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Liraglutide

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Liraglutide, sold under the brand name Victoza among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity.[6][7] It is a second-line therapy for diabetes following first-line therapy with metformin.[6][8] Its effects on long-term health outcomes like heart disease and life expectancy are unclear.[6][9] It is given by injection under the skin.[6]

Liraglutide
NMR structure of liraglutide. PDB entry 4apd​
Clinical data
Trade namesVictoza, others
AHFS/Drugs.comMonograph
MedlinePlusa611003
License data
Pregnancy
category
  • AU: B3
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.241.015 Edit this at Wikidata
Chemical and physical data
FormulaC172H265N43O51
Molar mass3751.262 g·mol−1
3D model (JSmol)
  • CCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCCC[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CN=CN1)[C@@H](C)O)[C@@H](C)O)C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CNC2=CC=CC=C12)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)C(O)=O
  • InChI=1S/C172H265N43O51/c1-18-20-21-22-23-24-25-26-27-28-29-30-37-53-128(223)193-112(59-64-132(227)228)148(244)180-68-41-40-50-111(154(250)199-116(62-67-135(233)234)155(251)204-120(73-100-44-33-31-34-45-100)160(256)214-140(93(11)19-2)168(264)192-97(15)146(242)201-122(76-103-79-183-108-49-39-38-48-106(103)108)158(254)203-118(72-90(5)6)159(255)212-138(91(7)8)166(262)200-110(52-43-70-182-172(177)178)150(246)184-81-129(224)194-109(51-42-69-181-171(175)176)149(245)187-84-137(237)238)196-144(240)95(13)189-143(239)94(12)191-153(249)115(58-63-127(174)222)195-130(225)82-185-152(248)114(61-66-134(231)232)198-156(252)117(71-89(3)4)202-157(253)119(75-102-54-56-105(221)57-55-102)205-163(259)124(85-216)208-165(261)126(87-218)209-167(263)139(92(9)10)213-162(258)123(78-136(235)236)206-164(260)125(86-217)210-170(266)142(99(17)220)215-161(257)121(74-101-46-35-32-36-47-101)207-169(265)141(98(16)219)211-131(226)83-186-151(247)113(60-65-133(229)230)197-145(241)96(14)190-147(243)107(173)77-104-80-179-88-188-104/h31-36,38-39,44-49,54-57,79-80,88-99,107,109-126,138-142,183,216-221H,18-30,37,40-43,50-53,58-78,81-87,173H2,1-17H3,(H2,174,222)(H,179,188)(H,180,244)(H,184,246)(H,185,248)(H,186,247)(H,187,245)(H,189,239)(H,190,243)(H,191,249)(H,192,264)(H,193,223)(H,194,224)(H,195,225)(H,196,240)(H,197,241)(H,198,252)(H,199,250)(H,200,262)(H,201,242)(H,202,253)(H,203,254)(H,204,251)(H,205,259)(H,206,260)(H,207,265)(H,208,261)(H,209,263)(H,210,266)(H,211,226)(H,212,255)(H,213,258)(H,214,256)(H,215,257)(H,227,228)(H,229,230)(H,231,232)(H,233,234)(H,235,236)(H,237,238)(H4,175,176,181)(H4,177,178,182)/t93-,94-,95-,96-,97-,98+,99+,107-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,138-,139-,140-,141-,142-/m0/s1
  • Key:KAIWQAZASNVPLR-QCIJIYAXSA-N

Liraglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist) also known as incretin mimetics.[6] It works by increasing insulin release from the pancreas and decreases excessive glucagon release.[6]

Common side effects include low blood sugar, nausea, dizziness, abdominal pain, and pain at the site of injection.[6][10] Gastrointestinal side-effects tend to be strongest at the beginning of treatment period and subside over time.[10] Other serious side effects may include angioedema, pancreatitis, gallbladder disease, and kidney problems.[6] Use in pregnancy and breastfeeding is of unclear safety.[6] A black box warning cautions that medullary thyroid cancers have been observed in rats treated with liraglutide, but it is "Unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as relevance to humans of such tumors in rodents has not been determined."[6]

Liraglutide was approved for medical use in the European Union in 2009, and in the United States in 2010.[4][11] In 2022, it was the 139th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[12][13]

Medical uses

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Liraglutide is a medication used for the treatment of type 2 diabetes or obesity.[6]

Type 2 diabetes

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Liraglutide improves control of blood glucose.[14] In patients with high cardiovascular risk, liraglutide has been shown to reduce the risk for first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.[15] ADA guidelines currently consider liraglutide a first line pharmacologic therapy for type 2 diabetes (usually together with metformin), specifically for patients with atherosclerotic cardiovascular disease or obesity.[16] A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8 mg compared to insulin glargine, 0.33% more than exenatide 10 μg twice daily, sitagliptin and rosiglitazone.[10] In a randomized controlled trial (RCT) comparing liraglutide, glargine, glimepiride, and sitagliptin (all added to metformin) with a follow-up of five years, glargine and liraglutide were modestly more effective in achieving and maintaining target HbA1c,[17] with no difference in outcomes of microvascular and cardiovascular disease.[18]

Obesity

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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

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Thyroid cancer

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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 serum calcitonin, 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

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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]

Pharmacodynamics

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Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) receptor agonist, derived from human GLP-1-(7-37), a less common form of endogenous GLP-1.

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 pancreatic beta 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

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Endogenous GLP-1 has a plasma half-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

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Brand names

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Liraglutide is marketed under the brand name Victoza in the US, UK, UAE, Kuwait, India, Iran, Canada, Europe, Japan and the 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 Australia, Brazil, Canada, Germany, Indonesia, Iran, Ireland, Israel, Norway, Czech Republic, Poland,[27] Portugal,[28] South Korea, Switzerland, The United Kingdom and the US, and also as Enligria and Quinliro in Russia.[29]

Marketing

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Liraglutide was approved by the US Food and Drug Administration (FDA) in 2014,[30] 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.[31][32] 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.[33]

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.[31]

Novo Nordisk has made deals with generic manufacturers to enter the United States market in 2024.[34][35]

Controversy

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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.[36]

In 2012, the non-profit consumer advocacy group Public Citizen petitioned the US Food and Drug Administration (FDA) to immediately remove liraglutide from the market because they concluded that risks of thyroid cancer and pancreatitis outweigh any documented benefits.[37]

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.[38] 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.[39]

Research

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In September 2024, it was reported that a study found that liraglutide helped children aged 6 to 12 years of age reduce their body mass index by 7.4% in a 56-week trial.[40]

References

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  21. ^ Parks M, Rosebraugh C (March 2010). "Weighing risks and benefits of liraglutide--the FDA's review of a new antidiabetic therapy". The New England Journal of Medicine. 362 (9): 774–7. doi:10.1056/NEJMp1001578. PMID 20164475.
  22. ^ Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB (April 2013). "Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study". JAMA Internal Medicine. 173 (7): 534–539. doi:10.1001/jamainternmed.2013.2720. PMID 23440284. S2CID 425632.
  23. ^ Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, Rosebraugh C (February 2014). "Pancreatic safety of incretin-based drugs--FDA and EMA assessment". The New England Journal of Medicine. 370 (9): 794–797. doi:10.1056/NEJMp1314078. PMID 24571751.
  24. ^ a b c Goldstein BJ, Mueller-Wieland D (14 November 2007). Type 2 Diabetes: Principles and Practice (2nd ed.). CRC Press. ISBN 978-0-8493-7958-1. Archived from the original on 18 January 2015. Retrieved 17 January 2015.
  25. ^ Beglinger C, Degen L (November 2006). "Gastrointestinal satiety signals in humans--physiologic roles for GLP-1 and PYY?". Physiology & Behavior. 89 (4): 460–464. doi:10.1016/j.physbeh.2006.05.048. PMID 16828127. S2CID 32598231.
  26. ^ "Victoza (liraglutide)". Drugs.com. May 2008. Archived from the original on 15 December 2017. Retrieved 23 January 2018.
  27. ^ "Saxenda - ulotka (dawkowanie, zastosowanie, interakcje) - KtoMaLek.pl". ktomalek.pl (in Polish). Archived from the original on 21 March 2023. Retrieved 18 January 2023.
  28. ^ "Infomed, Detalhes do Medicamento: Saxenda" (in Portuguese). Retrieved 1 May 2024.
  29. ^ Chudnovskyi, Alexey (19 September 2023). "Promomed vyvodit na rynok pervyi otechestvennyi liraglutid" «Промомед» выводит на рынок первый отечественный лираглутид [Promomed launches the first domestic liraglutide]. Vademecum (in Russian). Archived from the original on 21 September 2023. Retrieved 22 November 2023.
  30. ^ "Drug Approval Package: Saxenda Injection (Liraglutide [rDNA origin])". U.S. Food and Drug Administration (FDA). 1 October 2015. Archived from the original on 10 April 2021. Retrieved 5 June 2021.
  31. ^ a b "FDA approves weight-management drug Saxenda". U.S. Food and Drug Administration (Press release). 23 December 2014. Archived from the original on 26 April 2016. Retrieved 26 April 2016.
  32. ^ "Saxenda recommended for approval in weight management in adults". News and Events. European Medicines Agency. Archived from the original on 11 August 2017. Retrieved 26 April 2016.
  33. ^ "FDA approves new treatment for pediatric patients with type 2 diabetes". U.S. Food and Drug Administration. 17 June 2019. Archived from the original on 21 June 2019. Retrieved 21 June 2019.
  34. ^ "The Biopharma Patent Cliff: 9 Drugs Losing Exclusivity by the End of 2023". BioSpace. Archived from the original on 29 November 2023. Retrieved 1 December 2023.
  35. ^ Kansteiner F (23 March 2022). "Novo Nordisk and Novartis put Victoza patent suit to bed, teeing up Sandoz copycat by 2024". Fierce Pharma. Archived from the original on 21 March 2023. Retrieved 1 December 2023.
  36. ^ "Novo Nordisk Limited, Eli Lilly and Company Limited, Grünenthal Ltd and Napp Pharmaceuticals Limited named in advertisements". Prescription Medicines Code of Practice Authority (PMCPA). Archived from the original on 24 May 2012. Retrieved 7 February 2011.
  37. ^ "Public Citizen to FDA: Pull Diabetes Drug Victoza From Market Immediately". Public Citizen. Archived from the original on 28 November 2016. Retrieved 2 April 2013.
  38. ^ "Novo Nordisk Agrees to Pay $58 Million for Failure to Comply with FDA-Mandated Risk Program" (Press release). U.S. Department of Justice. 5 September 2017. Archived from the original on 9 May 2018. Retrieved 8 May 2018.
  39. ^ "Whistleblower recoveries from insurance cases brought by Phillips & Cohen bring Novo Nordisk's Victoza settlement to $60 million" (Press release). Phillips & Cohen LLP. 5 September 2017. Archived from the original on 9 May 2018. Retrieved 8 May 2018.
  40. ^ Chen E, Cooney E (10 September 2024). "Obesity drug worked in children ages 6 to 12, study says, raising hopes and concerns". STAT. Retrieved 12 September 2024.
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