Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Insulin degludec: Difference between pages

{{Short description|Ultralong-acting basal insulin analogue}}

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| image = Insulin degludec hexamer 4AKJ.png

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| caption = An insulin degludec [[hexamer]]. A chains are chartreuse, B chains are tan, and the central [[zinc]] atom is teal. From {{PDB|4AKJ}}.

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| Drugs.com = {{Drugs.com|monograph|insulin-degludec}}

| MedlinePlus = a615055

| DailyMedID = Insulin degludec

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| routes_of_administration = [[Subcutaneous injection|Subcutaneous]]

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| ATC_suffix = AE06

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| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017 | access-date=9 April 2023 | archive-date=10 April 2023 | archive-url=https://web.archive.org/web/20230410060848/https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017 | url-status=live }}</ref><ref>https://www.tga.gov.au/resources/publication/scheduling-decisions-final/scheduling-delegates-final-decisions-january-2018/111-insulin-deglude</ref><ref>{{cite web | title=Prescription medicines and biologicals: TGA annual summary 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 | access-date=31 March 2024}}</ref>

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| legal_CA_comment = <ref>{{cite web | title=Diabetic health | website=[[Health Canada]] | date=8 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/diabetic-health.html | access-date=13 April 2024}}</ref>

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| legal_US = Rx-only

| legal_US_comment = <ref name="Tresiba FDA label">{{cite web | title=Tresiba- insulin degludec injection, solution | website=DailyMed | date=1 July 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=456c5e87-3dfd-46fa-8ac0-c6128d4c97c6 | access-date=11 February 2024 | archive-date=7 July 2022 | archive-url=https://web.archive.org/web/20220707173549/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=456c5e87-3dfd-46fa-8ac0-c6128d4c97c6 | url-status=live }}</ref>

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Tresiba EPAR">{{cite web | title=Tresiba EPAR | website=[[European Medicines Agency]] | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tresiba | access-date=15 January 2021 | archive-date=22 January 2021 | archive-url=https://web.archive.org/web/20210122023112/https://www.ema.europa.eu/en/medicines/human/EPAR/tresiba | url-status=live }}</ref>

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| CAS_number = 844439-96-9

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| IUPAC_name = B29N(ε)-ω-carboxypentadecanoyl-γ-<small>L</small>-glutamyl desB30 human insulin

| C=274 | H=411 | N=65 | O=81 | S=6

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'''Insulin degludec''' ([[International Nonproprietary Name|INN]]/[[United States Adopted Name|USAN]]) is an ultralong-acting basal [[insulin analogue]] that was developed by [[Novo Nordisk]] under the brand name '''Tresiba'''.<ref name=CHMP2012/> 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,<ref>{{cite journal | vauthors = Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T | title = Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes | journal = Diabetes, Obesity & Metabolism | volume = 9 | issue = 3 | pages = 290–299 | date = May 2007 | pmid = 17391154 | doi = 10.1111/j.1463-1326.2006.00685.x | s2cid = 23810204 }}</ref><ref>{{cite journal | vauthors = Haahr H, Heise T | title = A review of the pharmacological properties of insulin degludec and their clinical relevance | journal = Clinical Pharmacokinetics | volume = 53 | issue = 9 | pages = 787–800 | date = September 2014 | pmid = 25179915 | pmc = 4156782 | doi = 10.1007/s40262-014-0165-y }}</ref><ref>{{cite web | work = European Medicines Agency | url = http://ec.europa.eu/health/documents/community-register/2013/20130121124987/anx_124987_en.pdf | title = Tresiba Summary of product characteristics | access-date = 29 September 2014 | archive-date = 4 March 2016 | archive-url = https://web.archive.org/web/20160304131842/http://ec.europa.eu/health/documents/community-register/2013/20130121124987/anx_124987_en.pdf | url-status = live }}</ref> 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-<small>L</small>-glutamyl spacer at the amino acid [[lysine]] at position B29.

It is included on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]]<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> as an equivalent to [[insulin glargine]]. In 2021, it was the 146th most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Insulin Degludec - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/InsulinDegludec | access-date = 14 January 2024 }}</ref>

== Medical uses ==

Insulin degludec is [[indicated]] to improve glycemic control in people with diabetes.<ref name="Tresiba FDA label" /><ref name="Tresiba EPAR" />

==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&nbsp;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.<ref name="systematicrev"/> A more recent [[Cochrane (organisation)|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.<ref name=":0">{{cite journal | vauthors = Hemmingsen B, Metzendorf MI, Richter B | title = (Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 3 | pages = CD013498 | date = March 2021 | pmid = 33662147 | pmc = 8094220 | doi = 10.1002/14651858.cd013498.pub2 }}</ref>

==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.<ref name="Degludec review">{{cite journal | vauthors = Nasrallah SN, Reynolds LR | title = Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin? | journal = Clinical Medicine Insights. Endocrinology and Diabetes | volume = 5 | pages = 31–37 | year = 2012 | pmid = 22879797 | pmc = 3411522 | doi = 10.4137/CMED.S9494 }}</ref> This allows for the formation of a subcutaneous [[Injection (medicine)#Depot|depot]] that results in slow insulin release into the systemic circulation.<ref name="Drugs article">{{cite journal | vauthors = Robinson JD, Neumiller JJ, Campbell RK | title = Can a new ultra-long-acting insulin analogue improve patient care? Investigating the potential role of insulin degludec | journal = Drugs | volume = 72 | issue = 18 | pages = 2319–2325 | date = December 2012 | pmid = 23145524 | doi = 10.2165/11642240-000000000-00000 | s2cid = 21557012 }}</ref>

===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.<ref name="Degludec review" /><ref name=systematicrev>{{cite journal | vauthors = Wang F, Surh J, Kaur M | title = Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review | journal = Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy| volume = 5 | pages = 191–204 | year = 2012 | pmid = 22826637 | pmc = 3402007 | doi = 10.2147/DMSO.S21979 | doi-access = free }}</ref>

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.<ref name="auto">{{cite web |title=Duration of Action |url=https://www.novomedlink.com/diabetes/products/treatments/tresiba/about/hear-from-your-peers/missed-insulin-dose.html |website=Novo Nordisk |access-date=28 April 2022 |archive-date=28 May 2022 |archive-url=https://web.archive.org/web/20220528004132/https://www.novomedlink.com/diabetes/products/treatments/tresiba/about/hear-from-your-peers/missed-insulin-dose.html |url-status=live }}</ref> A missed dose is advised to be taken as soon as remembered, then return to a normal schedule.<ref name="auto"/>

==Effectiveness profile==

Studies have shown that participants taking insulin degludec needed to take significantly smaller doses of [[basal rate|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.<ref name=":0" /> 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.<ref name=monograph>{{cite web|url=http://www.medscape.com/druginfo/monograph?cid=med&drugid=20805&drugname=Insulin+Glargine+SubQ&monotype=monograph&secid=3|title=Monograph - Insulin Glargine: Dosage & Administration|work=American Society of Health-System Pharmacists, Inc.|access-date=7 November 2010|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828125442/https://reference.medscape.com/|url-status=live}}</ref><ref name=reuters>{{cite news|url=https://www.reuters.com/article/idUSLDE65P0DB20100626|work=[[Reuters]]|vauthors=Ringstrom A|title=Novo says degludec has potential to lower blood sugar|access-date=7 November 2010|date=26 June 2010|archive-date=12 July 2010|archive-url=https://web.archive.org/web/20100712083251/http://www.reuters.com/article/idUSLDE65P0DB20100626|url-status=live}}</ref> A physician involved in the trials was quoted as saying,

{{blockquote|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.<ref name=medscape>{{cite news|url=http://www.medscape.com/viewarticle/724316|title=Novel Ultralong-Acting Insulin as Effective as Insulin Glargine|vauthors=Lowry F|work=[[Medscape]]|access-date=2010-11-07|archive-date=1 April 2011|archive-url=https://web.archive.org/web/20110401030716/http://www.medscape.com/viewarticle/724316|url-status=live}}</ref>

}}

==History==

Insulin degludec has been filed for registration in the United States.<ref name=novo>{{cite web|url=http://www.novonordisk.com/science/pipeline/rd_pipeline.asp?sort=6&phase=000.All&indication=Diabetes|work=[[Novo Nordisk]]|title=R&D Pipeline|access-date=27 January 2012|archive-date=25 December 2014|archive-url=https://web.archive.org/web/20141225022626/http://www.novonordisk.com/science/pipeline/rd_pipeline.asp?sort=6&phase=000.All&indication=Diabetes}}</ref> After the completion of additional cardiac safety studies requested by the US [[Food and Drug Administration]] (FDA) in February 2013,<ref name=reuters2>{{cite news|url=https://www.reuters.com/article/idUSLDE69Q13H20101027|work=Reuters|title=New Novo insulin fails to knock out rival Sanofi|vauthors=Hirschler B|date=27 October 2010|access-date=7 November 2010|archive-date=2 July 2022|archive-url=https://web.archive.org/web/20220702200943/https://www.reuters.com/article/idUSLDE69Q13H20101027|url-status=live}}</ref> it received FDA approval in September 2015<ref>{{cite press release | title = FDA approves two new drug treatments for diabetes mellitus| url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm464321.htm | archive-url = https://web.archive.org/web/20160116022750/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm464321.htm | archive-date = 16 January 2016 | work = U.S. [[Food and Drug Administration]] (FDA) }}</ref> and marketing began in January 2016.<ref>{{cite web|url=http://press.novonordisk-us.com/2016-01-26-Novo-Nordisk-Launches-Tresiba-insulin-degludec-injection-200-Units-mL-in-the-United-States|title=Novo Nordisk Launches Tresiba (insulin degludec injection 200 Units/mL) in the United States|website=novonordisk-us.com|access-date=18 August 2016|archive-date=22 May 2018|archive-url=https://web.archive.org/web/20180522042030/http://press.novonordisk-us.com/2016-01-26-Novo-Nordisk-Launches-Tresiba-insulin-degludec-injection-200-Units-mL-in-the-United-States}}</ref>

==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.<ref>{{cite journal | vauthors = Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell-Jones D, Philotheou A, Francisco AM, Pei H, Bode B | title = 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 | journal = Lancet | volume = 379 | issue = 9825 | pages = 1489–1497 | date = April 2012 | pmid = 22521071 | doi = 10.1016/S0140-6736(12)60204-9 | s2cid = 5868807 }}</ref>

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.<ref name=":0" /> 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]], [[Quality of life (healthcare)|health-related quality of life]] (QoL), severe hypoglycemia, non-fatal [[myocardial infarction]]/[[stroke]] (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse effects (SAE) and [[Glycated hemoglobin|Glycosated haemoglobin A1c (HbA1c)]].<ref name=":0" />

===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).<ref>{{cite journal | vauthors = Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Francisco AM, Hollander P | title = 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 | journal = Lancet | volume = 379 | issue = 9825 | pages = 1498–1507 | date = April 2012 | pmid = 22521072 | doi = 10.1016/S0140-6736(12)60205-0 | s2cid = 205965206 }}</ref>

==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.<ref name="Degludec CUA Sweden">{{cite journal | vauthors = Ericsson Å, Pollock RF, Hunt B, Valentine WJ | title = Evaluation of the cost-utility of insulin degludec vs insulin glargine in Sweden | journal = Journal of Medical Economics | volume = 16 | issue = 12 | pages = 1442–1452 | date = December 2013 | pmid = 24147661 | doi = 10.3111/13696998.2013.852099 | s2cid = 826947 | doi-access = free }}</ref> 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.<ref name="Degludec CUA Sweden" />

== References ==

{{reflist|refs=

<ref name=CHMP2012>{{Cite web |date=18 October 2012 |title=Summary of opinion 1 (initial authorisation): Tresiba |type=PDF |work=Pending EC decisions |publisher=[[European Medicines Agency]] |url=http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002498/WC500134060.pdf |access-date=6 November 2012 |author=Committee for Medicinal Products for Human Use |archive-date=11 January 2017 |archive-url=https://web.archive.org/web/20170111004707/http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002498/WC500134060.pdf }}</ref>

}}

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