Skip to main content
SpringerLink
Log in

Insulin Degludec and Insulin Degludec/Insulin Aspart: A Review of Their Use in the Management of Diabetes Mellitus

  • Adis Drug Evaluation
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Insulin degludec (Tresiba®) is an ultra-long-acting insulin analogue that is also available as a coformulation with rapid-acting insulin aspart (insulin degludec/insulin aspart) [Ryzodeg®]. Insulin degludec has a flat, stable glucose-lowering profile with a duration of action of >42 h, and less within-patient day-to-day variability in glucose-lowering effect than the long-acting insulin analogue insulin glargine. In clinical trials, insulin degludec achieved similar glycaemic control to that seen with insulin glargine in patients with type 1 or 2 diabetes, but with a lower risk of nocturnal hypoglycaemia. In addition, trials examining a flexible dosing regimen of insulin degludec in patients with type 1 or 2 diabetes show the potential for adjusting the injection time, without compromising glycaemic control or safety. A 200 U/mL formulation of insulin degludec is also available for use in patients who require large volumes of basal insulin. Insulin degludec/insulin aspart was noninferior to the long-acting insulin analogue insulin detemir in patients with type 1 diabetes and has the potential to reduce the number of daily injections. Trial results also indicate that insulin degludec/insulin aspart may be an appropriate option for initiating insulin therapy in patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs. Subcutaneous insulin degludec was generally well tolerated in patients with type 1 or 2 diabetes. In conclusion, insulin degludec and insulin degludec/insulin aspart represent a useful advance in the treatment of type 1 or 2 diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32(1):187–92.

    Article  PubMed  Google Scholar 

  2. American Diabetes Association. Standard of medical care in diabetes: 2013. Diabetes Care. 2013;36(Suppl 1):S11–66.

    Article  Google Scholar 

  3. Heise T, Pieber TR. Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies. Diabetes Obes Metab. 2007;9(5):648–59.

    Article  PubMed  CAS  Google Scholar 

  4. Arnolds S, Kuglin B, Kapitza C, et al. How pharmacokinetic and pharmacodynamic principles pave the way for optimal basal insulin therapy in type 2 diabetes. Int J Clin Pract. 2010;64(10):1415–24.

    Article  PubMed  CAS  Google Scholar 

  5. Peterson GE. Intermediate and long-acting insulins: a review of NPH insulin, insulin glargine and insulin detemir. Curr Med Res Opin. 2006;22(12):2613–9.

    Article  PubMed  CAS  Google Scholar 

  6. Ashwell SG, Gebbie J, Home PD. Twice-daily compared with once-daily insulin glargine in people with type 1 diabetes using meal-time insulin aspart. Diabet Med. 2006;23(8):879–86.

    Article  PubMed  CAS  Google Scholar 

  7. European Medicines Agency. Tresiba (insulin degludec): EU summary of product characteristics. 2013. http://www.emea.europa.eu/ema/. Accessed 1 Feb 2013.

  8. European Medicines Agency. Ryzodeg (insulin degludec/insulin aspart): EU summary of product characteristics. 2013. http://www.emea.europa.eu/ema/. Accessed 1 Feb 2013.

  9. Jonassen IB, Havelund S, Ribel U, et al. Insulin degludec is a new-generation ultra-long acting basal insulin with a unique mechanism of protraction based on multi-hexamer formation [abstract no. 39-OR]. 70th Annual Scientific Sessions of the American Diabetes Association; Orlando, FL; 25–29 June 2010.

  10. Kurtzhals P, Heise T, Strauss HM, et al. Multi-hexamer formation is the underlying basis for the ultra-long glucose-lowering effect of insulin degludec [abstract no. 1049]. Diabetologia. 2011;54(Suppl 1):S426.

    Google Scholar 

  11. Seested T, Havelund S, Jonassen IB, et al. Ultrastructural visualisation of insulin degludec multi-hexamers in the subcutaneous depot in vivo supports a unique mechanism of protraction [abstract no. 980-P]. Diabetes. 2012;61(Suppl 1):A250.

    Google Scholar 

  12. Jonassen I, Hoeg-Jensen T, Havelund S, et al. Ultra-long acting insulin degludec can be combined with rapid-acting insulin aspart in a soluble co-formulation [abstract no 380]. J Pept Sci. 2010;16(Suppl 1):32.

    Google Scholar 

  13. Nishimura E, Sørensen AR, Hansen BF, et al. Insulin degludec: a new ultra-long, basal insulin designed to maintain full metabolic effect while minimizing mitogenic potential [abstract no. 974]. Diabetologia. 2010;53(Suppl 1):S388–9.

    Google Scholar 

  14. Nosek L, Coester H-V, Thomsen HF, et al. Glucose-lowering effect of insulin degludec is independent of subcutaneous injection region [abstract no. 899-P]. Diabetes. 2012;61(Suppl 1):A228.

    Google Scholar 

  15. Korsatko S, Deller S, Zahiragic S, et al. Ultra-long-acting insulin degludec: two different formulations (U100 and U200) are bioequivalent and show similar pharmacodynamics [abstract no. 2349-PO]. Diabetes. 2011;60 Suppl:A624.

    Google Scholar 

  16. Hövelmann U, Heise T, Nosek L, et al. Insulin degludec 200 U/ml is ultra-long-acting and has a flat and stable glucose-lowering effect [abstract no. 912]. Diabetologia. 2012;55(Suppl 1):S374–5.

    Google Scholar 

  17. Heise T, Nosek L, Bøttcher SG, et al. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab. 2012;14(10):944–50.

    Article  PubMed  CAS  Google Scholar 

  18. Nasrallah SN, Reynolds LR. Insulin degludec, the new generation basal insulin or just another basal insulin? Clin Med Insights Endocrinol Diabetes. 2012;5:31–7.

    Article  PubMed  CAS  Google Scholar 

  19. Steensgaard DB, Schluckebier G, Strauss HM, et al. Ligand-controlled assembly of hexamers, dihexamers, and linear multihexamer structures by the engineered acylated insulin degludec. Biochemistry (Moscow). 2013;52(2):295–309.

    Article  CAS  Google Scholar 

  20. Jonassen I, Havelund S, Hoeg-Jensen T, et al. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29(8):2104–14.

    Article  PubMed  CAS  Google Scholar 

  21. Robinson JD, Neumiller JJ, Campbell RK. Can a new ultra-long acting insulin analog improve patient care? Investigating the potential role of insulin degludec. Drugs. 2012;72(18):2319–25.

    Article  PubMed  CAS  Google Scholar 

  22. Hirsch IB, Bode B, Courreges J-P, et al. Insulin degludec/insulin aspart administered once daily at any meal, with insulin aspart at other meals versus a standard basal-bolus regimen in patients with type 1 diabetes: a 26-week, phase 3, randomized, open-label, treat-to-target trial. Diabetes Care. 2012;35(11):2174–81.

    Article  PubMed  CAS  Google Scholar 

  23. European Medicines Agency. Insulin degludec/insulin aspart: CHMP assessment report. 2013. http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002499/WC500139013.pdf. Accessed 28 Feb 2013.

  24. Heise T, Hermanski L, Nosek L, et al. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab. 2012;14(9):859–64.

    Article  PubMed  CAS  Google Scholar 

  25. Reynolds NA, Wagstaff AJ. Insulin aspart: a review of its use in the management of type 1 or 2 diabetes mellitus. Drugs. 2004;64(17):1957–74.

    Article  PubMed  CAS  Google Scholar 

  26. Heise T, Hövelmann U, Nosek L, et al. Insulin degludec: two-fold longer half-life and a more consistent pharmacokinetic profile than insulin glargine [abstract no. 1046]. Diabetologia. 2011;54(Suppl 1):S425.

    Google Scholar 

  27. Haahr HL, Arold G, Bottcher SG, et al. Insulin degludec has similar pharmacokinetic properties in subjects with renal impairment and subjects with normal renal function [abstract no. 923]. Diabetologia. 2012;55(Suppl 1):S379.

    Google Scholar 

  28. Arold G, Kupčová V, Thrane M, et al. Insulin degludec has similar pharmacokinetic properties in subjects with hepatic impairment when compared to subjects with normal hepatic function [abstract no. 1119-P]. Diabetes. 2012;61 Suppl:A289.

    Google Scholar 

  29. Danne T, Biester T, Blaesig S, et al. Ultra-long pharmacokinetic properties of insulin degludec in adults with type 1 diabetes is preserved in children and adolescents after single-dose administration [abstract no. 1047]. Diabetologia. 2011;54(Suppl 1):S425–6.

    Google Scholar 

  30. Korsatko S, Deller S, Mader J, et al. Ultra-long pharmacokinetic properties of insulin degludec in younger adults are preserved in geriatric subjects with type 1 diabetes [abstract no. 924]. Diabetologia. 2012;55(Suppl 1):S379–80.

    Google Scholar 

  31. Hompesch M, Morrow L, Watkins E, et al. Insulin degludec provides similar pharmacokinetic and pharmacodynamic responses in Black, White and Hispanic/Latino patients with type 2 diabetes [abstract no. 925]. Diabetologia. 2012;55(Suppl 1):S380.

    Google Scholar 

  32. European Medicines Agency. Insulin degludec: CHMP assessment report. 2013. http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002498/WC500139010.pdf. Accessed 28 Feb 2013.

  33. Bergenstal R, Bhargava A, Jain R, et al. 200 U/mL insulin degludec improves glycemic control similar to insulin glargine with a low risk of hypoglycemia in insulin-naïve people with type 2 diabetes [abstract no. 207]. American Association of Clinical Endocrinologists 21st Annual Scientific and Clinical Congress; Philadelphia, PA; 23–27 May 2012.

  34. Birkeland KI, Home PD, Wendisch U, et al. Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine. Diabetes Care. 2011;34(3):661–5.

    Article  PubMed  Google Scholar 

  35. Zinman B, Fulcher G, Rao PV, et al. Insulin degludec, an ultra-long-acting basal insulin, once a day or three times a week versus insulin glargine once a day in patients with type 2 diabetes: a 16-week, randomised, open-label, phase 2 trial. Lancet. 2011;377(9769):924–31.

    Article  PubMed  CAS  Google Scholar 

  36. 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(9825):1489–97.

    Article  PubMed  CAS  Google Scholar 

  37. 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(3):1154–62.

    Article  PubMed  CAS  Google Scholar 

  38. Onishi Y, Park SW, Yoo SJ, et al. Insulin degludec improves glycemic control in insulin-naïve patients with type 2 diabetes: results of a randomized pan-Asian trial [abstract no. 1059-P]. Diabetes. 2012;61(Suppl 1):A272.

    Google Scholar 

  39. 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(12):2464–71.

    Article  PubMed  CAS  Google Scholar 

  40. 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(9825):1498–507.

    Article  PubMed  CAS  Google Scholar 

  41. Philis-Tsimikas A, Del Prato S, Satman I, et al. Insulin degludec is superior to sitagliptin in improving glycaemic control in uncontrolled patients with type 2 diabetes on oral agents [abstract no. 40]. Diabetologia. 2012;55(Suppl 1):S22.

    Google Scholar 

  42. 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(4):858–64.

    Article  PubMed  Google Scholar 

  43. Rodbard HW, Handelsman Y, Cariou B, et al. Insulin degludec reduces hypoglycemia and improves health status vs. insulin glargine in insulin-naïve type 2 diabetes [abstract no. 1192-P]. Diabetes. 2012;61(Suppl 1):A307–8.

    Google Scholar 

  44. Rodbard HW, Zinman B, Cariou B, et al. Reduced nocturnal hypoglycaemia with insulin degludec as compared to insulin glargine: results of a 2-year randomised trial in type 2 diabetes [abstract no. 920]. Diabetologia. 2012;55(Suppl 1):S378.

    Google Scholar 

  45. Novo Nordisk. Comparison of NN1250 with sitagliptin in subjects with type 2 diabetes never treated with insulin [ClinicalTrials.gov identifier NCT01046110]. US National Institutes of Health, ClinicalTrials.gov (online). 2011. http://www.clinicaltrials.gov. Accessed 13 Nov 2012.

  46. Novo Nordisk. Comparison of NN1250 versus insulin glargine in subjects with type 2 diabetes (BEGIN™) [ClinicalTrials.gov identifier NCT01059799]. US National Institutes of Health, ClinicalTrials.gov (online). 2011. http://www.clinicaltrials.gov. Accessed 13 Nov 2012.

  47. Novo Nordisk. Comparison of NN1250 with insulin glargine in subjects with type 2 diabetes (BEGIN™) [ClinicalTrials.gov identifier NCT01068665]. US National Institutes of Health, ClinicalTrials.gov (online). 2011. http://www.clinicaltrials.gov. Accessed 15 Nov 2012.

  48. Freemantle N, Meneghini L, Christensen T, et al. Insulin degludec improves health-related quality of life (SF-36®) compared with insulin glargine in people with type 2 diabetes starting on basal insulin: a meta-analysis of phase 3a trials. Diabet Med. 2013;30(2):226–32.

    Article  PubMed  CAS  Google Scholar 

  49. Heise T, Tack CJ, Cuddihy R, et al. A new-generation ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naïve people with type 2 diabetes: a randomized, controlled trial. Diabetes Care. 2011;34(3):669–74.

    Article  PubMed  CAS  Google Scholar 

  50. Nakamura S, Ono Y, Rabøl R, et al. Superior glycaemic control with once-daily IDegAsp vs insulin glargine in Japanese adults with type 2 diabetes mellitus inadequately controlled with OADs: a randomised controlled, phase 3 trial [abstract no. 949]. Diabetologia. 2012;55(Suppl 1):S390.

    Google Scholar 

  51. Niskanen L, Leiter LA, Franek E, et al. Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes: a randomised trial. Eur J Endocrinol. 2012;167(2):287–94.

    PubMed  CAS  Google Scholar 

  52. Novo Nordisk. Comparison of NN5401 with insulin glargine in insulin naive subjects with type 2 diabetes (BOOST™) [ClinicalTrials.gov identifier NCT01272193]. US National Institutes of Health, ClinicalTrials.gov (online). 2012. http://www.clinicaltrials.gov. Accessed 15 Nov 2012.

  53. US Food and Drug Administration. FDA briefing document: NDA 203313 and NDA 203314 (insulin degludec and insulin degludec/insulin aspart. 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM327015.pdf. Accessed 28 Feb 2013.

  54. Ratner R, Gough SCL, Mathieu C, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab. 2013;15(2):175–84.

    Article  PubMed  CAS  Google Scholar 

  55. Muggeo M, Verlato G, Bonora E, et al. Long-term instability of fasting plasma glucose, a novel predictor of cardiovascular mortality in elderly patients with non-insulin-dependent diabetes mellitus: the Verona Diabetes Study. Circulation. 1997;96(6):1750–4.

    Article  PubMed  CAS  Google Scholar 

  56. European Medicine Agency. Lantus (insulin glargine): EU summary of product characteristics. 2012. http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000284/WC500036082.pdf. Accessed 15 Mar 2013.

  57. Wakil A, Atkin SL. Efficacy and safety of ultra-long-acting insulin degludec. Ther Adv Endocrinol Metab. 2012;3(2):55–9.

    Article  PubMed  CAS  Google Scholar 

  58. American Diabetes Association Workgroup on Hypoglycemia. Defining and reporting hypoglycaemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5):1245–9.

    Article  Google Scholar 

  59. European Medicine Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Accessed 4 Apr 2013.

  60. Tahrani AA, Bailey CJ, Barnett AH. Insulin degludec: a new ultra-longacting insulin. Lancet. 2012;379(9825):1465–7.

    Article  PubMed  Google Scholar 

  61. Keating GM. Insulin detemir: a review of its use in the management of diabetes mellitus. Drugs. 2012;72(17):2255–87.

    Article  PubMed  CAS  Google Scholar 

  62. Novo Nordisk. Novo Nordisk receives complete response letter in the US for Tresiba® and Ryzodeg® (media release). 2013. http://www.novonordisk.com/include/asp/exe_news_attachment.asp?sAttachmentGUID=83700060-0ce3-4577-a35a-f3e57801637d. Accessed 7 Mar 2013.

  63. Pharmaceuticals and Medical Devices Agency. Insulin degludec submission file. 2013. http://www.pmda.go.jp/index.html. Accessed 5 Apr 2013.

  64. Novo Nordisk. Tresiba® now ready to be launched in Japan (media release). 2013. http://novonordisk.com/investors/sea/sea.asp?sNewsTypeGUID=&lMonth=&lYear=&sLanguageCode=&sSearchText=&fb=4350&cat=pr&sShowNewsItemGUID=33a77fce-8192-47d1-a360-68275268a048&sShowLanguageCode=en-GB. Accessed 4 Apr 2013.

  65. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33(7):1674–85.

    Article  PubMed  Google Scholar 

  66. Dejgaard A, Lynggaard H, Råstam J, et al. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia. 2009;52(12):2507–12.

    Article  PubMed  CAS  Google Scholar 

  67. Evans M, Schumm-Draeger PM, Vora J, et al. A review of modern insulin analogue pharmacokinetic and pharmacodynamic profiles in type 2 diabetes: improvements and limitations. Diabetes Obes Metab. 2011;13(8):677–84.

    Article  PubMed  CAS  Google Scholar 

  68. Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–28.

    Article  PubMed  CAS  Google Scholar 

  69. Wang F, Surh J, Kaur M. Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review. Diabetes Metab Syndr Obes. 2012;5:191–204.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand

    Gillian M. Keating

Authors
  1. Gillian M. Keating
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gillian M. Keating.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keating, G.M. Insulin Degludec and Insulin Degludec/Insulin Aspart: A Review of Their Use in the Management of Diabetes Mellitus. Drugs 73, 575–593 (2013). https://doi.org/10.1007/s40265-013-0051-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-013-0051-1

Keywords

Search

Navigation