Liraglutide
Encyclopedia
Liraglutide 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.
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.
The Victoza label carries a Black Box Warning: 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.
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.
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.
Liraglutide may have advantages over current therapies:
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.
code of conduct by failing to provide information about side effects of Victoza, and by promoting Victoza prior to being granted market authorization.
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.
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.
Glucagon-like peptide-1
Glucagon-like peptide-1 is derived from the transcription product of the proglucagon gene. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. The biologically active forms of GLP-1 are: GLP-1- and GLP-1-NH2...
(GLP-1) analog that has been developed by Novo Nordisk
Novo Nordisk
Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
for the treatment of type 2 diabetes. The product was approved by the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.
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.
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.The Victoza label carries a Black Box Warning: 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.
Novo Nordisk
Novo Nordisk
Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
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.
Pharmacodynamics
Studies to date suggest liraglutide improves control of blood glucose.It reduces meal-related hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
(for 12 hours after administration) by increasing insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion, delaying gastric emptying, and suppressing prandial glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
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.
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 hypoglycemiaHypoglycemiaHypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
. - It has the potential for inhibiting apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and stimulating regeneration of beta cellBeta cellBeta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
s (seen in animal studies). - It decreases appetite and maintains body weight, as shown in a head-to-head study versus glimepirideGlimepirideGlimepiride is a medium-to-long acting sulfonylurea anti-diabetic drug. It is marketed as Amaryl by Sanofi-Aventis and GLIMY by Dr.Reddy's Labs...
. - It lowers blood triglycerideTriglycerideA triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
levels. - It has only mild and transient side effects, mainly gastrointestinal.
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 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
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
molecule at one position of the GLP-1 molecule, enabling it to bind to albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
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.
Controversy
In 2010, Novo Nordisk breached the ABPIsAssociation of the British Pharmaceutical Industry
The Association of the British Pharmaceutical Industry is the trade association for 150 companies in the UK producing prescription medicines for humans...
code of conduct by failing to provide information about side effects of Victoza, and by promoting Victoza prior to being granted market authorization.
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.One of the marketing tactics Novo Nordisk is using to promote Victoza is a reusable coupon
Drug Coupon
A drug coupon is a coupon intended to help consumers save money on pharmaceutical drugs. They are offered by drug companies or distributed to consumers via doctors and pharmacists, and most can be obtained online...
that yields a savings of up to $25 per prescription for six prescriptions.
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.
See also
- Glucagon-like peptide-1 analogGlucagon-like peptide-1 analogGlucagon-like peptide-1 analogs are a new class of drug for treatment of type 2 diabetes.One of their advantages is that they have a lower risk of causing hypoglycemia.Licenced : exenatide , liraglutide...
s:
- exenatideExenatideExenatide is a medication approved in April 2005 for the treatment of diabetes mellitus type 2. It belongs to the group of incretin mimetics and is manufactured by Amylin Pharmaceuticals and Eli Lilly and Company....
(Byetta) - albiglutideAlbiglutideAlbiglutide is a GLP-1 analog drug under investigation by GlaxoSmithKline for treatment of type 2 diabetes.It is a dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin....
- taspoglutideTaspoglutideTaspoglutide is a pharmaceutical drug. It is a glucagon-like peptide-1 analog, under investigation for treatment of type 2 diabetes being codeveloped by Ipsen and Roche.Two phase II trials reported it was effective and well tolerated....
- DPP4 inhibitors
- IncretinIncretinIncretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by...