Liraglutide

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Liraglutide

Systematic (IUPAC) name

L-histidyl-L-alanyl-L--glutamylglycyl-L-threonyl-L-phenylalanyl-Lthreonyl-L-seryl-L--aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-[N-(1-oxohexadecyl)L--glutamyl]-L-lysyl-L--glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-Ltryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl-glycine

Clinical data
Licence data
Pregnancy cat.
Legal status
Routes

EMA:Link, US FDA:link
?
POM (UK) -only (US)
Subcutaneous
Pharmacokinetic data

Bioavailability
Half-life

N/A
11-15 hours
Identifiers

CAS number

204656-20-2

ATC code

A10BX07

ChemSpider

24571200

UNII
KEGG
Synonyms

839I73S42A
D06404
Arg34Lys26-(N--(-Glu(N-hexadecanoyl)))-GLP-1[7-37]
Chemical data

Formula

C172H265N43O51

Mol. mass

3751.20 g/mol

SMILES

eMolecules & PubChem

InChI[show]
(what is this?) (verify)

Liraglutide (NN2211), marketed under the brand name Victoza, is a long-acting glucagonlike peptide-1 (GLP-1) analog that has been developed by Novo Nordisk for the treatment of
type 2 diabetes. The product was approved by the European Medicines Agency (EMA) on
July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.[1][2][3]
[4][5]

Liraglutide is marketed under the brandname Victoza in the U.S., Canada, Europe and Japan.
It has been launched in Germany, Denmark, the Netherlands, the United Kingdom, Ireland,
Sweden, Japan, Canada the United States, France, Malaysia and Singapore.
Phase I trials of an oral variant of Victoza (NN9924) started in 2010.[6]

Contents
[hide]

1 Cancer concerns
2 Pharmacodynamics
3 Pharmacokinetics
4 Controversy
5 Marketing

6 See also

7 References

[edit] Cancer concerns

On April 2, 2009, an FDA advisory panel reviewed the significance of malignant C-cell
carcinoma and thyroid C-cell focal hyperplasia in rats and mice. Some say the tumors were
caused by a nongenotoxic, specific receptor-mediated mechanism to which rodents are
particularly sensitive, whereas nonhuman primates and humans are not.[7][8] The Victoza label
carries a Black Box Warning, "Because of the uncertain relevance of the rodent thyroid C-cell
tumor findings to humans, prescribe Victoza only to patients for whom the potential benefits
are considered to outweigh the potential risk".[9] The FDA said serum calcitonin, a biomarker
of medulliary thyroid cancer, was slightly increased in liraglutide patients, but still within
normal ranges, and it required ongoing monitoring for 15 years in a cancer registry.[10]

[edit] Pharmacodynamics
Studies to date suggest liraglutide improves control of blood glucose.[11]
It reduces meal-related hyperglycemia (for 12 hours after administration) by increasing
insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.
Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, with a
97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37)
represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide
activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl
cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases
intracellular cyclic AMP (cAMP), leading to insulin release in the presence of elevated
glucose concentrations. This insulin secretion subsides as blood glucose concentrations
decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a
glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay
in gastric emptying. GLP-1(7-37) has a half-life of 1.52 minutes due to degradation by the
ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral
endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic
degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous
administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once
daily administration, is a result of self-association that delays absorption, plasma protein
binding and stability against metabolic degradation by DPP-IV and NEP.[12]
Liraglutide may have advantages over current therapies:

It acts in a glucose-dependent manner, meaning it will stimulate insulin secretion only

when blood glucose levels are higher than normal. Consequently, it shows negligible risk
of hypoglycemia.
It has the potential for inhibiting apoptosis and stimulating regeneration of beta cells
(seen in animal studies).
It decreases appetite and maintains body weight, as shown in a head-to-head study
versus glimepiride.[13]

It lowers blood triglyceride levels.

It has only mild and transient side effects, mainly gastrointestinal.

[edit] Pharmacokinetics
Liraglutide is a once-daily GLP-1 derivative for the treatment of type 2 diabetes. GLP-1, in its
natural form, is short-lived in the body (the half-life after subcutaneous injection is
approximately one hour), so it is not very useful as a therapeutic agent. However, liraglutide
has a half-life after subcutaneous injection of 1115 hours, making it suitable for once-daily
dosing (less frequent than the currently approved Byetta form of exenatide, which is twice
daily, but considerably more frequent than the once weekly Bydureon form of exenatide
awaiting a decision from the FDA regarding marketing approval).
The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at one
position of the GLP-1 molecule, enabling it to bind to albumin within the subcutaneous tissue
and bloodstream. The active GLP-1 is then released from albumin at a slow, consistent rate.
Binding with albumin also results in slower degradation and reduced elimination of liraglutide
from the circulation by the kidneys compared to GLP-1.[citation needed]glp-1

[edit] Controversy
In 2010, Novo Nordisk breached the ABPIs code of conduct by failing to provide information
about side effects of Victoza, and by promoting Victoza prior to being granted market
authorization.[14]

[edit] Marketing
Published reports suggest Novo Nordisk will market liraglutide in the United States with a
sales force of 1,900 sales representatives, and the sales force will emphasize the product's
weight loss properties.[15]
One of the marketing tactics Novo Nordisk is using to promote Victoza is a reusable coupon
that yields a savings of up to $25 per prescription for six prescriptions.[16]
Novo Nordisk has made direct-to-consumer advertising of liraglutide in Sweden (May 2011),
through a 6-page supplement in the free newspaper Metro. Although the name of the drug was
not explicitly mentioned (this is illegal in the European Union), it could easily be identified
through supplied information on dosage and pharmacodynamics.

[edit] See also

Glucagon-like peptide-1 analogs:

exenatide (Byetta)
albiglutide
taspoglutide
DPP4 inhibitors
Incretin

[edit] References
1. ^ http://www.drugs.com/nda/liraglutide_080530.html May 2008
2. ^ http://www.medicalnewstoday.com/articles/110349.php "Clinical Study Shows
Liraglutide Reduced Blood Sugar, Weight, And Blood Pressure In Patients With
Type 2 Diabetes" June 2008
3. ^ http://www.drugdevelopment-technology.com/projects/liraglutide/
4. ^ http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp Oct
2008 Inc results of LEAD 6 extension
5. ^ http://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm
January 2009
6. ^ Hirschler, Ben (January 13, 2010). "UPDATE 1-Novo starts tests on pill
version of Victoza drug". Reuters.
http://www.reuters.com/article/idUSLDE60C0CB20100113.
7. ^ "Sector Snap: New Diabetes Drugs Under FDA Review". Forbes.
http://www.forbes.com/feeds/ap/2009/03/26/ap6217929.html. Retrieved March
27, 2009.[dead link]
8. ^
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateri
als/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148659.p
df
9. ^ Victoza Package Insert Date of Issue: January 2010 Version: 1
10. ^ N Engl J Med, 362:774
11. ^ http://diabetes.webmd.com/news/20080924/new-diabetes-drug-liraglutideworks Sept 2008
12. ^ (www.drugs.com)
13. ^ http://care.diabetesjournals.org/cgi/content/abstract/32/1/84 "Efficacy and
Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination
With Metformin, in Type 2 Diabetes" Diabetes Care. Oct 2008
14. ^ "Novo Nordisk Limited, Eli Lilly and Company Limited, Grnenthal Ltd and
Napp Pharmaceuticals Limited named in advertisements". Prescription
Medicines Code of Practice Authority (PMCPA). http://www.pmcpa.org.uk/?
q=node/878. Retrieved 2011-02-07.
15. ^ http://www.mmm-online.com/novo-reps-to-spotlight-weight-loss-for-victozalaunch/article/163167/ | Medical Media & Marketing; Novo reps to spotlight
weight loss for Victoza launch; 2/4/2010; Ben Comer
16. ^ http://www.internetdrugcoupons.com/Victoza-Coupon%7C
Internetdrugcoupons.com; Victoza Coupon; 3/23/2010;

[hide]v d eOral anti-diabetic drugs and Insulin analogs (A10)

BiguanidesMetformin# Buformin Phenformin
Sensitizers
Insulin

TZDs (PPAR)
Dual PPAR agonist

Secretagogues

K+ ATP

Pioglitazone Rivoglitazone
Rosiglitazone Troglitazone
Aleglitazar Muraglitazar
Tesaglitazar
Sulfonylureas1st generation:
Acetohexamide
Carbutamide

Chlorpropamide
Tolbutamide
Tolazamide
2nd generation:
Glibenclamide
(Glyburide)#
Glipizide
Gliquidone
Glyclopyramide
Glimepiride
Gliclazide
Nateglinide
Meglitinides/"glinides"Repaglinide
Mitiglinide
GLP-1 analogs
DPP-4 inhibitors

Exenatide Liraglutide Taspoglutide

Albiglutide Lixisenatide
Alogliptin Linagliptin Saxagliptin
Sitagliptin Vildagliptin

fast-acting (Insulin lispro Insulin aspart Insulin

glulisine) short-acting (Regular insulin) long-acting
Analogs/other insulins
(Insulin glargine Insulin detemir NPH insulin) ultralong-acting (Insulin degludec) inhalable Exubera
Alpha-glucosidase inhibitorsAcarbose Miglitol Voglibose
Amylin analogPramlintide
Other

Canagliflozin Dapagliflozin Remogliflozin

SGLT2 inhibitors
Sergliflozin
OtherBenfluorex Tolrestat

WHO-EM. Withdrawn from market. Clinical trials: Phase III. Never to phase III
M: END

anat/phys/devp/horm

noco(d)/cong/tumr,
sysi/epon

proc, drug
(A10/H1/H2/H3/H5)

Liraglutide - Next-Generation Antidiabetic

Medication

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Key Data
Drug (Brand/Generic)
Liraglutide
Company/Licensee
Novo Nordisk
Therapy Class
GLP-1 analogue
Product Description
Long-acting human analogue of naturally occurring hormone, GLP-1
Current Indication
Type 2 diabetic patients poorly controlled with diet plus metformin and/or sulfonylureas
Market Sector
Diabetes
Development Status
Approved Europe, US and Japan
Full specifications
Under development by Novo Nordisk, liraglutide is a member of a new class of antidiabetic
medications called GLP-1 analogues. These mirror the effects of naturally produced glucagonlike peptide-1 (GLP-1), which includes glucose-dependent stimulation of insulin secretion,
suppression of glucagon secretion, reduction of appetite and delay of food absorption.
Based primarily on data from the LEAD Phase III trials, in May 2008 the company submitted
a New Drug Application (NDA) to regulatory authorities in the US and Europe. Somewhat
earlier than expected, filling subsequently followed in Japan in July 2008.