Liraglutide

Identification

Name

Liraglutide

Accession Number

DB06655

Description

Victoza contains liraglutide, a synthetic analog of human glucagon-like peptide-1(GLP-1) and acts as a GLP-1 receptor agonist^Label,1. Liraglutide is 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34¹. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor¹. Liraglutide was granted FDA approval on Januray 25, 2010⁴.

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Hormones

Protein Chemical Formula

C₁₇₂H₂₆₅N₄₃O₅₁

Protein Average Weight

3751.2 Da

Sequences

>Liraglutide Sequence (gamma-E-palmitoyl at E21)
HAEGTFTSDVSSYLEGQAAKEEFIAWLVRGRG

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Synonyms

Arg34Lys26-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1[7-37]
Liraglutida
Liraglutide (genetical recombination)
Liraglutide (rDNA origin)
Liraglutide recombinant
Liraglutidum
N²⁶-(hexadecanoyl-gamma-glutamyle)-[34-arginine]GLP-1-(7-37)-peptide
N²⁶-(N-Hexadecanoyl-L-gamma-glutamyl)-[34-L-arginine]glucagon-like peptide 1-(7-37)-peptide

External IDs

NN 2211
NN-2211
NN-9924
NN2211
NN9924
NNC 90-1170
NNC-90-1170

Pharmacology

Indication

Liraglutide is indicated in combination with diet and exercise to improve glycemic control in patients 10 years and older with type 2 diabetes mellitus^Label,5. It is also indicated to reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes mellitus as well as cardiovascular disease^Label.

Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Liraglutide is a once-daily GLP-1 derivative for the treatment of type 2 diabetes^Label,2. The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at position 26 of the GLP-1 molecule, enabling it to bind reversibly to albumin within the subcutaneous tissue and bloodstream and be released slowly over time^Label,2,3. Binding with albumin results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1^2,3. The effect of liraglutide is the increased secretion of insulin and decreased secretion of glucagon in response to glucose as well as slower gastric emptying^Label. Liraglutide also does not adversely affect glucagon secretion in response to low blood sugar^Label,2.

Mechanism of action

Liraglutide is an acylated synthetic glucagon-like peptide-1 analog^Label,1,2. Liraglutide is an agonist of the glucagon-like peptide-1 receptor which is coupled to adenylate cyclase^Label. The increase in cyclic AMP stimulates the glucose dependant release of insulin, inhibits the glucose dependant release of glucagon, and slows gastric emptying to increase control of blood sugar^Label,3.

Target	Actions	Organism
AGlucagon-like peptide 1 receptor	agonist	Humans

Absorption

Bioavailability of liraglutide after subcutaneous injection is approximately 55%^Label and maximum concentrations are reached after 11.7 hours¹.

Volume of distribution

13L^Label.

Protein binding

>98%^Label.

Metabolism

Liraglutide is less sensitive to metabolism than the endogenous GLP-1 and so is more slowly metabolized by dipeptidyl peptidase-4 and neutral endopeptidase to various smaller polypeptides which have not all been structurally determined¹. A portion of Liraglutide may be completely metabolized to carbon dioxide and water¹.

Route of elimination

6% excreted in urine and 5% excreted in feces¹.

Half-life

Terminal half life of 13 hours¹.

Clearance

1.2L/h^Label.

Adverse Effects

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Toxicity

There is no clinical significance of race or ethnicity on the safety or efficacy of liraglutide^Label. Geriatric patients do not experience clinically significant differences in pharmacokinetics though patients at an especially advanced age may be more susceptible to adverse effects^Label. Female patients have reduced clearance of liraglutide but no dose adjustment is necessary^Label. The risk and benefit of liraglutide in pregnancy must be weighed before prescribing^Label. In animal studies, liraglutide is associated with an increased risk of embryonic death and fetal abnormalities though an HbA1c > 7 is also associated with a 20-25% risk of birth defects^Label. In animal studies, liraglutide is present in the milk of lactating rats at half the plasma concentration of the mother but these results may not translate to humans^Label. Because it is not known if liraglutide is present in breast milk and the effects on infants are also unknown, the risk and benefit of liraglutide in breastfeeding must be considered before prescribing^Label. Liraglutide was shown to be safe and effective in patients up to 160kg in weight but has not been studied in patients at a higher weight^Label. A patient's weight significantly affects the pharmacokinetics of liraglutide^Label. Liraglutide has not been investigated for use in pediatric patients^Label. No dosage adjustments are necessary in patients with renal impairment but studies have not been performed in patients with end stage renal disease^Label. There are no recommendations on dosage adjustment in patients with hepatic impairment, though caution should still be exercised when prescribing to this population^Label.

Affected organisms

Humans and other mammals

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.

Drug	Interaction
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Acarbose	The risk or severity of hypoglycemia can be increased when Acarbose is combined with Liraglutide.
Acebutolol	The therapeutic efficacy of Liraglutide can be increased when used in combination with Acebutolol.
Acetazolamide	The therapeutic efficacy of Liraglutide can be increased when used in combination with Acetazolamide.
Acetohexamide	Liraglutide may increase the hypoglycemic activities of Acetohexamide.
Acetyl sulfisoxazole	The therapeutic efficacy of Liraglutide can be increased when used in combination with Acetyl sulfisoxazole.
Acetylsalicylic acid	The risk or severity of hypoglycemia can be increased when Acetylsalicylic acid is combined with Liraglutide.
Albiglutide	The risk or severity of hypoglycemia can be increased when Liraglutide is combined with Albiglutide.
Alclometasone	The risk or severity of hyperglycemia can be increased when Alclometasone is combined with Liraglutide.
Alogliptin	The risk or severity of hypoglycemia can be increased when Alogliptin is combined with Liraglutide.
Amcinonide	The risk or severity of hyperglycemia can be increased when Amcinonide is combined with Liraglutide.

Additional Data Available

Extended Description

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Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

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A severity rating for each drug interaction, from minor to major.

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Evidence Level

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A rating for the strength of the evidence supporting each drug interaction.

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Action

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An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

Take with or without food.

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Saxenda	Injection, solution	6 mg/ml	Subcutaneous	Novo Nordisk	2015-03-23	Not applicable
Saxenda	Injection, solution	6 mg/1mL	Subcutaneous	Novo Nordisk	2014-12-31	Not applicable
Saxenda	Injection, solution	6 mg/ml	Subcutaneous	Novo Nordisk	2015-03-23	Not applicable
Saxenda	Solution	6 mg	Subcutaneous	Novo Nordisk	2015-05-27	Not applicable
Saxenda	Injection, solution	6 mg/1mL	Subcutaneous	A-S Medication Solutions	2014-12-31	Not applicable
Saxenda	Injection, solution	6 mg/ml	Subcutaneous	Novo Nordisk	2015-03-23	Not applicable
Victoza	Injection, solution	6 mg/ml	Subcutaneous	Novo Nordisk	2009-06-30	Not applicable
Victoza	Solution	6 mg	Subcutaneous	Novo Nordisk	2010-05-27	Not applicable
Victoza	Injection, solution	6 mg/ml	Subcutaneous	Novo Nordisk	2009-06-30	Not applicable
Victoza	Injection, solution	6 mg/ml	Subcutaneous	Novo Nordisk	2009-06-30	Not applicable

Additional Data Available

Application Number

Available for Purchase

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

Available for Purchase

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Xultophy	Liraglutide (3.6 mg) + Insulin degludec (100 unit)	Solution	Subcutaneous	Novo Nordisk	2018-06-06	Not applicable
Xultophy	Liraglutide (3.6 mg/ml) + Insulin degludec (100 U/ml)	Injection, solution	Subcutaneous	Novo Nordisk	2016-09-08	Not applicable
Xultophy	Liraglutide (3.6 mg/ml) + Insulin degludec (100 U/ml)	Injection, solution	Subcutaneous	Novo Nordisk	2016-09-08	Not applicable
Xultophy	Liraglutide (3.6 mg/ml) + Insulin degludec (100 U/ml)	Injection, solution	Subcutaneous	Novo Nordisk	2016-09-08	Not applicable
Xultophy 100/3.6	Liraglutide (3.6 mg/1mL) + Insulin degludec (100 [iU]/1mL)	Injection, solution	Subcutaneous	Novo Nordisk	2016-11-21	Not applicable
Xultophy Pre-filled Pen	Liraglutide (3.6 mg/ml) + Insulin degludec (100 U/ml)	Injection, solution	Subcutaneous	Novo Nordisk	2016-09-08	Not applicable

Chemical Identifiers

UNII: 839I73S42A
CAS number: 204656-20-2

References

General References

Malm-Erjefalt M, Bjornsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, van Lier JJ, Zdravkovic M, Olsen AK: Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010 Nov;38(11):1944-53. doi: 10.1124/dmd.110.034066. Epub 2010 Aug 13. [PubMed:20709939]
Knudsen B, Jesper Lau: The Discovery and Development of Liraglutide and Semaglutide Frontiers in Endocrinology.
Russell-Jones D: Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):137-40. doi: 10.1016/j.mce.2008.11.018. Epub 2008 Nov 25. [PubMed:19041364]
FDA Drug Approval Package: Liraglutide [Link]
FDA News Release: Liraglutide Indication [Link]

External Links

UniProt: P01275
KEGG Drug: D06404
PubChem Substance: 347910356
RxNav: 475968
ChEBI: 71193
ChEMBL: CHEMBL1201866
PharmGKB: PA165958364
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Liraglutide

AHFS Codes

68:20.06 — Incretin Mimetics

FDA label

Download (1.32 MB)

MSDS

Download (569 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Basic Science	Insulin Resistance	1
4	Active Not Recruiting	Other	BMI >30 kg/m2	1
4	Active Not Recruiting	Other	Type 2 Diabetes Mellitus	1
4	Active Not Recruiting	Treatment	BMI >30 kg/m2	2
4	Active Not Recruiting	Treatment	BMI >30 kg/m2 / Diabetes Mellitus / Weight Loss	1
4	Active Not Recruiting	Treatment	Type 2 Diabetes Mellitus	1
4	Active Not Recruiting	Treatment	Type II Diabetes in Subjects BMI 27 to 32	1
4	Completed	Basic Science	Diabetes / Effects of Liraglutide Administration on Brain Activity / Hunger / Weight Loss	1
4	Completed	Basic Science	Healthy Human Male Subjects	1
4	Completed	Basic Science	Systolic Hypertension / Type 2 Diabetes Mellitus	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Subcutaneous	6 mg/ml
Injection, solution	Subcutaneous	6 mg/1mL
Injection	Subcutaneous	6 mg/ml
Solution	Subcutaneous	6 mg
Injection	Subcutaneous	6 mg/1mL
Injection, solution		18 mg/3mL
Injection, solution	Parenteral; Subcutaneous	6 MG/ML
Injection	Subcutaneous	100 IU/ml
Injection, solution		100 iu/1mL
Injection, solution	Parenteral; Subcutaneous	100 IU/ml
Injection, solution	Subcutaneous
Solution	Subcutaneous
Injection	Subcutaneous	3.6 mg/mL
Solution	Subcutaneous	100 U

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
Unlock Additional Data
CA2264243	No	2004-10-05	2017-08-22
US8672898	Yes	2014-03-18	2022-07-02
US8684969	Yes	2014-04-01	2026-04-20
US9132239	Yes	2015-09-15	2032-08-01
US8920383	Yes	2014-12-30	2027-01-17
US7686786	No	2010-03-30	2026-08-03
US6899699	Yes	2005-05-31	2022-07-01
US9108002	Yes	2015-08-18	2026-07-26
USRE41956	Yes	2010-11-23	2021-07-21
US9265893	Yes	2016-02-23	2033-03-23
US6004297	Yes	1999-12-21	2019-07-28
USRE43834	No	2012-11-27	2019-01-28
US6458924	No	2002-10-01	2017-08-22
US6268343	Yes	2001-07-31	2023-02-22
US8846618	Yes	2014-09-30	2022-12-27
US8114833	Yes	2012-02-14	2026-02-13
US7235627	No	2007-06-26	2017-08-22
US7615532	Yes	2009-11-10	2029-12-28
US9486588	Yes	2016-11-08	2022-07-02
US9457154	Yes	2016-10-04	2028-03-27
USRE46363	Yes	2017-04-11	2027-02-03
US8937042	Yes	2015-01-20	2029-11-05
US9687611	Yes	2017-06-27	2027-08-27
US9775953	Yes	2017-10-03	2027-01-17
US8579869	Yes	2013-11-12	2023-12-30
US7762994	Yes	2010-07-27	2024-11-23
US9968659	Yes	2018-05-15	2037-07-09
US9861757	Yes	2018-01-09	2026-07-20
US9616180	Yes	2017-04-11	2026-07-20
US10220155	Yes	2019-03-05	2027-01-17
US10357616	No	2019-07-23	2026-01-20
US10376652	No	2019-08-13	2026-01-20

Additional Data Available

Filed On

Available for Purchase

The date on which a patent was filed with the relevant government.

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Properties

State

Solid

Experimental Properties

Property	Value	Source
isoelectric point	4.9	https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206321Orig1s000ChemR.pdf

Targets

Details1. Glucagon-like peptide 1 receptor

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Agonist

General Function: Transmembrane signaling receptor activity
Specific Function: This is a receptor for glucagon-like peptide 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name: GLP1R
Uniprot ID: P43220
Uniprot Name: Glucagon-like peptide 1 receptor
Molecular Weight: 53025.22 Da

References

Bock T, Pakkenberg B, Buschard K: The endocrine pancreas in non-diabetic rats after short-term and long-term treatment with the long-acting GLP-1 derivative NN2211. APMIS. 2003 Dec;111(12):1117-24. [PubMed:14678021]
Larsen PJ, Wulff EM, Gotfredsen CF, Brand CL, Sturis J, Vrang N, Knudsen LB, Lykkegaard K: Combination of the insulin sensitizer, pioglitazone, and the long-acting GLP-1 human analog, liraglutide, exerts potent synergistic glucose-lowering efficacy in severely diabetic ZDF rats. Diabetes Obes Metab. 2008 Apr;10(4):301-11. doi: 10.1111/j.1463-1326.2008.00865.x. [PubMed:18333889]

Enzymes

Details1. Dipeptidyl peptidase 4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Virus receptor activity
Specific Function: Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by bindi...
Gene Name: DPP4
Uniprot ID: P27487
Uniprot Name: Dipeptidyl peptidase 4
Molecular Weight: 88277.935 Da

References

Malm-Erjefalt M, Bjornsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, van Lier JJ, Zdravkovic M, Olsen AK: Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010 Nov;38(11):1944-53. doi: 10.1124/dmd.110.034066. Epub 2010 Aug 13. [PubMed:20709939]

Details2. Neprilysin

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Zinc ion binding
Specific Function: Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptide...
Gene Name: MME
Uniprot ID: P08473
Uniprot Name: Neprilysin
Molecular Weight: 85513.225 Da

References

Malm-Erjefalt M, Bjornsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, van Lier JJ, Zdravkovic M, Olsen AK: Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010 Nov;38(11):1944-53. doi: 10.1124/dmd.110.034066. Epub 2010 Aug 13. [PubMed:20709939]

Carriers

Details1. Serum albumin

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