|Systematic (IUPAC) name|
|B29N(epsilon)-omega-carboxypentadecanoyl-gamma-L-glutamyl desB30 human insulin|
|Molecular mass||6103.972 g/mol|
|(what is this?)|
Insulin degludec (INN/USAN) is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. 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 40 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir), which would allow for a two or three times weekly administration. It is however not approved for such a dosing scheme.
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.
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. This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation.
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.
Studies have shown that patients taking insulin degludec needed to take significantly smaller doses of basal insulin than those taking insulin glargine, 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. 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."
Insulin degludec has been filed for registration in the United States. 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.
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.
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).
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.
- CHMP (October 18, 2012), "Summary of opinion 1 (initial authorisation): Tresiba", Pending EC decisions (PDF) (EMA), retrieved November 6, 2012
- "Good News for Novo's Thrice-Weekly Insulin". DiabetesInControl.com. Retrieved 2010-11-07.
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- European Medicines Agency: Tresiba Summary of product characteristics
- for Tresiba
- 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 3411522. PMID 22879797.
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- "R&D Pipeline". Novo Nordisk. Retrieved 2012-01-27.
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- 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.