Insulin degludec

Identification

Summary

Insulin degludec is a long acting insulin used to treat hyperglycemia caused by type 1 and 2 diabetes mellitus.

Brand Names
Ryzodeg, Tresiba, Xultophy
Generic Name
Insulin degludec
DrugBank Accession Number
DB09564
Background

Insulin degludec is an ultra-long-acting form of insulin used for the treatment of hyperglycemia caused by Type 1 and Type 2 Diabetes. Insulin is typically prescribed for the management of diabetes mellitus to mimic the activity of endogenously produced human insulin, a peptide hormone produced by beta cells of the pancreas that promotes glucose metabolism. Insulin is released from the pancreas following a meal to promote the uptake of glucose from the blood into internal organs and tissues such as the liver, fat cells, and skeletal muscle. Absorption of glucose into cells allows for its transformation into glycogen or fat for storage. Insulin also inhibits hepatic glucose production, enhances protein synthesis, and inhibits lipolysis and proteolysis among many other functions.

Insulin is an important treatment in the management of Type 1 Diabetes (T1D) which is caused by an autoimmune reaction that destroys the beta cells of the pancreas, resulting in the body not being able to produce or synthesize the insulin needed to manage circulating blood sugar levels. As a result, people with T1D rely primarily on exogenous forms of insulin, such as insulin degludec, to lower glucose levels in the blood. Insulin is also used in the treatment of Type 2 Diabetes (T2D), another form of diabetes mellitus that is a slowly progressing metabolic disorder caused by a combination of genetic and lifestyle factors that promote chronically elevated blood sugar levels. Without treatment or improvement in non-pharmacological measures such as diet and exercise to lower blood glucose, high blood sugar eventually causes cellular resistance to endogenous insulin, and in the long term, damage to pancreatic islet cells. Insulin is typically prescribed later in the course of T2D, after several oral medications such as Metformin, Gliclazide, or Sitagliptin have been tried, when sufficient damage has been caused to pancreatic cells that the body is no longer able to produce insulin on its own.

Marketed as the brand name product Tresiba, insulin degludec has a duration of action up to 42 hours allowing for once-daily dosing, typically at bedtime. Due to its duration of action, Tresiba is considered "basal insulin" as it provides low concentrations of background insulin that can keep blood sugar stable between meals or overnight. Basal insulin is often combined with short-acting "bolus insulin" such as Insulin lispro, Insulin glulisine, or Insulin aspart to provide higher doses of insulin required following meals. Use of basal and bolus insulin together is intended to mimic the pancreas' production of endogenous insulin, with a goal of avoiding any periods of hypoglycemia.

Compared to endogenous insulin, insulin degludec has an added hexadecanedioic acid on lysine at the B29 position which allows for the formation of multi-hexamers. When injected subcutaneously, these multi-hexamers form a drug depot store from which monomers are slowly and continuously absorbed into the circulation. As a result, Insulin Degludec has a protracted time action profile due to the delayed absorption from subcutaneous tissue depots into the systemic circulation. Compared to available long-acting analogues such as Insulin glargine and Insulin detemir, which have a duration of action of 20-24 hours, insulin degludec provides a consistent level of basal insulin over 42 hours with a low peak:trough ratio. Limitations of shorter acting analogues include more frequent dosing and less stable pharmacokinetics, which may negatively impact patient adherence and glucose control, particularly nocturnal control.

Without an adequate supply of insulin to promote absorption of glucose from the bloodstream, blood sugar levels can climb to dangerously high levels and can result in symptoms such as fatigue, headache, blurred vision, and increased thirst. If left untreated, the body starts to break down fat, instead of glucose, for energy which results in a build-up of ketone acids in the blood and a syndrome called ketoacidosis, which is a life-threatening medical emergency. In the long term, elevated blood sugar levels increase the risk of heart attack, stroke, and diabetic neuropathy.

Insulin Degludec was approved by the FDA in September 2015 as the product Tresiba, for use in providing glycemic control to adults with diabetes mellitus.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Hormones / Insulins
Protein Structure
Db09564
Protein Chemical Formula
C274H411N65O81S6
Protein Average Weight
6103.97 Da
Sequences
>A Chain
GIVEQCCTSICSLYQLENYCN
>B Chain
FVNQHLCGSHLVEALYLVCGERGFFYTPK
References:
  1. FDA Approved Drug Products: Tresiba (insulin degludec) for subcutaneous injection [Link]
Download FASTA Format
Synonyms
  • Insulin degludec
  • Insulina degludec
External IDs
  • NN-1250
  • NN1250

Pharmacology

Indication

Insulin degludec is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by the liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin.

Mechanism of action

Insulin detemir binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signalling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism.

TargetActionsOrganism
AInsulin receptor
agonist
Humans
UInsulin-like growth factor 1 receptor
activator
Humans
Absorption

In patients with type 1 diabetes, after 8 days of once daily subcutaneous dosing with 0.4 U/kg, maximum degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (tmax). After the first dose of, median onset of appearance was around one hour. The glucose lowering effect lasted at least 42 hours after the last of 8 once-daily injections. Insulin degludec concentration reach steady state levels after 3-4 days.

Volume of distribution

Not Available

Protein binding

The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma. The results of the in vitro protein binding studies demonstrate that there is no clinically relevant interaction between insulin degludec and other protein bound drugs.

Metabolism

All insulin degludec metabolites are inactive.

Route of elimination

Not Available

Half-life

The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue. On average, the half-life at steady state is approximately 25 hours independent of dose.

Clearance

The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individual) after single subcutaneous dose of 0.4 units/kg.

Adverse Effects
Medicalerrors
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Toxicity

Observe for signs and symptoms of hypoglycemia, hypokalemia, and fluid retention and heart failure with concomitant use of Thiazolidinediones. Pregnancy Category C

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Insulin degludec.
AcebutololThe therapeutic efficacy of Insulin degludec can be increased when used in combination with Acebutolol.
AcetazolamideThe therapeutic efficacy of Insulin degludec can be increased when used in combination with Acetazolamide.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Insulin degludec.
Acetyl sulfisoxazoleThe therapeutic efficacy of Insulin degludec can be increased when used in combination with Acetyl sulfisoxazole.
Acetylsalicylic acidThe risk or severity of hypoglycemia can be increased when Acetylsalicylic acid is combined with Insulin degludec.
AlbiglutideAlbiglutide may increase the hypoglycemic activities of Insulin degludec.
AlclometasoneThe risk or severity of hyperglycemia can be increased when Alclometasone is combined with Insulin degludec.
AlogliptinAlogliptin may increase the hypoglycemic activities of Insulin degludec.
AmcinonideThe risk or severity of hyperglycemia can be increased when Amcinonide is combined with Insulin degludec.
Interactions
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Food Interactions
  • Avoid alcohol. Alcohol may impair blood glucose control.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TresibaInjection, solution100 U/mlSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
TresibaInjection, solution200 U/mlSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
TresibaInjection, solution200 U/1mLSubcutaneousNovo Nordisk2015-09-25Not applicableUS flag
TresibaInjection, solution200 U/mlSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
TresibaInjection, solution100 U/mlSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
TresibaInjection, solution100 U/mlSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
TresibaSolution100 unit / mLSubcutaneousNovo Nordisk2017-09-15Not applicableCanada flag
TresibaInjection, solution200 U/mlSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
TresibaInjection, solution100 U/mlSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
TresibaInjection, solution100 U/1mLSubcutaneousNovo Nordisk2015-09-25Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
Ryzodeg 70/30Insulin degludec (70 U/1mL) + Insulin aspart (30 U/1mL)Injection, solutionSubcutaneousNovo Nordisk2018-01-012018-01-01US flag
RYZODEG FLEXTOUCH 100 U/ML ENJEKSİYONLUK ÇOZELTİ İÇEREN KULLANIMA HAZIR KALEM, 1 ADETInsulin degludec (2.56 mg) + Insulin aspart (1.05 mg)InjectionNOVO NORDİSK SAĞLIK ÜRÜNLERİ TİC. LTD. ŞTİ.2020-08-14Not applicableTurkey flag
RYZODEG FLEXTOUCH 100 U/ML ENJEKSİYONLUK ÇOZELTİ İÇEREN KULLANIMA HAZIR KALEM, 10 ADETInsulin degludec (300 IU) + Insulin aspart (100 IU)InjectionNOVO NORDİSK SAĞLIK ÜRÜNLERİ TİC. LTD. ŞTİ.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
A10AD06 — Insulin degludec and insulin aspartA10AE56 — Insulin degludec and liraglutideA10AE06 — Insulin degludec
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
54Q18076QB
CAS number
844439-96-9

References

General References
  1. Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, Rosenstock J, Endahl LA, Francisco AM, Hollander P: 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. 2012 Apr 21;379(9825):1498-507. doi: 10.1016/S0140-6736(12)60205-0. [Article]
  2. Wang F, Surh J, Kaur M: Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review. Diabetes Metab Syndr Obes. 2012;5:191-204. doi: 10.2147/DMSO.S21979. Epub 2012 Jul 5. [Article]
  3. Haahr H, Heise T: A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet. 2014 Sep;53(9):787-800. doi: 10.1007/s40262-014-0165-y. [Article]
  4. Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U: Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012 Aug;29(8):2104-14. doi: 10.1007/s11095-012-0739-z. Epub 2012 Apr 7. [Article]
  5. Thuillier P, Alavi Z, Kerlan V: Long-term safety and efficacy of insulin degludec in the management of type 2 diabetes. Diabetes Metab Syndr Obes. 2015 Oct 1;8:483-93. doi: 10.2147/DMSO.S54953. eCollection 2015. [Article]
  6. FDA Approved Drug Products: Tresiba (insulin degludec) for subcutaneous injection [Link]
KEGG Drug
D09727
PubChem Substance
347910463
RxNav
1670007
ChEMBL
CHEMBL2107869
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Insulin_degludec
AHFS Codes
  • 68:20.08.16 — Long-acting Insulins
FDA label
Download (7.77 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentType 2 Diabetes Mellitus1
4CompletedTreatmentNocturnal Hypoglycemia / Recurrent Severe Hypoglycaemia / Type 1 Diabetes Mellitus1
4CompletedTreatmentType 1 Diabetes Mellitus2
4CompletedTreatmentType 2 Diabetes Mellitus5
4CompletedTreatmentType1 Diabetes Mellitus1
4RecruitingTreatmentType 1 Diabetes Mellitus3
4RecruitingTreatmentType 2 Diabetes Mellitus1
4TerminatedTreatmentType 2 Diabetes Mellitus1
4Unknown StatusTreatmentType 1 Diabetes Mellitus1
4Unknown StatusTreatmentType 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous
Injection
Injection, solutionSubcutaneous
Injection, solutionSubcutaneous100 U/1mL
Injection, solutionSubcutaneous100 U/ml
Injection, solutionSubcutaneous200 U/1mL
Injection, solutionSubcutaneous200 U/ml
SolutionSubcutaneous100 unit / mL
SolutionSubcutaneous200 unit / mL
SolutionSubcutaneous100 IU
SolutionSubcutaneous200 IU
InjectionSubcutaneous100 IU/ml
Injection, solutionParenteral; Subcutaneous
InjectionSubcutaneous
SolutionSubcutaneous
Injection, solution
Injection, solutionSubcutaneous100 iu/1ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8672898Yes2014-03-182022-07-02US flag
US8684969Yes2014-04-012026-04-20US flag
US9132239Yes2015-09-152032-08-01US flag
US8920383Yes2014-12-302027-01-17US flag
US7686786No2010-03-302026-08-03US flag
US6899699Yes2005-05-312022-07-01US flag
US5866538Yes1999-02-022017-12-20US flag
US9108002Yes2015-08-182026-07-26US flag
US6458924No2002-10-012017-08-22US flag
US6268343Yes2001-07-312023-02-22US flag
US8846618Yes2014-09-302022-12-27US flag
US7235627No2007-06-262017-08-22US flag
US7615532Yes2009-11-102029-12-28US flag
US9486588Yes2016-11-082022-07-02US flag
US9457154Yes2016-10-042028-03-27US flag
USRE46363Yes2017-04-112027-02-03US flag
US8937042Yes2015-01-202029-11-05US flag
US9687611Yes2017-06-272027-08-27US flag
US9775953Yes2017-10-032027-01-17US flag
US8579869Yes2013-11-122023-12-30US flag
US7762994Yes2010-07-272024-11-23US flag
US9884094No2018-02-062033-05-01US flag
US9861757Yes2018-01-092026-07-20US flag
US9616180Yes2017-04-112026-07-20US flag
US10220155Yes2019-03-052027-01-17US flag
US10357616No2019-07-232026-01-20US flag
US10376652No2019-08-132026-01-20US flag

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor signaling protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (...
Gene Name
INSR
Uniprot ID
P06213
Uniprot Name
Insulin receptor
Molecular Weight
156331.465 Da
References
  1. De Meyts P: The Insulin Receptor and Its Signal Transduction Network . [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Activator
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involv...
Gene Name
IGF1R
Uniprot ID
P08069
Uniprot Name
Insulin-like growth factor 1 receptor
Molecular Weight
154791.73 Da
References
  1. Wang F, Surh J, Kaur M: Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review. Diabetes Metab Syndr Obes. 2012;5:191-204. doi: 10.2147/DMSO.S21979. Epub 2012 Jul 5. [Article]
  2. Varewijck AJ, Janssen JA: Insulin and its analogues and their affinities for the IGF1 receptor. Endocr Relat Cancer. 2012 Sep 5;19(5):F63-75. doi: 10.1530/ERC-12-0026. Print 2012 Oct. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Barnett CR, Wilson J, Wolf CR, Flatt PR, Ioannides C: Hyperinsulinaemia causes a preferential increase in hepatic P4501A2 activity. Biochem Pharmacol. 1992 Mar 17;43(6):1255-61. doi: 10.1016/0006-2952(92)90500-i. [Article]
  2. Pass GJ, Becker W, Kluge R, Linnartz K, Plum L, Giesen K, Joost HG: Effect of hyperinsulinemia and type 2 diabetes-like hyperglycemia on expression of hepatic cytochrome p450 and glutathione s-transferase isoforms in a New Zealand obese-derived mouse backcross population. J Pharmacol Exp Ther. 2002 Aug;302(2):442-50. doi: 10.1124/jpet.102.033553. [Article]
  3. Flockhart Table of Drug Interactions [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Ryberg LA, Sonderby P, Barrientos F, Bukrinski JT, Peters GHJ, Harris P: Solution structures of long-acting insulin analogues and their complexes with albumin. Acta Crystallogr D Struct Biol. 2019 Mar 1;75(Pt 3):272-282. doi: 10.1107/S2059798318017552. Epub 2019 Feb 26. [Article]

Drug created on November 30, 2015 19:10 / Updated on June 12, 2021 01:53