Science in Society Archive

Important Books & Reports

Banishing Glyphosate

Banishing Glyphosate - Dr. Eva Sirinathsinghji, Dr. Mae-Wan Ho and others

Glyphosate/Roundup, falsely claimed by Monsanto to be safe and harmless, has become the world’s most widely and pervasively used herbicide; it has brought rising tides of birth defects, cancers, fatal kidney disease, sterility, and dozens of other illnesses - more

Ban GMOs Now

Ban GMOs Now - Dr. Mae-Wan Ho and Dr. Eva Sirinathsinghji

Health & environmental hazards especially in the light of the new genetics - more

Living Rainbow H2O

Living Rainbow H2O - Dr. Mae-Wan Ho

A unique synthesis of the latest findings in the quantum physics and chemistry of water that tells you why water is the “means, medium, and message of life” - more

The Rainbow and the Worm - the Physics of Organisms

The Rainbow and the Worm - the Physics of Organisms - Dr. Mae-Wan Ho

“Probably the Most Important Book for the Coming Scientific Revolution” - more

New Diabetes Drug and Cancer Risk

Liraglutide, a synthetic long-lasting glucagon-like peptide appears to have the perfect ability to control blood glucose, except for potential risk of a rare thyroid cancer Dr. Mae-Wan Ho

Liraglutide (see Figure 1) is a drug developed by the pharmaceutical company Novo Nordisk for the treatment of type 2 diabetes, and is a long-acting analogue of glucagon-like peptide-1 (GLP-1) [1]. It has an acyl (fatty acid) group attached to the amino acid lysine. The drug was approved by the European Medicines Agency (EMA) in 2009, and by the US Food and Drug Administration (FDA) in 2010  It is marketed under the brand name Victoza in the US, Canada, Europe and Japan, and launched in Germany, Denmark, the Netherlands, the UK, Ireland, Sweden, Japan, Canada, US, France, Malaysia and Singapore.

Figure 1  Liraglutide, a long-acting analogue of glucagon-like peptidel-1, courtesy of Anypodetos, Wikimedia

History

The GLP-1 drugs are the result of decades-old findings on blood-sugar regulation [2]. In the late 1970s, Harvard Medical School researcher Joel Habener discovered a hormone in monkfish called GLP-1 that stimulated the body to secrete just the amount of insulin needed to control blood sugar, but not too much. But GLP-1 turned out to be impractical as a medicine because it degraded quickly once injected into the body. But in the early 1990s, endocrinologist John Eng at the VA Medical Center, Bronx, New York, found a chemical in venomous Gila monster saliva that mimicked the effects of GLP-1. When injected in diabetic mice, it controlled their blood sugar through the night. That finding led to Byetta, a synthetic version of the Gila monster agent.

Mechanism of action

Studies to date suggest that liraglutide does improve the control of blood glucose [1]. It reduces meal-related hyperglycaemia for 12 hours after administration by increasing insulin secretion, delaying gastric emptying, and suppressing meal-related glucagon secretion.

Liraglutide is an acylated peptide with a 97 percent amino acid sequence identity to endogenous human GLP-1. GLP-1 is secreted from cells in the distal ileum and colon minutes after food intake that can lower blood glucose [1, 3]. Like GLP-1, liraglutide activates the GLP-1 membrane-bound cell surface receptor by binding to it, increasing cyclic AMP levels in the beta cells of the pancreas, resulting in insulin releases in the presence of elevated glucose concentrations. The insulin secretion drops as blood glucose concentrations decrease to resting levels. Liraglutide further decreases glucagon secretion in a glucose-dependent manner. The mechanism of lowering blood glucose also involves a delay in gastric emptying. While natural human GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the ubiquitous endogenous peptidases,  liraglutide is stable against metabolic degradation, and has a plasma half-life of 13 hours after subcutaneous injection.

Liraglutide may have advantages over current drugs, with numerous potential benefits (see [4] Treating Diabetes with a Glucagon-like Peptide, SiS 52).

· It stimulates insulin secretion only when blood glucose levels are higher than normal, consequently, has neglible risks from hypoglycaemia

· It has the potential for inhibiting apoptosis (programmed cell death) and stimulating regeneration of beta cells (in animal studies)

· It decreases apetite and maintains body weight, as shown in study versus glimepiride (a sulphonylurea antibiotic drug)

· It lowers blood triglyceride levels

The side-effects listed are mainly gastrointestinal [5]

Constipation; decreased appetite; diarrhea; dizziness; headache; mild back pain; nausea; pain, swelling, or redness at the injection site; sinus inflammation; sore throat; upset stomach; vomiting

However, there are persistent cancer concerns that need to be highlighted.

Cancer concerns

Several months before the FDA approval, the FDA advisory panel was split over its vote on whether the drug should be approved [2, 6]. The worry was animal studies showing that the drug causes a rare type of thyroid cancer – medullary thyroid cancer – in both mice and rats. Although Novo Nordisk said there was no evidence of such cancers in humans, the FDA panel of doctors said the company had not ruled out the possibility. After the hearing, the FDA said it was “very rare” for a drug that causes cancer in multiple animal species to be approved. Some panel members were worried that the thyroid risk might apply to the whole class of glucagon-like peptide drugs.  Peter Savage of the National Institutes of Health, who voted against approval said: “It certainly sounded from what I heard today that this may be a class effect for any of the longer-acting agents.” He added: “I am not sure the benefits outweigh the trade-offs.”

The problem is that medullary cancer is so rare and develops so slowly over decades that it is difficult to rule out the possibility. At least one member of the panel, Michael Tuttle of memorial Sloan-Kettering Cancer Center, voted for approval because he thought there was no obvious study that could be done to rule out the risk.

Novo Nordisk said the mice and rat data are irrelevant to humans and got the drug approved by promising to study the thyroid issue in a big study involving 9 000 people, that will also look at cardiovascular safety.

In June 2011, Novo Nordisk issued an “Important Drug Warning Concerning Victoza” to health professionals on “Potential Risks of Thyroid C-Cell Tumors and Acute Pancreatitis Associated with Victoza [7], as required by the FDA. Because of these risks, “Victoza is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.”

Article first published 19/10/11



References

  1. Liraglutide, Wikipedia, 5 October 2011, http://en.wikipedia.org/wiki/Liraglutide
  2. “FDA faces tough choice on new diabetes drug, Novo Nordisk’s liraglutide may help thousands of patients. It may also cause thyroid cancer.” Robert Langreth, 4 March 2009, Forbes.com, http://www.forbes.com/2009/04/03/diabetes-liraglutide-novo-nordisk-business-healthcare-diabetes.html
  3. Tahrani AA, Piya MK, Kennedy A and Barnett AH. Glycaemic control in type 2 diabetes: targets and new therapies. Pharmacology & Therapeutics 2010, 125, 328-61.
  4. Cummins J. Treating diabetes with glucagon-like peptide. Science in Society 52 (to appear).
  5. Liraglutide side effects, Drugs.com, 12 September 2011, http://www.drugs.com/sfx/liraglutide-side-effects.html
  6. NovoNordisk, Lirablutide (injection) for the Treatment of Patients with Type 2 Diabetes, NDA 22-341, Briefing Document, Endocrine and Metabolic Drug Advisory Committee, 2 April 2009, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148659.pdf
  7. Important Drug Warning Concerning Victoza. Subject: Potential Risks fo Thyroid C-Cell Tumors and Acute Pancreatitis Associated with Victoza, 13 June 2011, Drugs.com,
    http://www.drugs.com/fda/victoza-liraglutide-rdna-origin-rems-risk-thyroid-c-cell-tumors-acute-pancreatitis-12979.html; also
    http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM258828.pdf

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There are 3 comments on this article so far. Add your comment above.

Dr. See Comment left 20th October 2011 08:08:58
I will not give to my patient. why not improve the patient's immune status,since diabetes is a immunological disease. I have been asking diabetic patients to take high dose of vitamin c with some success. Vit. c can improve immune status and also the contributor of acetyl group for cell metabolism.

HMS Comment left 2nd December 2011 16:04:35
Thanks for sharing this information. It was really helpful to solve my confusion. Occupational Medicine

tony villar Comment left 14th April 2012 06:06:11
Homeopathy offers many remedies for Diabetes. all are safe and cheap.

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