Liraglutide was approved for medical use in the European Union in 2009, and in the United States in 2010.[4][11] In 2021, it was the 166th most commonly prescribed medication in the United States, with more than 3million prescriptions.[12][13]
Liraglutide may also be used together with
diet and
exercise for chronic weight management in adults.[6] Liraglutide led to greater weight loss than some previous glucagon-like peptide analogues,[10] but is less effective than the standard weight loss dose of
semaglutide.[19][20]
Adverse effects
Thyroid cancer
At exposures eight times greater than those used in humans, liraglutide caused a statistically significant increase in thyroid tumors in
rats. The clinical relevance of these findings is unknown.[2] In clinical trials, the rate of thyroid tumors in patients treated with liraglutide was 1.3 per 1000 patient years (4 people) compared to 1.0 per 1000 patients (1 person) in comparison groups. The sole person in the comparator group and four of the five persons in the liraglutide group had serum markers (elevated calcitonin) suggestive of pre-existing disease at baseline.[2]
The FDA said
serumcalcitonin, a
biomarker of medullary 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.[21]
Pancreatitis
In 2013, a group at
Johns Hopkins reported an apparently statistically significant association between hospitalization for acute
pancreatitis and prior treatment with GLP-1 derivatives (such as exenatide) and DPP-4 inhibitors (such as sitagliptin).[22] In response, the United States FDA and the European Medicines Agency conducted a review of all available data regarding the possible connection between incretin mimetics and pancreatitis or pancreatic cancer. In a joint 2014 letter to the New England Journal of Medicine, the agencies concluded that "A pooled analysis of data from 14,611 patients with type 2 diabetes from 25 clinical trials in the sitagliptin database provided no compelling evidence of an increased risk of pancreatitis or pancreatic cancer" and "Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data. The FDA and the EMA have not reached a final conclusion at this time regarding such a causal relationship. Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal."[23]
It reduces meal-related
hyperglycemia (for 24 hours after administration) by increasing
insulin secretion (only) when required by increasing glucose levels, delaying gastric emptying, and suppressing prandial
glucagon secretion.[24][25]
Liraglutide leads to
insulin release in
pancreaticbeta cells in the presence of elevated blood
glucose. This insulin secretion subsides as glucose concentrations decrease and approach euglycemia (normal blood glucose level). It also decreases
glucagon secretion in a glucose-dependent manner and delays
gastric emptying. Unlike
endogenous GLP-1, liraglutide is stable against
metabolic degradation by
peptidases, with a
plasma half-life of 13 hours.[26][24]
Pharmacokinetics
Endogenous GLP-1 has a
plasmahalf-life of 1.5–2 minutes due to degradation by the ubiquitous
enzymes,
dipeptidyl peptidase-4 (DPP4) and
neutral endopeptidases (NEP). The half-life after intramuscular injection is approximately half an hour, so even administered this way, it has limited use as a therapeutic agent. The metabolically active forms of GLP-1 are the
endogenous GLP-1-(7-36)NH2 and the more rare GLP-1-(7-37). The prolonged action of liraglutide is achieved by attaching a
fatty acid molecule at one position of the GLP-1-(7-37) molecule, enabling it to both self-associate and bind to
albumin within the
subcutaneous tissue and bloodstream. The active GLP-1 is then released from albumin at a slow, consistent rate. Albumin binding also results in slower degradation and reduced
renal elimination compared to that of GLP-1-(7-37).[24]
Society and culture
Brand names
Liraglutide is marketed under the brand name Victoza in the U.S., U.K. UAE, Kuwait, India, Iran, Canada, Europe, Japan and Philippines. It has been launched in Germany, Italy, Denmark, the Netherlands, Sweden, Japan, Canada, the United States, France, Indonesia, Malaysia and Singapore. Liraglutide is also known to be marketed as Saxenda in Norway, Australia, Germany, Indonesia, Iran, Israel, Canada, Brazil, Switzerland, The United Kingdom, Ireland, South Korea, Poland[27] and the U.S, and also as Enligria and Quinliro in Russia.[28]
Marketing
Liraglutide was approved by the U.S.
Food and Drug Administration (FDA) in 2014,[29] and by the
European Medicines Agency (EMA) in 2015,[5] for adults with a
body mass index (BMI) of 30 or greater (obesity) or a BMI of 27 or greater (overweight) who have at least one weight-related condition.[30][31] Liraglutide was approved by the FDA in 2019, for treatment of children 10 years or older with type 2 diabetes, making it the first non-insulin drug approved to treat type 2 diabetes in children since
metformin was approved in 2000.[32]
Novo Nordisk stated that it plans to use 500 of its 3,000-strong sales force in the United States to promote Saxenda in 2015, because it is considered to have the potential for sales of $1 billion a year within 8–10 years of launch around the world. Analysts at
Citi Research concur, assuming that the drug will reach less than 0.5 percent of the 107 million people in the United States classified as obese, and a daily price of $30 over 6 to 12 months' use. The company estimates that it has spent about $1 billion over ten years to take Saxenda from research to marketing.[30]
Novo Nordisk has made deals with generic manufacturers to enter the United States market in 2024.[33][34]
Controversy
In 2010, Novo Nordisk breached the
ABPI's code of conduct by failing to provide information about side effects, and by promoting it prior to being granted market authorization.[35]
In 2017, Novo Nordisk agreed to pay $58.65 million to settle multiple whistleblower lawsuits alleging that the company had illegally marketed, promoted, and sold Victoza for
off-label uses (such as for type 1 diabetes) in violation of the
Federal Food, Drug, and Cosmetic Act and the
False Claims Act.[37] Novo Nordisk paid an additional $1.45 million to the states of California and Illinois to settle whistleblower cases alleging fraud against private commercial health insurers.[38]
^O'Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, Carson CG, Jepsen CH, Kabisch M, Wilding JPH (25 August 2018). "Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial". The Lancet. 392 (10148): 637–649.
doi:
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