| Systematic (IUPAC) name | |
|---|---|
| L-histidyl-L-alanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-α-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-[N-(1-oxohexadecyl)-L-γ-glutamyl]-L-lysyl-L-α-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl-glycine | |
| Clinical data | |
| AHFS/Drugs.com | Consumer Drug Information |
| MedlinePlus | a611003 |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. | ? |
| Legal status | POM (UK) ℞-only (US) |
| Routes | Subcutaneous |
| Pharmacokinetic data | |
| Bioavailability | N/A |
| Half-life | 11-15 hours |
| Identifiers | |
| CAS number | 204656-20-2 |
| ATC code | A10BX07 |
| DrugBank | DB06655 |
| ChemSpider | 24571200 |
| UNII | 839I73S42A |
| KEGG | D06404 |
| Synonyms | Arg34Lys26-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1[7-37] |
| Chemical data | |
| Formula | C172H265N43O51 |
| Mol. mass | 3751.20 g/mol |
| SMILES | eMolecules & PubChem |
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Liraglutide (NN2211), marketed under the brand name Victoza, is a long-acting glucagon-like 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]
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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]
Novo Nordisk has reminded healthcare professionals of the serious risks associated with the use of Victoza. Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors in rats and mice. It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans.[11]
Studies to date suggest liraglutide improves control of blood glucose.[12]
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 identity 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 1.5–2 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.[13]
Liraglutide may have advantages over current therapies:
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 11–15 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.
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.[15]
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.[16]
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.[17]
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.
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