Insulin degludec ( INN/

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...

) is an ultralong-acting basal insulin analogue that was developed by

Novo Nordisk Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...

under the brand name Tresiba. It is administered via

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, c ...

once daily to help control the

blood sugar Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the b ...

level of those with

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

. 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 Insulin glargine, sold under the brand name Lantus among others, is a long-acting modified form of medical insulin, used in the management of type I and type II diabetes. It is typically the recommended long acting insulin in the United Kin ...

and insulin detemir), making it a once-daily basal insulin, 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 Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated − ...

at position B29. It is included in the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

as an equivalent to

. In 2020, it was the 136th most commonly prescribed medication in the United States, with more than 4million prescriptions.

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. A more recent

Cochrane Cochrane may refer to: Places Australia *Cochrane railway station, Sydney, a railway station on the closed Ropes Creek railway line Canada * Cochrane, Alberta * Cochrane Lake, Alberta * Cochrane District, Ontario ** Cochrane, Ontario, a town wit ...

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on t ...

found there was no significant differences in rates of diurnal, nocturnal hypoglycemia or any other studies outcomes when using insulin degludec as compared to insulin glargine, insulin detemir and

NPH insulin Neutral Protamine Hagedorn (NPH) insulin, also known as isophane insulin, is an intermediate-acting insulin given to help control blood sugar levels in people with diabetes. It is used by injection under the skin once to twice a day. Onset of ...

for the management of

type I Diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

in neither adults nor children.

Pharmacology

Mechanism of action

Insulin degludec is an ultra-long acting insulin that, unlike

, is active at a physiologic pH. The addition of hexadecanedioic acid via an

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

linkage 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.

Pharmacokinetics

Insulin degludec has an onset of action of 30–90 minutes (similar to

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. Because the half-life is longer than 24 hours, it is approved for daily dosing at any time each day - as long as more than 8 hours has elapsed since the previous dose. A missed dose is advised to be taken as soon as remembered, then return to a normal schedule.

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. However, in a recent Cochrane systematic review no clinically significant differences in measures of effectiveness were found when using insulin degludec as compared to insulin glargine, insulin detemir and NPH insulin for the management of type I Diabetes in neither adults nor children. Insulin degludec also has the ability to be mixed with other insulins, thereby improving

glycemic control The term ''diabetes'' includes several different metabolic disorders that all, if left untreated, result in abnormally high concentration of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces ...

. This cannot be done using current long-acting insulins. A physician involved in the trials was quoted as saying,

History

Insulin degludec has been filed for registration in the United States. After the completion of additional cardiac safety studies requested by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) in February 2013, it received FDA approval 25 September 2015 and marketing began on 26 January 2016.

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 Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...

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 Glycated hemoglobin, also known as HbA1c, glycohemoglobin, hemoglobin A1c, A1C, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously (i.e. non-enzymati ...

(0.40% vs. 0.39%) meeting the criteria for noninferiority. Adverse events were similar in the two treatment arms; however, rates of nocturnal

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

(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. A Cochrane systematic review has compared the use of insulin degludec to that of insulin glargine, insulin detemir and NPH insulin in adults and children diagnosed with type I Diabetes. This review included Randomized Control Trials (RCTs) with a duration of 24 to 104 weeks and had a total sample of 8784 participants randomized across studies: 2428 participants allocated to NPH insulin; 2889 participants to insulin detemir; 2095 participants to insulin glargine; 1372 participants to insulin degludec. 21% of all participants were children. No studies directly compared insulin degludec with NPH insulin. In the studies comparing insulin degludec to insulin detemir (2 RCTs) and insulin degludec to insulin glargine (4 RCTs), no clinically relevant difference was found for the outcomes of

all-cause mortality Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. Mortality rate is typically expressed in units of de ...

health-related quality of life In general, quality of life (QoL or QOL) is the perceived quality of an individual's daily life, that is, an assessment of their well-being or lack thereof. This includes all emotional, social and physical aspects of the individual's life. In h ...

(QoL), severe hypoglycemia, non-fatal

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...

stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...

(NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse effects (SAE) and Glycosated haemoglobin A1c (HbA1c).

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 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

. 995 patients were randomized to receive either insulin degludec (n=755) or insulin glargine (n=251), in addition to either mealtime insulin aspart,

metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...

, 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).

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. 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.

References

External links

* {{DEFAULTSORT:Insulin Degludec Human proteins Insulin receptor agonists Insulin therapies Peptide hormones Recombinant proteins