. 2017;318(1):45-56.

16. Weatherall J, Bludek L, Buchs S. Budget impact of treating commercially insured type 1 and type 2 diabetes patients in the United States with insulin degludec compared to insulin glargine. Curr Med Res Opin. 2017;33(2):231-238.

17. Mezquita-Raya P, Darbà J, Ascanio M, Ramírez de Arellano A. Cost-effectiveness analysis of insulin degludec compared with insulin glargine u100 for the management of type 1 and type 2 diabetes mellitus—from the Spanish National Health System perspective. Expert Rev Pharmacoecon Outcomes Res. 2017:1-9. [Epub ahead of print.]

18. Landstedt-Hallin L, Gundgaard J, Ericsson Å, Ellfors-Zetterlund S. Cost-effectiveness of switching to insulin degludec from other basal insulins: evidence from Swedish real-world data. Curr Med Res Opin. 2017;33(4):647-655.

19. Pollock RF, Tikkanen CK. A short-term cost-utility analysis of insulin degludec versus insulin glargine U100 in patients with type 1 or type 2 diabetes in Denmark. J Med Econ. 2017;20(3):213-220.

20. Becker RH, Dahmen R, Bergmann K, Lehmann A, Jax T, Heise T. New insulin glargine 300 units · mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 units · mL-1. Diabetes Care. 2015;38(4):637-643.

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

22. Riddle MC, Bolli GB, Ziemen M, Muehlen-Bartmer I, Bizet F, Home PD; EDITION 1 Study Investigators. 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(10):2755-2762.

23. Yki-Järvinen H, Bergenstal R, Ziemen M, et al; EDITION 2 Study Investigators. 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(12):3235-3243.

24. Bolli GB, Riddle MC, Bergenstal RM, et al; on behalf of the EDITION 3 Study Investigators. 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(4):386-394.

25. 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(12):2217-2225.

26. Monero S, Delgado M, Rubio M, Gasche D, Fournier M. Cost-utility evaluation of insulin glargine 300 (GLA-300) versus insulin glargine 100 (GLA-100) in patients with type 2 diabetes mellitus (T2DM). Poster presented at: International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 19th Annual European Congress; October 29-November 2, 2016; Vienna, Austria.

27. 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(9):859-867.

28. Eby EL, Wang P, Curtis BH, et al. Cost, healthcare resource utilization, and adherence of individuals with diabetes using U-500 or U-100 insulin: a retrospective database analysis. J Med Econ. 2013;16(4):529-538.

29. Lilly USA. Pharmacy tips about Humulin R U-500 KwikPen syringe and vial. http://www.humulin.com/pharmacy-tips.aspx#about-the-u500-syringe_and_vial. Accessed August 22, 2017.

30. Meneghini, L. New insulin preparations: a primer for the clinician. Cleve Clin J Med. 2016;83(5 suppl 1):S27-S33.

31. Humulin R U-500 KwikPen [package insert]. Indianapolis, IN: Eli Lilly & Co; 2016.

32. 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. Diabetes Care. 2011;34(12):2496-2501.

33. 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. [Correction: Endocr Pract. 2016;22(7):905]

34. 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.

35. 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 U500 insulin in severely insulin-resistant patients with type 2 diabetes. Endocr Pract. 2016;22(6):653-665.

36. Kabul S, Hood RC, Duan R, DeLozier AM, Settles J. Patient-reported outcomes in transition from high-dose U-100 insulin to human regular U-500 insulin in severely insulin-resistant patients with type 2 diabetes: analysis of a randomized clinical trial. Health Qual Life Outcomes. 2016;14(1):139.

37. Hirsch IB. Lipodystrophy: metabolic and clinical aspects. https://www.endo crine.org/~/media/endosociety/files/education/lypodystrophy-files/hirsch_tdeg-2013_lrc_final.pdf?la=en. Accessed September 7, 2017.

Economic Analysis

Weatherall and colleagues used a budget impact model to evaluate the costs of degludec and glargine for commercially insured patients with DM in the U.S.¹⁶ Three treatment groups were analyzed: basal/bolus combination in T1DM and T2DM, and basal/oral combination in T2DM. Although degludec cost more, overall cost was reduced in T1DM because of reduced insulin usage and fewer hypoglycemic episodes in T2DM with basal/oral combination therapy. The authors acknowledged the many assumptions needed and the potential oversimplification of their model.¹⁶ In other countries, economic analyses had similar findings.^17-19

Dosing

Degludec converts 1:1 to other basal insulins. Recommended starting doses for U-200 degludec are 10 U once daily for insulin-naïve adults with T2DM and one-third to one-half the total weight-based daily insulin dose for insulin-naïve adults with T1DM.⁴

Recommendations

For some patients, lower PD variability may make degludec a desirable alternative. As degludec retains its efficacy with variable dosing times, it may be ideal for patients who have difficulty with a once-daily dosing schedule. It is important to inform patients that the degludec pen allows for 2-U increments. Given the lower frequency of nocturnal hypoglycemic events with degludec compared with glargine, degludec is an appropriate basal insulin option for patients with nocturnal hypoglycemia. In addition, U-200 degludec may be considered for DM patients who require high doses of basal insulin and who may benefit from smaller volumes of degludec.

U-300 Isulin Glargine

Pharmacokinetics/Pharmacodynamics

U-300 glargine is a concentrated basal insulin. There are notable differences between its U-100 and U-300 concentrations. For U-300 glargine dosed at 0.4 U/kg, duration of action is 24 hours; for U-300 glargine dosed at 0.6 U/kg or higher, longer duration is expected.²⁰ Steady state is reached after 5 days.²¹ The U-300 glargine pen contains 1.5 mL, less than the 3 mL in the U-100 pen. U-300 glargine typically is administered in 1 injection once daily if the dose is < 80 U; 2 injections are required if the dose is > 80 U.

Safety/Efficacy

In the EDITION trials, which compared U-300 and U-100 glargine in patients with T1DM and T2DM, the primary endpoint was 6-month HbA_1c reduction.^22-24 Comparable HbA_1c reductions were found in all of the studies. In EDITION 1, in which 2,474 patients with T2DM were taking concomitant bolus insulin with or without metformin, 11% more U-300 glargine than U-100 glargine was needed to achieve similar results.²² In EDITION 4, in which bolus insulin was used in combination in 546 patients with T1DM, 17.5% more U-300 glargine than U-100 glargine was needed to achieve similar glycemic goals.²⁵

Economic Analysis

Compared with other insulins, U-300 glargine has limited published data and economic analyses. Using a cost-utility model to compare U-300 with U-100 glargine in Spanish patients with T2DM, and reporting results in euros per quality-adjusted life years, Monero and colleagues concluded that the hypoglycemia reduction and possible time-of-dose flexibility found with U-300 glargine may contribute to its cost-effectiveness.²⁶

Dosing

U-300 glargine should be converted in a 1:1 ratio from U-100 glargine or detemir. The U-300 glargine dose should be reduced by 20% when switching from NPH insulin.²¹

Recommendations

A meta-analysis of the EDITION trials 1 to 3 revealed a lower incidence of daytime and nocturnal hypoglycemia with use of U-300 glargine over U-100 glargine and a beneficial shorter hold time after injection of U-300 glargine (5 seconds) compared with U-100 glargine (10 seconds).²⁷ There was statistically lower weight gain with U-300 glargine compared with U-100 glargine however weight gain was < 1 kg in both groups.²⁷ These characteristics of U-300 glargine may prove advantageous for individual patients.

U-500 Insulin

Pharmacokinetics/Pharmacodynamics

U-500 insulin (Humulin R) has been available in a vial since 1997, but other formulations have been used therapeutically since 1952.²⁸ The U-500 KwikPen device, recently added to the market, has improved the vial and syringe dosing. The new U-500 BD (Becton, Dickinson, Franklin Lakes, NJ) syringes allow doses up to 250 U, and the U-500 KwikPens provide up to 300 U per injection.²⁹ When it was first introduced, U-500 insulin had no dedicated delivery device and dose conversion was required to deliver the appropriate dose using an allergy or TB syringe. As a consequence, confusion often resulted between prescribers, pharmacists and patients.^30,31 U-500 insulin acts as basal and bolus insulins do. Onset of action is ~15 minutes, time to peak is 4 to 8 hours, and duration of action is ≤ 21 hours.³² As its onset of action is similar to that of U-100, U-500 should be injected 30 minutes before meals.

A single-site, randomized, double-blind, crossover euglycemic clamp study that compared equivalent doses of U-500 and U-100 in healthy obese patients found the formulations had similar overall exposures and effects—the only differences were that U-500 had an extended time to peak and a prolonged post-peak effect. The longer post-peak effect contributes to longer duration of action and allows for fewer daily injections.³³