liraglutide

Liraglutide is a medication used for the treatment of type{{nbsp}}2 diabetes or obesity.

Liraglutide improves control of blood glucose.{{cite web |title=Understanding Diabetes -- Diagnosis and Treatment |url=https://www.webmd.com/diabetes/understanding-diabetes-detection-treatment |date=13 November 2021 |access-date=16 January 2023 |website=WebMD |archive-date=16 May 2013 |archive-url=https://web.archive.org/web/20130516060702/http://diabetes.webmd.com/news/20080924/new-diabetes-drug-liraglutide-works |url-status=live }} In people 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.{{cite journal | vauthors = Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB | display-authors = 6 | title = Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes | journal = The New England Journal of Medicine | volume = 375 | issue = 4 | pages = 311–322 | date = July 2016 | pmid = 27295427 | pmc = 4985288 | doi = 10.1056/nejmoa1603827 }} American Diabetes Association (ADA) guidelines consider liraglutide a first line pharmacologic therapy for type{{nbsp}}2 diabetes (usually together with metformin), specifically for people with atherosclerotic cardiovascular disease or obesity.{{cite journal | title = Introduction: Standards of Medical Care in Diabetes-2022 | journal = Diabetes Care | volume = 45 | issue = Suppl 1 | pages = S1–S2 | date = January 2022 | pmid = 34964812 | doi = 10.2337/dc22-Sint | s2cid = 245454068 | author1 = American Diabetes Association | doi-access = free }} A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8{{nbsp}}mg compared to insulin glargine, 0.33% more than exenatide 10{{nbsp}}μg twice daily, sitagliptin and rosiglitazone. 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,{{cite journal | vauthors = Nathan DM, Lachin JM, Balasubramanyam A, Burch HB, Buse JB, Butera NM, Cohen RM, Crandall JP, Kahn SE, Krause-Steinrauf H, Larkin ME, Rasouli N, Tiktin M, Wexler DJ, Younes N | display-authors = 6 | title = Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes | journal = The New England Journal of Medicine | volume = 387 | issue = 12 | pages = 1063–1074 | date = September 2022 | pmid = 36129996 | pmc = 9829320 | doi = 10.1056/NEJMoa2200433 | s2cid = 252437415 }} with no difference in outcomes of microvascular and cardiovascular disease.{{cite journal | vauthors = Nathan DM, Lachin JM, Bebu I, Burch HB, Buse JB, Cherrington AL, Fortmann SP, Green JB, Kahn SE, Kirkman MS, Krause-Steinrauf H, Larkin ME, Phillips LS, Pop-Busui R, Steffes M, Tiktin M, Tripputi M, Wexler DJ, Younes N | display-authors = 6 | title = Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes | journal = The New England Journal of Medicine | volume = 387 | issue = 12 | pages = 1075–1088 | date = September 2022 | pmid = 36129997 | pmc = 9832916 | doi = 10.1056/NEJMoa2200436 | s2cid = 252437195 }}

Liraglutide may also be used together with diet and exercise for chronic weight management in adults. Liraglutide led to greater weight loss than some previous glucagon-like peptide analogues, but is less effective than the standard weight loss dose of semaglutide.{{cite journal | vauthors = Xie Z, Yang S, Deng W, Li J, Chen J | title = Efficacy and Safety of Liraglutide and Semaglutide on Weight Loss in People with Obesity or Overweight: A Systematic Review | journal = Clinical Epidemiology | volume = 14 | pages = 1463–1476 | date = 6 December 2022 | pmid = 36510488 | pmc = 9738168 | doi = 10.2147/CLEP.S391819 | doi-access = free }}{{cite journal | vauthors = O'Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, Carson CG, Jepsen CH, Kabisch M, Wilding JP | display-authors = 6 | title = 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 | journal = Lancet | volume = 392 | issue = 10148 | pages = 637–649 | date = August 2018 | pmid = 30122305 | doi = 10.1016/S0140-6736(18)31773-2 | s2cid = 52041320 }}

File:Saxenda Injection (Liraglutide) on arm.jpg

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. In clinical trials, the rate of thyroid tumors in participants treated with liraglutide was 1.3 per 1000 participant years (4 people) compared to 1.0 per 1000 participants (1 person) in comparison groups. The sole participant in the comparator group and four of the five participants in the liraglutide group had serum markers (elevated calcitonin) suggestive of pre-existing disease at baseline.

The US Food and Drug Administration (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.{{cite journal | vauthors = Parks M, Rosebraugh C | title = Weighing risks and benefits of liraglutide--the FDA's review of a new antidiabetic therapy | journal = The New England Journal of Medicine | volume = 362 | issue = 9 | pages = 774–7 | date = March 2010 | pmid = 20164475 | doi = 10.1056/NEJMp1001578 }}

In 2013, a group at Johns Hopkins University 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).{{cite journal | vauthors = Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB | title = Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study | journal = JAMA Internal Medicine | volume = 173 | issue = 7 | pages = 534–539 | date = April 2013 | pmid = 23440284 | doi = 10.1001/jamainternmed.2013.2720 | s2cid = 425632 | doi-access = }} 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, the agencies concluded that "A pooled analysis of data from 14,611 patients with type{{nbsp}}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 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."{{cite journal | vauthors = Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, Rosebraugh C | title = Pancreatic safety of incretin-based drugs--FDA and EMA assessment | journal = The New England Journal of Medicine | volume = 370 | issue = 9 | pages = 794–797 | date = February 2014 | pmid = 24571751 | doi = 10.1056/NEJMp1314078 | doi-access = free }}

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.{{cite book| title=Type 2 Diabetes: Principles and Practice| edition=2nd| isbn=978-0-8493-7958-1| vauthors=Goldstein BJ, Mueller-Wieland D| publisher=CRC Press| date=2007 }}{{cite journal | vauthors = Beglinger C, Degen L | title = Gastrointestinal satiety signals in humans--physiologic roles for GLP-1 and PYY? | journal = Physiology & Behavior | volume = 89 | issue = 4 | pages = 460–464 | date = November 2006 | pmid = 16828127 | doi = 10.1016/j.physbeh.2006.05.048 | s2cid = 32598231 }}

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.{{cite web | title = Victoza (liraglutide) | url = https://www.drugs.com/nda/liraglutide_080530.html | date = May 2008 | work = Drugs.com | access-date = 23 January 2018 | archive-date = 15 December 2017 | archive-url = https://web.archive.org/web/20171215054200/https://www.drugs.com/nda/liraglutide_080530.html | url-status = live }}

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).

File:Saxenda Injection (Liraglutide) set in 24mg on hand.jpg

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,{{Cite web |title=Saxenda - ulotka (dawkowanie, zastosowanie, interakcje) - KtoMaLek.pl |url=https://ktomalek.pl/saxenda-ulotka-cena-zastosowanie-apteka-roztwor-do-wstrzykiwan-6-mg-ml-3-wstrz-po-3-ml/ub-3092962 |access-date=18 January 2023 |website=ktomalek.pl |language=pl |archive-date=21 March 2023 |archive-url=https://web.archive.org/web/20230321181605/https://ktomalek.pl/saxenda-ulotka-cena-zastosowanie-apteka-roztwor-do-wstrzykiwan-6-mg-ml-3-wstrz-po-3-ml/ub-3092962 |url-status=live }} Portugal,{{cite web| url=https://extranet.infarmed.pt/INFOMED-fo/detalhes-medicamento.xhtml?med_guid=f215e2c0c26a11e48f0089326a0b4556 | title=Infomed, Detalhes do Medicamento: Saxenda | access-date= 1 May 2024 |language = pt}} South Korea, Switzerland, The United Kingdom and the US, and also as Enligria and Quinliro in Russia.{{cite web

|url = https://vademec.ru/news/2023/09/19/promomed-vyvodit-na-rynok-pervyy-otechestvennyy-liraglutid/

|title = Promomed vyvodit na rynok pervyi otechestvennyi liraglutid

|last = Chudnovskyi

|first = Alexey

|date = 19 September 2023

|website = Vademecum

|language = ru

|script-title = ru:«Промомед» выводит на рынок первый отечественный лираглутид

|trans-title = Promomed launches the first domestic liraglutide

|access-date = 22 November 2023

|archive-date = 21 September 2023

|archive-url = https://web.archive.org/web/20230921071829/https://vademec.ru/news/2023/09/19/promomed-vyvodit-na-rynok-pervyy-otechestvennyy-liraglutid/

|url-status = live

}}

Liraglutide was approved by the US Food and Drug Administration (FDA) in 2014,{{cite web | title=Drug Approval Package: Saxenda Injection (Liraglutide [rDNA origin]) | website=U.S. Food and Drug Administration (FDA) | date=1 October 2015 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206321Orig1s000TOC.cfm | access-date=5 June 2021 | archive-date=10 April 2021 | archive-url=https://web.archive.org/web/20210410050412/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206321Orig1s000TOC.cfm | url-status=live }} and by the European Medicines Agency (EMA) in 2015,{{cite web | title=Saxenda EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/saxenda | access-date=5 June 2021 | archive-date=6 June 2021 | archive-url=https://web.archive.org/web/20210606000018/https://www.ema.europa.eu/en/medicines/human/EPAR/saxenda | url-status=live }} 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.{{cite press release|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427913.htm|title=FDA approves weight-management drug Saxenda|date=23 December 2014|work=U.S. Food and Drug Administration (FDA) |access-date=26 April 2016|archive-date=26 April 2016|archive-url=https://web.archive.org/web/20160426154754/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427913.htm|url-status=dead}}{{cite press release | url = https://www.ema.europa.eu/en/news/saxenda-recommended-approval-weight-management-adults | publisher = European Medicines Agency | title = Saxenda recommended for approval in weight management in adults | date = 23 January 2015 | access-date = 26 April 2016 | archive-date = 11 August 2017 | archive-url = https://web.archive.org/web/20170811223320/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2015%2F01%2Fnews_detail_002255.jsp&mid=WC0b01ac058004d5c1 | url-status = live }} Liraglutide was approved by the FDA in 2019, for treatment of children ten years or older with type{{nbsp}}2 diabetes, making it the first non-insulin drug approved to treat type{{nbsp}}2 diabetes in children since metformin was approved in 2000.{{cite news|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-pediatric-patients-type-2-diabetes|title=FDA approves new treatment for pediatric patients with type 2 diabetes|date=17 June 2019|work=U.S. Food and Drug Administration (FDA)|access-date=21 June 2019|archive-date=21 June 2019|archive-url=https://web.archive.org/web/20190621095803/https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-pediatric-patients-type-2-diabetes|url-status=live}}

Novo Nordisk made deals with generic manufacturers to enter the United States market in 2024.{{cite news |title=The Biopharma Patent Cliff: 9 Drugs Losing Exclusivity by the End of 2023 |url=https://www.biospace.com/article/9-drugs-losing-patents-or-exclusivity-clauses-by-the-end-of-2023/ |access-date=1 December 2023 |work=BioSpace |archive-date=29 November 2023 |archive-url=https://web.archive.org/web/20231129212055/https://www.biospace.com/article/9-drugs-losing-patents-or-exclusivity-clauses-by-the-end-of-2023/ |url-status=live }}{{cite news |url=https://www.fiercepharma.com/pharma/novo-nordisk-and-novartis-put-victoza-patent-suit-bed-teeing-sandoz-copycat-2024-report |access-date=1 December 2023 | vauthors = Kansteiner F | date = 23 March 2022 | work = Fierce Pharma |title=Novo Nordisk and Novartis put Victoza patent suit to bed, teeing up Sandoz copycat by 2024 |archive-date=21 March 2023 |archive-url=https://web.archive.org/web/20230321013852/https://www.fiercepharma.com/pharma/novo-nordisk-and-novartis-put-victoza-patent-suit-bed-teeing-sandoz-copycat-2024-report |url-status=live }} The FDA approved the first generic liraglutide in December 2024, and granted the approval to Hikma Pharmaceuticals USA

In 2010, Novo Nordisk breached the Association of the British Pharmaceutical Industry's (ABPI) code of conduct by failing to provide information about side effects, and by promoting it prior to being granted market authorization.{{cite web |url=https://www.pmcpa.org.uk/cases/completed-cases/auth2234509-lilly-v-novo-nordisk/|title=Novo Nordisk Limited, Eli Lilly and Company Limited, Grünenthal Ltd and Napp Pharmaceuticals Limited named in advertisements|publisher=Prescription Medicines Code of Practice Authority (PMCPA)|access-date=7 February 2011|archive-date=24 May 2012|archive-url=https://web.archive.org/web/20120524032015/http://www.pmcpa.org.uk/?q=node%2F878|url-status=live}}

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.{{cite press release |url=https://www.citizen.org/news/statement-of-jonah-minkoff-zern-senior-organizer-public-citizens-democracy-is-for-people-campaign/ |title=Public Citizen to FDA: Pull Diabetes Drug Victoza From Market Immediately|publisher=Public Citizen|access-date=2 April 2013|archive-date=28 November 2016|archive-url=https://web.archive.org/web/20161128200215/http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=3586|url-status=live}}

In 2017, Novo Nordisk agreed to pay $58.65{{nbsp}}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{{nbsp}}1 diabetes) in violation of the Federal Food, Drug, and Cosmetic Act and the False Claims Act.{{cite press release |author= |title=Novo Nordisk Agrees to Pay $58 Million for Failure to Comply with FDA-Mandated Risk Program |url=https://www.justice.gov/opa/pr/novo-nordisk-agrees-pay-58-million-failure-comply-fda-mandated-risk-program/ |publisher=U.S. Department of Justice |date=5 September 2017 |access-date=8 May 2018 |archive-date=9 May 2018 |archive-url=https://web.archive.org/web/20180509080533/https://www.justice.gov/opa/pr/novo-nordisk-agrees-pay-58-million-failure-comply-fda-mandated-risk-program |url-status=live }} Novo Nordisk paid an additional $1.45{{nbsp}}million to the states of California and Illinois to settle whistleblower cases alleging fraud against private commercial health insurers.{{cite press release |author= |title=Whistleblower recoveries from insurance cases brought by Phillips & Cohen bring Novo Nordisk's Victoza settlement to $60 million |url=https://www.phillipsandcohen.com/novo-nordisk-whistleblower-settlement-victoza/ |publisher=Phillips & Cohen LLP |date=5 September 2017 |access-date=8 May 2018 |archive-date=9 May 2018 |archive-url=https://web.archive.org/web/20180509013153/https://www.phillipsandcohen.com/novo-nordisk-whistleblower-settlement-victoza/ |url-status=live }}

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.{{Cite web | vauthors = Chen E, Cooney E |date=10 September 2024 |title=Obesity drug worked in children ages 6 to 12, study says, raising hopes and concerns |url=https://www.statnews.com/2024/09/10/weight-loss-drugs-for-children-nejm-study-shows-efficacy-raises-questions/ |access-date=12 September 2024 |website=STAT }}

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