Liraglutide

Source: Wikipedia, the free encyclopedia.

Liraglutide
NMR structure of liraglutide. PDB entry 4apd
Clinical data
Trade namesVictoza, Saxenda, others
AHFS/Drugs.comMonograph
MedlinePlusa611003
License data
Pregnancy
category
  • AU: B3
Subcutaneous
ATC code
Legal status
Legal status
Identifiers
JSmol)
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  • 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, sold under the brand names Victoza and Saxenda among others, is an

injection under the skin.[6]

Liraglutide is a

mimetics.[6] It works by increasing insulin release from the pancreas and decreases excessive glucagon release.[6]

Common side effects include

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 2021, it was the 166th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[12][13]

Medical uses

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

Type 2 diabetes

Liraglutide improves control of

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

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 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

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

Liraglutide is an

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

peptidases, with a plasma half-life of 13 hours.[26][24]

Pharmacokinetics

Endogenous GLP-1 has a

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 2012, the non-profit consumer advocacy group

U.S. 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.[36]

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

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]

References

  1. FDA
    . Retrieved 22 October 2023.
  2. ^ a b c "Victoza- liraglutide injection". DailyMed. U.S. National Library of Medicine. Archived from the original on 27 March 2021. Retrieved 5 June 2021.
  3. ^ "Saxenda- liraglutide injection, solution". Archived from the original on 6 June 2021. Retrieved 5 June 2021.
  4. ^ a b "Victoza EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 23 March 2019. Retrieved 23 March 2019.
  5. ^ a b "Saxenda EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 6 June 2021. Retrieved 5 June 2021.
  6. ^ a b c d e f g h i j k l "Liraglutide Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 23 March 2019. Retrieved 23 March 2019.
  7. ^ "FDA approves weight management drug". U.S. Food and Drug Administration (FDA). 4 December 2020. Archived from the original on 14 June 2021. Retrieved 5 June 2021.
  8. from the original on 14 March 2023. Retrieved 14 May 2023.
  9. .
  10. ^ .
  11. ^ "Liraglutide injection". DailyMed. U.S. National Library of Medicine. Archived from the original on 27 March 2021. Retrieved 23 March 2019.
  12. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  13. ^ "Liraglutide - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  14. ^ "Understanding Diabetes -- Diagnosis and Treatment". WebMD. 13 November 2021. Archived from the original on 16 May 2013. Retrieved 16 January 2023.
  15. PMID 27295427
    .
  16. .
  17. .
  18. .
  19. PMID 36510488.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  20. .
  21. ^ N Engl J Med, 362:774
  22. S2CID 425632
    .
  23. .
  24. ^ from the original on 18 January 2015. Retrieved 17 January 2015.
  25. .
  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. ^ 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.
  29. ^ "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.
  30. ^ 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.
  31. ^ "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.
  32. ^ "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.
  33. ^ "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.
  34. ^ "Archived copy". Archived from the original on 21 March 2023. Retrieved 1 December 2023.{{cite news}}: CS1 maint: archived copy as title (link)
  35. ^ "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.
  36. ^ "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.
  37. ^ "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.
  38. ^ "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.