Patient Care

Concentrated Insulins: A Review and Recommendations

For diabetes mellitus patients who require higher doses of insulin, pen-delivered concentrated insulins offer smaller volumes and potentially a lower risk of dosing errors.

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

Author(s):

Jasmine D. Gonzalvo, PharmD, BCPS, BC-ADM, CDE, LDE

Dhiren K. Patel, PharmD, CDE, BC-ADM, BCACP

Jacqueline L. Olin, MS, PharmD, BCPS, CDE

PDF Download

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.

For a long time, 500 U/mL (U-500) insulin was the only concentrated insulin available on the market. With many diabetes mellitus (DM) patients requiring larger doses, additional 200 U/mL (U-200) and 300 U/mL (U-300) concentrations became available. As clinical guidelines lack specific recommendations for optimal use of U-200 and U-300 insulins, clinical discretion is warranted in identifying patients for whom use of these insulins is appropriate. U-500 insulin is recommended in cases that require ≥ 200 U/d or > 2 U/kg/d. Given the ongoing DM and obesity epidemics, increased use of concentrated insulins is likely. Clinicians must stay well informed about the characteristics and benefits of concentrated insulins to remain confident recommending, prescribing, and adjusting these medications.

U-200 Insulin Lispro

Pharmacokinetics/Pharmacodynamics

The amino acid structure of U-200 insulin lispro is different from that of endogenous insulin. In U-200 lispro, lysine replaces a proline at position B28, and proline replaces a lysine at position B29.

U-200 lispro is a bolus insulin with pharmacokinetics (PK) and pharmacodynamics (PD) similar to those of U-100 lispro: onset of action, ~15 minutes; time to peak, 30 to 90 minutes; and duration of action, 4 to 5 hours. U-200 lispro should be administered either 15 minutes before a meal or immediately after a meal.¹

In a euglycemic clamp study of patients without DM, a 20-U dose of U-200 lispro and a single 20-U dose of U-100 lispro were found to have similar mean area under the glucose infusion rate curves, mean area under the serum insulin concentration-time curves from time 0 to infinity, mean peak serum insulin levels, and time to maximum glucose-lowering effects.¹ For both U-200 lispro and U-100 lispro, time to maximum effect was 1 hour.²

Even numbers are marked on the dial of the pen. Odd numbers are not marked, but longer lines appear in their place. U-200 lispro should not be mixed with any other insulin, whereas U-100 lispro can be mixed with neutral protamine Hagedorn insulin.

Safety/Efficacy

There has been 1 bioequivalence study of euglycemic patients without type 2 DM (T2DM) but no studies of the safety or efficacy of U-200 lispro in patients with DM.^3,4 U-100 lispro converts 1:1 to U-200 lispro (eg, 60 U of U-100 lispro converts to 60 U of U-200 lispro).¹ The volume of U-200 lispro would be smaller than that of U-100 lispro.

Economic Analysis

There are no published U-200 lispro economic analyses.

Dosing

U-200 lispro should be converted from other bolus insulins in a 1:1 ratio.¹

Recommendations

Definitive recommendations await efficacy trials comparing use of U-200 lispro and other bolus insulins in patients with DM. Currently, U-200 lispro may be considered for patients with DM who require high doses of bolus insulin and who may benefit from smaller volumes of lispro.

U-200 Insulin Degludec

Pharmacokinetics/Pharmacodynamics

The basal insulin degludec (Tresiba) is available in U-100 and U-200 concentrations in a pen. After subcutaneous injection, degludec forms gradually dissociating multihexamer chains, which account for its flat and stable PK/PD profile. U-100 degludec and U-200 degludec have similar duration of action (≥ 42 hours) and time to steady state (2-3 days).^5,6 A patient who misses a regularly scheduled dose should allow at least 8 hours between injections. Taking degludec at variable times does not decrease efficacy as long as this 8-hour minimum interval is observed.⁷

Safety/Efficacy

During its development, degludec was evaluated in more than 5,000 patients across 11 therapeutic trials.⁸ The key studies that led to the approval of degludec used insulin glargine as a comparator. In a 52-week study of 1,030 insulin-naïve patients with T2DM, degludec was noninferior to glargine in hemoglobin A_1c (HbA_1c) reduction (1.06% vs 1.19%). Overall hypoglycemia rates were similar, though there were fewer nocturnal hypoglycemia episodes with degludec than with glargine (0.25 vs 0.39 per patient-year of exposure; P = .38).⁹

The BEGIN Basal-Bolus trial series evaluated use of degludec combined with bolus insulin aspart in insulin-experienced patients with T2DM (n = 992) and type 1 DM (T1DM) (n = 629) over 52 weeks.^10,11 Both trials found noninferiority in A_1c reduction: 1.1% (degludec) and 1.18% (glargine) in patients with T2DM and 0.4% (degludec) and 0.39% (glargine) in those with T1DM.^10,11 Significantly fewer episodes of overall hypoglycemia (11.09 vs 13.63 per patient-year) and nocturnal hypoglycemia (1.39 vs 1.84 per patient-year) were found with degludec in patients with T2DM.⁵ Overall hypoglycemia rates were similar, though there was a 25% lower rate of nocturnal hypoglycemia with degludec in patients with T1DM.¹¹

A meta-analysis of 7 phase 3a trials that compared degludec with glargine revealed significantly lower rates of overall, nocturnal, and severe hypoglycemia with degludec in insulin-naïve patients.¹² The analysis confirmed findings of significantly lower rates of overall and nocturnal hypoglycemia with degludec in the overall T2DM population and significantly lower rates of nocturnal hypoglycemia in the T1DM population.¹²

In the DEVOTE trial, which included 7,637 T2DM patients at high risk for a cardiovascular event, degludec and glargine were compared on the composite primary outcome of death with a cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke. After a median of 1.99 years, the primary outcome occurred in 8.5% of degludec patients and 9.3% of glargine patients (hazard ratio, 0.91; 95% confidence interval, 0.78-1.06; P < .001 for noninferiority). Mean HbA_1c level was 7.5 in both groups; severe hypoglycemia occurred more often in the glargine group (odds ratio, 0.73; P < .001 for superiority).¹³ Findings from the randomized, crossover SWITCH 1 and SWITCH 2 trials confirmed lower rates of symptomatic hypoglycemia with degludec compared with glargine in patients with T1DM and T2DM, respectively.^14,15 No statistically significant differences in weight gain were observed in the clinical trials comparing degludec and glargine.