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Insulin degludec

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Insulin degludec

Insulin degludec is an ultralong-acting basal insulin analogue being developed by Novo Nordisk under the brand name Tresiba.[1] It is administered via subcutaneous injection. It can be given daily or up to three-times a week to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 40 hours, unlike the 18 to 26 hours provided by current marketed long-acting insulins such as insulin glargine and insulin detemir.[2][3]

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.

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.[4] This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation.[5]

Pharmacodynamics

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.[4][6]

Effectiveness profile

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.[7][8] 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."[9]

Insulin degludec has been filed for registration in the United States.[10] 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.[11]

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.[12]

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).[13]

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 <56mg/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.[14]

References

External links

  • Novo Nordisk
  • U.S. National Library of Medicine: Drug Information Portal - Insulin degludec
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