Liraglutide

Liraglutide
NMR structure of liraglutide. PDB entry 4apd​
Clinical data
Trade names Victoza, Saxenda
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
    Chemical and physical data
    Formula C172H265N43O51
    Molar mass 3751.202 g/mol
    3D model (JSmol)

    Liraglutide (NN2211) is a derivative of human incretin (metabolic hormone) glucagon-like peptide-1 (GLP-1) that is used as a long-acting glucagon-like peptide-1 receptor agonist, binding to the same receptors as does the endogenous metabolic hormone GLP-1 that stimulates insulin secretion. Marketed under the brand name Victoza, it is an injectable drug developed by Novo Nordisk for the treatment of type 2 diabetes. In 2015, Novo Nordisk began marketing a separate strength in the U.S. and E.U. under the brand name Saxenda as a treatment for adults who are obese or overweight with at least one weight-related comorbid condition.

    The product was approved for treatment of type 2 diabetes by the European Medicines Agency (EMA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.[1][2][3] More recently, Liraglutide was approved by the FDA on December 23, 2014 and by the European Medicines Agency on January 23, 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.[4][5]

    Medical uses

    Liraglutide is a once-daily injectable derivative of the human incretin glucagon-like peptide-1 (GLP-1), for the treatment of type 2 diabetes or obesity.

    Type 2 diabetes

    Liraglutide improves control of blood glucose.[6] 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.[7][8] As of 2017 it is unclear if they affect a person's risk of death.[9]

    In common to various degrees with other GLP-1 receptor agonists, liraglutide has advantages over more traditional therapies for type 2 diabetes:[2][7][10]

    • It acts in a glucose-dependent manner, meaning it will stimulate insulin secretion only when blood glucose levels are higher than normal, preventing "overshoot". Consequently, it shows negligible risk of hypoglycemia.
    • It has the potential for inhibiting apoptosis and stimulating regeneration of beta cells (seen in animal studies).
    • It decreases appetite and inhibits body weight gain, as shown in a head-to-head study versus glimepiride.[11]
    • It lowers blood triglyceride levels.[12]

    Obesity

    Liraglutide has been approved as an injectable adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients. The specified criteria are an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight), in the presence of at least one weight-related comorbid condition (e.g. hypertension, type 2 diabetes mellitus, or dyslipidemia). In late 2014, data were reported from the SCALE™ Obesity and Prediabetes trial,[13] which is a randomised, double-blind, placebo-controlled, multinational trial in non-diabetic people with obesity and non-diabetic people who are overweight with comorbidities. In this phase 3a trial, there were 3,731 participants randomised to treatment with liraglutide 3 mg or placebo, both in combination with diet and exercise. Those who completed the 56-week trial achieved an average weight loss of 9.2%, to be compared with a 3.5% reduction in the placebo group.[14]

    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 concerns

    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.[15] 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.[15]

    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.[16]

    Pancreatitis concerns

    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).[17] 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."[18]

    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.

    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.[1][7]

    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).[7]

    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, Brazil, France, Malaysia and Singapore. Liraglutide is also known to be marketed as Saxenda in Australia, Canada and the U.S.

    Marketing

    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.[4]

    Controversy

    In 2010, Novo Nordisk breached the ABPI's code of conduct by failing to provide information about side effects of Victoza, and by promoting Victoza prior to being granted market authorization.[19]

    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.[20]

    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 in violation of the Federal Food, Drug, and Cosmetic Act and the False Claims Act.[21] 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.[22]

    Research

    Phase I trials of an oral variant of Victoza (NN9924) started in 2010.[23]

    References

    1. 1 2 https://www.drugs.com/nda/liraglutide_080530.html May 2008
    2. 1 2 http://www.drugdevelopment-technology.com/projects/liraglutide/ "Liraglutide—Next-Generation Antidiabetic Medication"
    3. ↑ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm198638.htm "FDA Approves New Treatment for Type 2 Diabetes" January 25, 2010
    4. 1 2 "FDA approves weight-management drug Saxenda". U.S. Food and Drug Administration. December 23, 2014. Retrieved April 26, 2016.
    5. ↑ "European Medicines Agency—News and Events—Saxenda recommended for approval in weight management in adults". www.ema.europa.eu. Retrieved 2016-04-26.
    6. ↑ http://diabetes.webmd.com/news/20080924/new-diabetes-drug-liraglutide-works Sept 2008
    7. 1 2 3 4 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.
    8. ↑ 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.
    9. ↑ 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.
    10. ↑ http://www.medicalnewstoday.com/articles/110349.php "Clinical Study Shows Liraglutide Reduced Blood Sugar, Weight, And Blood Pressure In Patients With Type 2 Diabetes" June 2008
    11. ↑ "Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes" Diabetes Care. Oct 2008
    12. ↑ 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.
    13. ↑ "Effect of Liraglutide on Body Weight in Non-diabetic Obese Subjects or Overweight Subjects With Co-morbidities: SCALE™—Obesity and Pre-diabetes". ClinicalTrials.gov. 13 November 2014. NCT01272219. Retrieved 17 January 2015.
    14. ↑ New phase 3a data demonstrate that 9 out of 10 adults with obesity lost weight with liraglutide 3 mg and clinical trial completers lost an average of 9.2% (PDF). ObesityWeek 2014. Boston: Novo Nordisk A/S. 4 November 2014. Retrieved 17 January 2015.
    15. 1 2 "www.accessdata.fda.gov" (PDF).
    16. ↑ N Engl J Med, 362:774
    17. ↑ 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: 534. doi:10.1001/jamainternmed.2013.2720.
    18. ↑ 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. Retrieved January 17, 2015.
    19. ↑ "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.
    20. ↑ "Public Citizen to FDA: Pull Diabetes Drug Victoza From Market Immediately". Public Citizen. Retrieved 2013-04-02.
    21. ↑ "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.
    22. ↑ "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.
    23. ↑ Hirschler, Ben (January 13, 2010). "UPDATE 1-Novo starts tests on pill version of Victoza drug". Reuters.
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