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| {{Drugbox
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| | Watchedfields = changed
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| | verifiedrevid = 476995027
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| | IUPAC_name = B29N(epsilon)-omega-carboxypentadecanoyl-gamma-L-glutamyl desB30 human insulin
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| <!--Clinical data-->
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| | Drugs.com = {{Drugs.com|UK|tresiba}}
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| | tradename = Tresiba
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| | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
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| | legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
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| | legal_status = Rx-only
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| | routes_of_administration = Subcutaneous
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| | CAS_number = 844439-96-9
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| | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| | ChemSpiderID = NA
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| | PubChemSubstance = 124490467
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| | KEGG = D09727
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| | ATC_prefix = A10
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| | ATC_suffix = AE06
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| <!--Chemical data-->
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| | C= 274 | H= 411 | N= 65 | O= 81 | S= 6
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| | molecular_weight = 6103.972 g/mol
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| }}
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| __NOTOC__
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| {{SI}}
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| {{CMG}}
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| == Overview ==
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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]] once daily to help control the [[blood sugar]] level of those with [[diabetes]]. It has a duration of action that lasts up to 40 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 pmid|17391154}}</ref><ref>{{cite pmid|25179915}}</ref><ref>European Medicines Agency: [http://ec.europa.eu/health/documents/community-register/2013/20130121124987/anx_124987_en.pdf Tresiba Summary of product characteristics]</ref> that is one that provides a base insulin level, as opposed to the fast and short acting bolus insulins.
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| 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.
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| ==Pharmacology==
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| ===Mechanism of action===
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| Insulin degludec is an ultra-long acting insulin that, unlike [[insulin glargine]], is active at a physiologic pH. The addition of hexadecanedioic acid to lysine at the B29 position allows for the formation of multi-hexamers in subcutaneous tissues.<ref name="Degludec review">{{cite journal|last=Nasrallah|first=SN|author2=Reynolds, LR|title=Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?|journal=Clinical medicine insights. Endocrinology and diabetes|year=2012|volume=5|pages=31–7|pmid=22879797|doi=10.4137/CMED.S9494|pmc=3411522}}</ref> This allows for the formation of a subcutaneous [[Injection (medicine)#Depot injection|depot]] that results in slow insulin release into the systemic circulation.<ref name="Drugs article">{{cite journal|last=Robinson|first=JD|author2=Neumiller, JJ |author3=Campbell, RK |title=Can a New Ultra-Long-Acting Insulin Analogue Improve Patient Care? Investigating the Potential Role of Insulin Degludec.|journal=Drugs|date=Nov 2, 2012|pmid=23145524|doi=10.2165/11642240-000000000-00000|volume=72|issue=18|pages=2319–25}}</ref>
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| ===Pharmacodynamics===
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| 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|last=Wang|first=F|author2=Surh, J |author3=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|year=2012|volume=5|pages=191–204|pmid=22826637|doi=10.2147/DMSO.S21979|pmc=3402007}}</ref>
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| ==Effectiveness profile==
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| Studies have shown that patients taking insulin degludec needed to take significantly smaller doses of [[basal rate|basal insulin]] than those taking insulin glargine, 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.<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.|accessdate=2010-11-07}}</ref><ref name=reuters>{{cite news|url=http://www.reuters.com/article/idUSLDE65P0DB20100626|work=[[Reuters]]|author=Ringstrom, Anna|title=Novo says degludec has potential to lower blood sugar|accessdate=2010-11-07|date=2010-06-26}}</ref> A physician involved in the trials was quoted as saying,
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| <blockquote>
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| "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|author=Lowry, Fran|work=[[Medscape]]|accessdate=2010-11-07}}</ref> </blockquote>
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| 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|accessdate=2012-01-27}}</ref> 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.<ref name=reuters2>{{cite news|url=http://www.reuters.com/article/idUSLDE69Q13H20101027?feedType=RSS&feedName=rbssHealthcareNews|work=Reuters|title=New Novo insulin fails to knock out rival Sanofi|author=Hirschler, Ben|date=2010-10-27|accessdate=2010-11-07}}</ref>
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| ==Clinical trial data==
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| ===Type 1 diabetes mellitus===
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| 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.<ref>{{cite journal|last=Heller|first=S|coauthors=Buse, J; Fisher, M; Garg, S; Marre, M; Merker, L; Renard, E; Russell-Jones, D; Philotheou, A; Francisco, AM; Pei, H; Bode, B; BEGIN Basal-Bolus Type 1 Trial, Investigators|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|date=Apr 21, 2012|volume=379|issue=9825|pages=1489–97|pmid=22521071|doi=10.1016/S0140-6736(12)60204-9}}</ref>
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| ===Type 2 diabetes mellitus===
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| 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 + 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|last=Garber|first=AJ|coauthors=King, AB; Del Prato, S; Sreenan, S; Balci, MK; Muñoz-Torres, M; Rosenstock, J; Endahl, LA; Francisco, AM; Hollander, P; NN1250-3582 (BEGIN BB T2D) Trial, Investigators|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|date=Apr 21, 2012|volume=379|issue=9825|pages=1498–507|pmid=22521072|doi=10.1016/S0140-6736(12)60205-0}}</ref>
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| ==Side effects==
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| A significant side effect of insulin therapy is hypoglycemia. A meta-analysis of clinical trails published in July 2012 found 39-47.9 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 3.7-5.1 events per patient year.<ref name="systematicrev"/>
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| ==References==
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| {{reflist|2|ref=
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| <ref name=CHMP2012>{{Citation |author=[[Committee for Medicinal Products for Human Use|CHMP]] |publication-date=October 18, 2012 |title=Summary of opinion 1 (initial authorisation): Tresiba |type=PDF |work=Pending EC decisions |publisher=[[European Medicines Agency|EMA]] |url=http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002498/WC500134060.pdf |accessdate=November 6, 2012 }}</ref>
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| }}
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| ==External links==
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| *[http://www.novonordisk.com/science/pipeline/rd_pipeline.asp?showid=4 Novo Nordisk]
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| *[http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Insulin+degludec U.S. National Library of Medicine: Drug Information Portal - Insulin degludec]
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| {{Oral hypoglycemics and insulin analogs}}
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| {{DEFAULTSORT:Insulin degludec}}
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| [[Category:Drug]]
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| [[Category:Insulin therapies]]
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| [[Category:Human proteins]]
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| [[Category:Recombinant proteins]]
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| [[Category:Peptide hormones]]
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