Insulin degludec

Insulin degludec
Clinical data
Trade names Tresiba
AHFS/Drugs.com UK Drug Information
Routes of
administration		 Subcutaneous
ATC code A10AE06 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Identifiers
CAS Number 844439-96-9 N
PubChem (SID) 124490467
ChemSpider none
KEGG D09727 N
Chemical and physical data
Formula C274H411N65O81S6
Molar mass 6103.972 g/mol
 NYesY (what is this?)  (verify)

Insulin degludec (INN/USAN) is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba.[1] It is administered via subcutaneous injection once daily to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 42 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir), making it a once-daily basal insulin,[2][3][4] that is one that provides a base insulin level, as opposed to the fast and short acting bolus insulins.

Insulin degludec is a modified insulin that has one single amino acid deleted in comparison to human insulin, and is conjugated to hexadecanedioic acid via gamma-L-glutamyl spacer at the amino acid lysine at position B29.

Side effects

A significant side effect of insulin therapy is hypoglycemia. A meta-analysis of clinical trails published in July 2012 found 39-47.9 events of hypoglycemia (defined as blood glucose <56 mg/dL) per patient year, with higher rates in the more concentrated degludec formulation. Rates of nocturnal hypoglycemia ranged from 3.7-5.1 events per patient year.[5]

Pharmacology

Mechanism of action

Insulin degludec is an ultra-long acting insulin that, unlike insulin glargine, is active at a physiologic pH. The addition of hexadecanedioic acid to lysine at the B29 position allows for the formation of multi-hexamers in subcutaneous tissues.[6] This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation.[7]

Pharmacokinetics

Insulin degludec has an onset of action of 30–90 minutes (similar to insulin glargine and insulin detemir). There is no peak in activity, due to the slow release into systemic circulation. The duration of action of insulin degludec is reported as being longer than 24 hours.[6][5]

Effectiveness profile

Studies have shown that patients taking insulin degludec needed to take significantly smaller doses of basal insulin than those taking insulin glargine U100, while achieving similar blood glucose levels. Insulin degludec also has the ability to be mixed with other insulins, thereby improving glycemic control. This cannot be done using current long-acting insulins.[8][9] A physician involved in the trials was quoted as saying,

"This allows the creation of a novel formulation that retains the smooth control of a long-acting basal with rapid-acting mealtime control from insulin aspart. This 2-component insulin retains the ultralow risk characteristics of degludec with simultaneous mealtime coverage."[10]

History

Insulin degludec has been filed for registration in the United States.[11] Novo Nordisk hopes to begin marketing the insulin analog in 2015 or 2016 after the completion of additional cardiac safety studies requested by the U.S. Food and Drug Administration (FDA) in February 2013.[12] Insulin degludec received FDA approval 25 September 2015[13] and marketing began on 26 January 2016.[14]

Clinical trial data

Type 1 diabetes mellitus

Insulin degludec was studied as an alternative to insulin glargine as part of a basal-bolus regimen in the BEGIN Basal-Bolus Type 1 trial. 629 patients with type 1 diabetes were randomized in a 3:1 ratio to either insulin degludec (n=472) or insulin glargine (n=157) in addition to mealtime insulin aspart. Patients in the degludec treatment arm were switched from their basal insulin to insulin degludec in a 1:1 ratio, with a 20-30% dose reduction in patients receiving multiple basal doses per day. After 52 weeks, patients treated with insulin degludec produced a similar reduction in HbA1c (0.40% vs. 0.39%) meeting the criteria for noninferiority. Adverse events were similar in the two treatment arms; however, rates of nocturnal hypoglycemia (between midnight and 6am) were 27% lower in patients treated with insulin degludec (3.91 vs. 5.22%,p=0.024). The reduction in the incidence of hypoglycemia was seen as a therapeutic benefit, as hypoglycemia is often a dose limiting toxicity in insulin therapy.[15]

Type 2 diabetes mellitus

In the BEGIN Basal-Bolus Type 2 trial, insulin degludec was studied as an alternative to insulin glargine in patients with type 2 diabetes mellitus. 995 patients were randomized to receive either insulin degludec (n=755) or insulin glargine (n=251), in addition to either mealtime insulin aspart, metformin, and/or pioglitazone. Patients in this trial had an average HbA1c of 8.3-8.4%, and 49-50% were on a regimen consisting of basal-bolus insulin + oral antidiabetic medications. After 52 weeks, insulin degludec was found to be noninferior to insulin glargine, providing a similar HbA1c lowering effect (-1.10 vs. -1.18%). Overall rates of hypoglycemia were significantly lower with insulin degludec (11.09 vs. 13.63%/yr, p=0.0359), including cases of nocturnal hypoglycemia (1.39 vs. 1.84%/yr, p=0.0399).[16]

References

  1. ↑ CHMP (October 18, 2012), "Summary of opinion 1 (initial authorisation): Tresiba" (PDF), Pending EC decisions (PDF), EMA, retrieved November 6, 2012
  2. ↑ Klein, O; Lynge, J; Endahl, L; Damholt, B; Nosek, L; Heise, T (2007). "Albumin-bound basal insulin analogues (insulin detemir and NN344): Comparable time-action profiles but less variability than insulin glargine in type 2 diabetes". Diabetes, Obesity and Metabolism. 9 (3): 290–9. doi:10.1111/j.1463-1326.2006.00685.x. PMID 17391154.
  3. ↑ Haahr, H; Heise, T (2014). "A review of the pharmacological properties of insulin degludec and their clinical relevance". Clinical Pharmacokinetics. 53 (9): 787–800. doi:10.1007/s40262-014-0165-y. PMC 4156782Freely accessible. PMID 25179915.
  4. ↑ European Medicines Agency: Tresiba Summary of product characteristics
  5. 1 2 Wang, F; Surh, J; Kaur, M (2012). "Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review.". Diabetes, metabolic syndrome and obesity : targets and therapy. 5: 191–204. doi:10.2147/DMSO.S21979. PMC 3402007Freely accessible. PMID 22826637.
  6. 1 2 Nasrallah, SN; Reynolds, LR (2012). "Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?". Clinical medicine insights. Endocrinology and diabetes. 5: 31–7. doi:10.4137/CMED.S9494. PMC 3411522Freely accessible. PMID 22879797.
  7. ↑ Robinson, JD; Neumiller, JJ; Campbell, RK (Nov 2, 2012). "Can a New Ultra-Long-Acting Insulin Analogue Improve Patient Care? Investigating the Potential Role of Insulin Degludec.". Drugs. 72 (18): 2319–25. doi:10.2165/11642240-000000000-00000. PMID 23145524.
  8. ↑ "Monograph - Insulin Glargine: Dosage & Administration". American Society of Health-System Pharmacists, Inc. Retrieved 2010-11-07.
  9. ↑ Ringstrom, Anna (2010-06-26). "Novo says degludec has potential to lower blood sugar". Reuters. Retrieved 2010-11-07.
  10. ↑ Lowry, Fran. "Novel Ultralong-Acting Insulin as Effective as Insulin Glargine". Medscape. Retrieved 2010-11-07.
  11. ↑ "R&D Pipeline". Novo Nordisk. Retrieved 2012-01-27.
  12. ↑ Hirschler, Ben (2010-10-27). "New Novo insulin fails to knock out rival Sanofi". Reuters. Retrieved 2010-11-07.
  13. ↑ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm464321.htm
  14. ↑ http://press.novonordisk-us.com/2016-01-26-Novo-Nordisk-Launches-Tresiba-insulin-degludec-injection-200-Units-mL-in-the-United-States
  15. ↑ Heller, S; Buse, J; Fisher, M; Garg, S; Marre, M; Merker, L; Renard, E; Russell-Jones, D; Philotheou, A; Francisco, AM; Pei, H; Bode, B; BEGIN Basal-Bolus Type 1 Trial Investigators (Apr 21, 2012). "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. 379 (9825): 1489–97. doi:10.1016/S0140-6736(12)60204-9. PMID 22521071.
  16. ↑ Garber, AJ; King, AB; Del Prato, S; Sreenan, S; Balci, MK; Muñoz-Torres, M; Rosenstock, J; Endahl, LA; Francisco, AM; Hollander, P; NN1250-3582 (BEGIN BB T2D) Trial Investigators (Apr 21, 2012). "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. 379 (9825): 1498–507. doi:10.1016/S0140-6736(12)60205-0. PMID 22521072.
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