Insulin degludec

Insulin degludec

An insulin degludec hexamer. A chains are chartreuse, B chains are tan, and the central zinc atom is teal. From PDB: 4AKJ​.
Clinical data
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN
Pregnancy category	AU: B3
Routes of administration	Subcutaneous
ATC code	A10AE06 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only EU: Rx-only [1] In general: ℞ (Prescription only)
Identifiers
show IUPAC name B29N(ε)-ω-carboxypentadecanoyl-γ-L-glutamyl desB30 human insulin
CAS Number	844439-96-9 N
PubChem SID	124490467
ChemSpider	none
UNII	54Q18076QB
KEGG	D09727 N
Chemical and physical data
Formula	C274H411N65O81S6
Molar mass	6104.04 g·mol−1
NY (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.^[2] 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,^[3][4][5] 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.

In 2018, it was the 185th most commonly prescribed medication in the United States, with more than 3 million prescriptions.^[6][7]

Side effects[]

A significant side effect of insulin therapy is hypoglycemia. A meta-analysis of clinical trials published in July 2012 found 39 to 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 to 5.1 events per patient year.^[8]

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 via an amide linkage to lysine at the B29 position allows for the formation of multi-hexamers in subcutaneous tissues.^[9] This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation.^[10]

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.^[9][8]

When taken at the same time of day, this long (but under 48 hour) duration can result in an overlap from one dose to the next, resulting in greater insulin action then. if the overlap should be during sleep, there is a risk of lower blood sugar, so it is important to dose in the morning so that the overlap will be when users are eating and otherwise checking their blood sugar. The dose should be titrated during this overlap period as well.^{[citation needed]}

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.^[11][12] 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.^[13]

History[]

Insulin degludec has been filed for registration in the United States.^[14] 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.^[15] Insulin degludec received FDA approval 25 September 2015^[16] and marketing began on 26 January 2016.^[17]

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.^[18]

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 plus 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).^[19]

Pharmacoeconomics[]

Given the treat-to-target nature of the BEGIN trial program, much of the health economic analysis of insulin degludec has focussed on short-term cost-effectiveness based on differences in insulin dosing and hypoglycemic event incidence rather than differences in glycemic control.^[20] The first cost-effectiveness analysis of this nature was conducted from a societal perspective in the Swedish setting in 2013, finding that insulin degludec would be cost-effective relative to insulin glargine in the treatment of type 1 diabetes, and type 2 diabetes as part of either a basal or basal-insulin regimen.^[20]

References[]

External links[]

• "Insulin degludec". Drug Information Portal. U.S. National Library of Medicine.