Insulin degludec

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Insulin degludec
Insulin degludec hexamer 4AKJ.png
An insulin degludec hexamer. A chains are chartreuse, B chains are tan, and the central zinc atom is teal. From PDB: 4AKJ ​.
Clinical data
Trade names Tresiba
AHFS/Drugs.com Monograph
MedlinePlus a615055
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Identifiers
  • B29N(ε)-ω-carboxypentadecanoyl-γ-L-glutamyl desB30 human insulin
CAS Number
PubChem SID
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C274H411N65O81S6
Molar mass 6104.04 g·mol−1
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Insulin degludec (INN/USAN) is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. [4] 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 (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, [5] [6] [7] that is one that provides a base insulin level, as opposed to the fast- and short-acting bolus insulins.

Contents

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 [8] as an equivalent to insulin glargine. In 2021, it was the 146th most commonly prescribed medication in the United States, with more than 4 million prescriptions. [9] [10]

Medical uses

Insulin degludec is indicated to improve glycemic control in people with diabetes. [2] [3]

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. [11] 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. [12]

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. [13] This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation. [14]

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. [13] [11]

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. [15] A missed dose is advised to be taken as soon as remembered, then return to a normal schedule. [15]

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. [12] 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. [16] [17] 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. [18]

History

Insulin degludec has been filed for registration in the United States. [19] After the completion of additional cardiac safety studies requested by the US Food and Drug Administration (FDA) in February 2013, [20] it received FDA approval in September 2015 [21] and marketing began in January 2016. [22]

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 (n=472) or insulin glargine (n=157) 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 (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 participants 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. [23]

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. [12] 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, health-related quality of life (QoL), severe hypoglycemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse effects (SAE) and Glycosated haemoglobin A1c (HbA1c). [12]

Type 2 diabetes

In the BEGIN Basal-Bolus Type 2 trial, insulin degludec was studied as an alternative to insulin glargine in participants with type 2 diabetes. 995 participants 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. Participants 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). [24]

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. [25] 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. [25]

Related Research Articles

<span class="mw-page-title-main">Insulin pump</span> Medical device to administer insulin

An insulin pump is a medical device used for the administration of insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin therapy. The device configuration may vary depending on design. A traditional pump includes:

Intensive insulin therapy or flexible insulin therapy is a therapeutic regimen for diabetes mellitus treatment. This newer approach contrasts with conventional insulin therapy. Rather than minimize the number of insulin injections per day, the intensive approach favors flexible meal times with variable carbohydrate as well as flexible physical activities. The trade-off is the increase from 2 or 3 injections per day to 4 or more injections per day, which was considered "intensive" relative to the older approach. In North America in 2004, many endocrinologists prefer the term "flexible insulin therapy" (FIT) to "intensive therapy" and use it to refer to any method of replacing insulin that attempts to mimic the pattern of small continuous basal insulin secretion of a working pancreas combined with larger insulin secretions at mealtimes. The semantic distinction reflects changing treatment.

Drugs used in diabetes treat diabetes mellitus by decreasing the glucose level in the blood. With the exception of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.

<span class="mw-page-title-main">Insulin glargine</span> Long-acting insulin

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 injected just under the skin. Effects generally begin an hour after use.

An insulin analog is any of several types of medical insulin that are altered forms of the hormone insulin, different from any occurring in nature, but still available to the human body for performing the same action as human insulin in terms of controlling blood glucose levels in diabetes. Through genetic engineering of the underlying DNA, the amino acid sequence of insulin can be changed to alter its ADME characteristics. Officially, the U.S. Food and Drug Administration (FDA) refers to these agents as insulin receptor ligands, although they are usually just referred to as insulin analogs or even just insulin.

<span class="mw-page-title-main">NPH insulin</span> Intermediate acting insulin formulation

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 effects is typically in 90 minutes and they last for 24 hours. Versions are available that come premixed with a short-acting insulin, such as regular insulin.

A diabetic diet is a diet that is used by people with diabetes mellitus or high blood sugar to minimize symptoms and dangerous complications of long-term elevations in blood sugar.

<span class="mw-page-title-main">Glucagon rescue</span>

Glucagon rescue is the emergency injection of glucagon in case of severe diabetic hypoglycemia. It is needed during seizures and/or unconsciousness by an insulin user who is unable at that point to help themselves. Glucagon will facilitate the release of stored glucose back into the bloodstream, raising the blood glucose level.

Insulin detemir, sold under the brand name Levemir among others, is a long-acting modified form of medical insulin used to treat both type 1 and type 2 diabetes. It is used by injection under the skin. It is effective for up to 24 hours.

<span class="mw-page-title-main">Insulin aspart</span> Rapid-acting man-made insulin

Insulin aspart, sold under the brand name NovoLog, among others, is a modified type of medical insulin used to treat type 1 and type 2 diabetes. It is generally used by injection under the skin but may also be used by injection into a vein. Maximum effect occurs after about 1–3 hours and lasts for 3–5 hours. Generally a longer-acting insulin like insulin NPH is also needed.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand names Victoza and Saxenda among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

<span class="mw-page-title-main">Insulin (medication)</span> Use of insulin protein and analogs as medical treatment

As a medication, insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose. Such conditions include type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. Insulin is also used along with glucose to treat hyperkalemia. Typically it is given by injection under the skin, but some forms may also be used by injection into a vein or muscle. There are various types of insulin, suitable for various time spans. The types are often all called insulin in the broad sense, although in a more precise sense, insulin is identical to the naturally occurring molecule whereas insulin analogues have slightly different molecules that allow for modified time of action. It is on the World Health Organization's List of Essential Medicines. In 2020, regular human insulin was the 307th most commonly prescribed medication in the United States, with more than 1 million prescriptions.

<span class="mw-page-title-main">Minimed Paradigm</span> Insulin pumps

MiniMed Paradigm is a series of insulin pumps manufactured by Medtronic for patients with diabetes mellitus. The pump operates with a single AAA battery and uses a piston-plunger pump to infuse a programmed amount of insulin into the patient through a length of tubing. The Paradigm uses a one-way wireless radio frequency link to receive blood sugar measurements from select glucose meters. The Paradigm RT series adds the ability to receive data from a mated continuous blood-glucose monitor. Although the pump can use these measurements to assist in calculating a dose of insulin, no actual change in insulin delivery occurs without manual user-intervention.

<span class="mw-page-title-main">Lente insulin</span> Historical formulation of insulin as medication

Lente insulin was an intermediate duration insulin that is no longer used in humans. The onset of lente insulin is one to two hours after the dose is administered, and the peak effect is approximately 8 to 12 hours after administration, with some effects lasting over 24 hours.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

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Avideh Nazeri is an Iranian endocrinologist who is director of clinical, medical, and regulatory for Novo Nordisk UK and Ireland.

Insulin degludec/insulin aspart, sold under the brand name Ryzodeg, is a fixed-dose combination medication for the treatment of diabetes mellitus. It contains insulin degludec and insulin aspart. It is given as an injection under the skin in the abdominal wall, upper arm or thigh.

Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.

Insulin icodec is an investigational ultralong-acting basal insulin analogue that is developed by Novo Nordisk.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 9 April 2023.
  2. 1 2 "Tresiba- insulin degludec injection, solution". DailyMed. 1 July 2022. Archived from the original on 7 July 2022. Retrieved 11 February 2024.
  3. 1 2 "Tresiba EPAR". European Medicines Agency . 17 September 2018. Archived from the original on 22 January 2021. Retrieved 15 January 2021.
  4. ↑ Committee for Medicinal Products for Human Use (18 October 2012). "Summary of opinion 1 (initial authorisation): Tresiba" (PDF). Pending EC decisions (PDF). European Medicines Agency. Archived from the original (PDF) on 11 January 2017. Retrieved 6 November 2012.
  5. ↑ Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T (May 2007). "Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes". Diabetes, Obesity & Metabolism. 9 (3): 290–299. doi:10.1111/j.1463-1326.2006.00685.x. PMID   17391154. S2CID   23810204.
  6. ↑ Haahr H, Heise T (September 2014). "A review of the pharmacological properties of insulin degludec and their clinical relevance". Clinical Pharmacokinetics. 53 (9): 787–800. doi:10.1007/s40262-014-0165-y. PMC   4156782 . PMID   25179915.
  7. ↑ "Tresiba Summary of product characteristics" (PDF). European Medicines Agency. Archived (PDF) from the original on 4 March 2016. Retrieved 29 September 2014.
  8. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  9. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  10. ↑ "Insulin Degludec - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  11. 1 2 Wang F, Surh J, Kaur M (2012). "Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 5: 191–204. doi: 10.2147/DMSO.S21979 . PMC   3402007 . PMID   22826637.
  12. 1 2 3 4 Hemmingsen B, Metzendorf MI, Richter B (March 2021). "(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus". The Cochrane Database of Systematic Reviews. 3 (3): CD013498. doi:10.1002/14651858.cd013498.pub2. PMC   8094220 . PMID   33662147.
  13. 1 2 Nasrallah SN, Reynolds LR (2012). "Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?". Clinical Medicine Insights. Endocrinology and Diabetes. 5: 31–37. doi:10.4137/CMED.S9494. PMC   3411522 . PMID   22879797.
  14. ↑ Robinson JD, Neumiller JJ, Campbell RK (December 2012). "Can a new ultra-long-acting insulin analogue improve patient care? Investigating the potential role of insulin degludec". Drugs. 72 (18): 2319–2325. doi:10.2165/11642240-000000000-00000. PMID   23145524. S2CID   21557012.
  15. 1 2 "Duration of Action". Novo Nordisk. Archived from the original on 28 May 2022. Retrieved 28 April 2022.
  16. ↑ "Monograph - Insulin Glargine: Dosage & Administration". American Society of Health-System Pharmacists, Inc. Archived from the original on 28 August 2021. Retrieved 7 November 2010.
  17. ↑ Ringstrom A (26 June 2010). "Novo says degludec has potential to lower blood sugar". Reuters . Archived from the original on 12 July 2010. Retrieved 7 November 2010.
  18. ↑ Lowry F. "Novel Ultralong-Acting Insulin as Effective as Insulin Glargine". Medscape . Archived from the original on 1 April 2011. Retrieved 7 November 2010.
  19. ↑ "R&D Pipeline". Novo Nordisk . Archived from the original on 25 December 2014. Retrieved 27 January 2012.
  20. ↑ Hirschler B (27 October 2010). "New Novo insulin fails to knock out rival Sanofi". Reuters. Archived from the original on 2 July 2022. Retrieved 7 November 2010.
  21. ↑ "FDA approves two new drug treatments for diabetes mellitus". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 16 January 2016.
  22. ↑ "Novo Nordisk Launches Tresiba (insulin degludec injection 200 Units/mL) in the United States". novonordisk-us.com. Archived from the original on 22 May 2018. Retrieved 18 August 2016.
  23. ↑ Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, et al. (April 2012). "Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial". Lancet. 379 (9825): 1489–1497. doi:10.1016/S0140-6736(12)60204-9. PMID   22521071. S2CID   5868807.
  24. ↑ Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, et al. (April 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): 1498–1507. doi:10.1016/S0140-6736(12)60205-0. PMID   22521072. S2CID   205965206.
  25. 1 2 Ericsson Å, Pollock RF, Hunt B, Valentine WJ (December 2013). "Evaluation of the cost-utility of insulin degludec vs insulin glargine in Sweden". Journal of Medical Economics. 16 (12): 1442–1452. doi: 10.3111/13696998.2013.852099 . PMID   24147661. S2CID   826947.
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