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In January 2012, diabetic chef [[Paula Deen]] and sons were used in consumer advertising.<ref>{{cite web | url=http://www.diabetesinanewlight.com/index.aspx |title=Diabetes in a new light}}}</ref>
In January 2012, diabetic chef [[Paula Deen]] and sons were used in consumer advertising.<ref>{{cite web | url=http://www.diabetesinanewlight.com/index.aspx |title=Diabetes in a new light}}}</ref>
The FDA has issued a warning about the risks of thyroid cancer and pancreatitis associated with the diabetes drug liraglutide (Victoza).

The agency issued the safety alert and directed drugmaker Novo Nordisk to send out a "Dear healthcare professional" letter after determining that some primary care providers were not fully aware of the serious risks.


==See also==
==See also==

Revision as of 04:34, 3 March 2012

Liraglutide
Clinical data
Other namesArg34Lys26-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1[7-37]
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa611003
License data
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityN/A
Elimination half-life11-15 hours
Identifiers
  • L-histidyl-L-alanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-α-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-[N-(1-oxohexadecyl)-L-γ-glutamyl]-L-lysyl-L-α-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl-glycine
CAS Number
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.241.015 Edit this at Wikidata
Chemical and physical data
FormulaC172H265N43O51
Molar mass3751.20 g/mol g·mol−1
3D model (JSmol)
  • CCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)NCCCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc2c[nH]c3c2cccc3)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)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)N)NC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc4ccc(cc4)O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc5ccccc5)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](Cc6cnc[nH]6)N
  • 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 checkY
  • Key:KAIWQAZASNVPLR-QCIJIYAXSA-N checkY
  (verify)

Liraglutide (NN2211), marketed under the brand name Victoza, is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been developed by Novo Nordisk for the treatment of type 2 diabetes. The product was approved by the European Medicines Agency (EMA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.[2][3][4][5][6]

Liraglutide is marketed under the brandname Victoza in the U.S., India, Canada, Europe and Japan. It has been launched in Germany, Denmark, the Netherlands, the United Kingdom, Ireland, Sweden, Japan, Canada, the United States, France, Malaysia and Singapore.

Phase I trials of an oral variant of Victoza (NN9924) started in 2010.[7]

Cancer concerns

On April 2, 2009, an FDA advisory panel reviewed the significance of malignant C-cell carcinoma and thyroid C-cell focal hyperplasia in rats and mice. Some[who?] say the tumors were caused by a nongenotoxic, specific receptor-mediated mechanism to which rodents are particularly sensitive, whereas nonhuman primates and humans are not.[8][9]

The Victoza label carries a Black Box Warning:

Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk.[10]

The FDA said serum calcitonin, a biomarker of medulliary 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.[11]

Novo Nordisk has reminded healthcare professionals of the serious risks associated with the use of Victoza. Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors in rats and mice. It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans.[12]

Pharmacodynamics

Studies to date suggest liraglutide improves control of blood glucose.[13]

It reduces meal-related hyperglycemia (for 12 hours after administration) by increasing insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.

Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, with a 97% amino acid sequence identity to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP), leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying. GLP-1(7-37) has a half-life of 1.5–2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP.[14]

Liraglutide may have advantages over current therapies:

  • It acts in a glucose-dependent manner, meaning it will stimulate insulin secretion only when blood glucose levels are higher than normal. 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 maintains body weight, as shown in a head-to-head study versus glimepiride.[15]
  • It lowers blood triglyceride levels.
  • It has only mild and transient side effects, mainly gastrointestinal.

Pharmacokinetics

Liraglutide is a once-daily GLP-1 derivative for the treatment of type 2 diabetes. GLP-1, in its natural form, is short-lived in the body (the half-life after subcutaneous injection is approximately one hour), so it is not very useful as a therapeutic agent. However, liraglutide has a half-life after subcutaneous injection of 11–15 hours, making it suitable for once-daily dosing (less frequent than the currently approved Byetta form of exenatide, which is twice daily, but considerably more frequent than the once weekly Bydureon form of exenatide, which received marketing approval from the FDA on January 27, 2012).

The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at one position of the GLP-1 molecule, enabling it to bind to albumin within the subcutaneous tissue and bloodstream. The active GLP-1 is then released from albumin at a slow, consistent rate. Binding with albumin also results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1.[citation needed]

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.[16]

Marketing

Published reports suggest Novo Nordisk will market liraglutide in the United States with a sales force of 1,900 sales representatives, and the sales force will emphasize the product's weight loss properties.[17]

One of the marketing tactics Novo Nordisk is using to promote Victoza is a reusable coupon that yields a savings of up to $25 per prescription for six prescriptions.[18]

Novo Nordisk has made direct-to-consumer advertising of liraglutide in Sweden (May 2011), through a 6-page supplement in the free newspaper Metro. Although the name of the drug was not explicitly mentioned (this is illegal in the European Union), it could easily be identified through supplied information on dosage and pharmacodynamics.

In January 2012, diabetic chef Paula Deen and sons were used in consumer advertising.[19] The FDA has issued a warning about the risks of thyroid cancer and pancreatitis associated with the diabetes drug liraglutide (Victoza).

The agency issued the safety alert and directed drugmaker Novo Nordisk to send out a "Dear healthcare professional" letter after determining that some primary care providers were not fully aware of the serious risks.

See also

exenatide (Byetta)
albiglutide
taspoglutide

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ http://www.drugs.com/nda/liraglutide_080530.html May 2008
  3. ^ 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
  4. ^ http://www.drugdevelopment-technology.com/projects/liraglutide/
  5. ^ http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp Oct 2008 Inc results of LEAD 6 extension
  6. ^ http://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm January 2009
  7. ^ Hirschler, Ben (January 13, 2010). "UPDATE 1-Novo starts tests on pill version of Victoza drug". Reuters.
  8. ^ "Sector Snap: New Diabetes Drugs Under FDA Review". Forbes. Retrieved March 27, 2009. [dead link]
  9. ^ http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148659.pdf
  10. ^ Victoza Package Insert Date of Issue: January 2010 Version: 1
  11. ^ N Engl J Med, 362:774
  12. ^ http://www.drugs.com/fda/victoza-liraglutide-rdna-origin-rems-risk-thyroid-c-cell-tumors-acute-pancreatitis-12979.html
  13. ^ http://diabetes.webmd.com/news/20080924/new-diabetes-drug-liraglutide-works Sept 2008
  14. ^ (www.drugs.com)
  15. ^ http://care.diabetesjournals.org/cgi/content/abstract/32/1/84 "Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes" Diabetes Care. Oct 2008
  16. ^ "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.
  17. ^ http://www.mmm-online.com/novo-reps-to-spotlight-weight-loss-for-victoza-launch/article/163167/ | Medical Media & Marketing; Novo reps to spotlight weight loss for Victoza launch; 2/4/2010; Ben Comer
  18. ^ http://www.internetdrugcoupons.com/Victoza-Coupon Internetdrugcoupons.com; Victoza Coupon; 3/23/2010;
  19. ^ "Diabetes in a new light".}
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