Liraglutide

Liraglutide, sold under the brand name Victoza among others, is a medication used to treat diabetes mellitus type 2 and obesity.[1] In diabetes it is a less preferred agent compared to metformin.[1][2] Its effects on long-term health outcomes like heart disease and life expectancy are unclear.[1] In obesity if after 12 weeks less than 5% of body weight is lost it is recommended the medication be stopped.[3] It is given by injection under the skin.[1]

Liraglutide
X-ray structure of liraglutide. PDB entry 4apd​
Clinical data
Trade namesVictoza, Saxenda, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    administration    		Subcutaneous
    ATC code
    Legal status
    Legal status
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    CompTox Dashboard (EPA)
    ECHA InfoCard100.241.015
    Chemical and physical data
    FormulaC172H265N43O51
    Molar mass3751.262 g·mol−1
    3D model (JSmol)

    Common side effects include low blood sugar, nausea, dizziness, abdominal pain, and pain at the site of injection.[1] Other serious side effects may include medullary thyroid cancer, angioedema, pancreatitis, gallbladder disease, and kidney problems.[1] Use in pregnancy and breastfeeding is of unclear safety.[1] Liraglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist) also known as incretin mimetics.[1] It works by increasing insulin release from the pancreas and decreases excessive glucagon release.[1]

    Liraglutide was approved for medical use in Europe in 2009 and in the United States in 2010.[4][5] A month supply in the United Kingdom costs the NHS about £78.50 as of 2019.[3] In the United States the wholesale cost of this amount is about US$98.30.[6] In 2017, it was the 163rd most commonly prescribed medication in the United States, with more than three million prescriptions.[7][8]

    Medical uses

    Liraglutide is a medication used for the treatment of type 2 diabetes or obesity.[1]

    Type 2 diabetes

    Liraglutide improves control of blood glucose.[9] As of 2017 it is unclear if they affect a person's risk of death.[10]

    In diabetes it is a less preferred agent.[1] It may be used in those in who metformin and another antidiabetic medication such as a sulfonylurea are not sufficient.[2]

    Obesity

    Liraglutide may also be used together with diet and exercise for chronic weight management in adult patients.[1] The body mass index (BMI) needs to be greater than 30 kg/m2, or greater than 27 kg/m2 together with high blood pressure, type 2 diabetes mellitus, or dyslipidemia.[1]

    It is unknown if the weight loss will be permanent. Appetite suppression may be temporary and appetite might return even if one continues to use liraglutide after 56 weeks.

    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.[11] 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.[11]

    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.[12]

    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).[13] 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."[14]

    Pharmacodynamics

    Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) 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.[15][16]

    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.[17][15]

    Pharmacokinetics

    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).[15]

    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 and Japan. It has been launched in Germany, Italy, Denmark, the Netherlands, the United Kingdom, Ireland, Sweden, Japan, Canada, the United States, France, Malaysia and Singapore. Liraglutide is also known to be marketed as Saxenda in Australia, Iran, Israel, Canada, Brazil, Switzerland and the U.S.

    Marketing

    Liraglutide was approved by the FDA in 2014 and by the European Medicines Agency in 2015, 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.[18][19] 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.[20]

    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.[18]

    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.[21]

    In 2012, the non-profit consumer advocacy group Public Citizen petitioned the 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.[22]

    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 [23]) in violation of the Federal Food, Drug, and Cosmetic Act and the False Claims Act.[24] 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.[25]

    Novo-Nordisk applied to the USFDA in April 2019 for approval of oral semaglutide.[26]

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    References
    1. "Liraglutide Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 23 March 2019.
    2. Shyangdan D, Cummins E, Royle P, Waugh N (May 2011). "Liraglutide for the treatment of type 2 diabetes". Health Technol Assess. 15 Suppl 1: 77–86. doi:10.3310/hta15suppl1/09. PMID 21609656.
    3. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 685. ISBN 9780857113382.
    4. "Liraglutide". European Medicines Agency. 17 September 2018. Retrieved 23 March 2019.
    5. "DailyMed - liraglutide injection". dailymed.nlm.nih.gov. Retrieved 23 March 2019.
    6. "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
    7. "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
    8. "Liraglutide - Drug Usage Statistics". ClinCalc. Retrieved 11 April 2020.
    9. http://diabetes.webmd.com/news/20080924/new-diabetes-drug-liraglutide-works Sept 2008
    10. Liu, J; Li, L; Deng, K; Xu, C; Busse, JW; Vandvik, PO; Li, S; Guyatt, GH; Sun, X (8 June 2017). "Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis". BMJ (Clinical Research Ed.). 357: j2499. doi:10.1136/bmj.j2499. PMC 5463186. PMID 28596247.
    11. "www.accessdata.fda.gov" (PDF).
    12. N Engl J Med, 362:774
    13. Sonal Singh; Hsien-Yen Chang; Thomas M. Richards; Jonathan P. Weiner; Jeanne M. Clark; Jodi B. Segal (April 8, 2013). "Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus". JAMA Internal Medicine. 173 (7): 534–9. doi:10.1001/jamainternmed.2013.2720. PMID 23440284.CS1 maint: uses authors parameter (link)
    14. Egan, A. G.; Blind, E; Dunder, K; De Graeff, P. A.; Hummer, B. T.; Bourcier, T; Rosebraugh, C (February 27, 2014). "Pancreatic Safety of Incretin-Based Drugs—FDA and EMA Assessment—NEJM". The New England Journal of Medicine. 370 (9): 794–7. doi:10.1056/NEJMp1314078. PMID 24571751.
    15. Goldstein, Barry J.; Mueller-Wieland, Dirk (14 November 2007). Type 2 Diabetes: Principles and Practice (2nd ed.). CRC Press. ISBN 978-0-8493-7958-1. Retrieved 17 January 2015.
    16. Beglinger C, Degen L (2007). "Gastrointestinal satiety signals in humans—physiologic roles for GLP-1 and PYY ?". Physiol. Behav. 89 (4): 460–4. doi:10.1016/j.physbeh.2006.05.048. PMID 16828127.
    17. https://www.drugs.com/nda/liraglutide_080530.html May 2008
    18. "FDA approves weight-management drug Saxenda". U.S. Food and Drug Administration. December 23, 2014. Retrieved April 26, 2016.
    19. "European Medicines Agency—News and Events—Saxenda recommended for approval in weight management in adults". www.ema.europa.eu. Retrieved 2016-04-26.
    20. "FDA approves new treatment for pediatric patients with type 2 diabetes". U.S. Food and Drug Administration. June 17, 2019. Retrieved June 21, 2019.
    21. "Novo Nordisk Limited, Eli Lilly and Company Limited, Grünenthal Ltd and Napp Pharmaceuticals Limited named in advertisements". Prescription Medicines Code of Practice Authority (PMCPA). Retrieved 2011-02-07.
    22. "Public Citizen to FDA: Pull Diabetes Drug Victoza From Market Immediately". Public Citizen. Retrieved 2013-04-02.
    23. Hoskins, Mike (July 24, 2019). "Going "Off-Label": All About Using Type 2 Diabetes Drugs for T1D". healthline.com. Healthline. Retrieved 2020-04-16.
    24. "Novo Nordisk Agrees to Pay $58 Million for Failure to Comply with FDA-Mandated Risk Program" (Press release). U.S. Department of Justice. September 5, 2017. Retrieved 2018-05-08.
    25. "Whistleblower recoveries from insurance cases brought by Phillips & Cohen bring Novo Nordisk's Victoza settlement to $60 million" (Press release). Phillips & Cohen LLP. September 5, 2017. Retrieved 2018-05-08.
    26. Campbell, Patrick (June 8, 2019). "Oral Semaglutide Compared to Liraglutide". MD Mag. Retrieved October 29, 2019.
    • "Liraglutide". Drug Information Portal. U.S. National Library of Medicine.
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