Insulin degludec
Insulin degludec is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. It is administered via subcutaneous injection to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 42 hours, 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 at position B29.
It is included on the World Health Organization's List of Essential Medicines as an equivalent to insulin glargine. In 2023, it was the 152nd most commonly prescribed medication in the United States, with more than 3million prescriptions.
Medical uses
Insulin degludec is indicated to improve glycemic control in people with diabetes.In a meta-analysis involving data from 3 randomized controlled trials having 1171 patients, thrice weekly insulin degludec had similar efficacy as daily insulin glargine injections with regards to the fasting blood glucose reduction, having similar safety and risk of low blood glucose profile. However the overall HbA1c reduction with thrice weekly insulin degludec injection was marginally lower than that of daily insulin glargine injections. Hence thrice weekly degludec injections can be considered in extremely needle prick phobic patients as a choice for basal insulin therapy.
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 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 systematic review 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 for the management of type 1 diabetes in either adults or children.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. 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. 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 participants 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 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 1 diabetes in either adults or children. Insulin degludec also has the ability to be mixed with other insulins, thereby improving glycemic control. This cannot be done using other 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 US Food and Drug Administration in February 2013, it received FDA approval in September 2015 and marketing began in January 2016.Clinical trial data
Type 1 diabetes
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 participants with type 1 diabetes were randomized in a 3:1 ratio to either insulin degludec or insulin glargine in addition to mealtime insulin aspart. Participants 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 participants receiving multiple basal doses per day. After 52 weeks, participants treated with insulin degludec produced a similar reduction in HbA1c meeting the criteria for noninferiority. Adverse events were similar in the two treatment arms; however, rates of nocturnal hypoglycemia were 27% lower in participants treated with insulin degludec. 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 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 1 diabetes. This review included Randomized Control Trials 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 and insulin degludec to insulin glargine, no clinically relevant difference was found for the outcomes of all-cause mortality, health-related quality of life, severe hypoglycemia, non-fatal myocardial infarction/stroke, severe nocturnal hypoglycaemia, serious adverse effects and Glycated haemoglobin A1c (HbA1c).