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Should we be concerned about thyroid cancer in patients taking glucagon-like peptide 1 receptor agonists?

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The question is complicated, as there are different types of thyroid cancer, and a causal relationship is hard to prove.

Glucagon-like peptide 1 (GLP-1) receptor agonists can be safely used in all patients with thyroid cancers that are derived from the thyroid follicular epithelium (papillary and follicular thyroid cancer). However, they are currently contraindicated in patients with medullary thyroid cancer and in patients with multiple endocrine neoplasia 2 (MEN-2), which is not a form of thyroid cancer but is relevant to our discussion. We probably should be cautious about using them in patients with familial thyroid cancer and those with a genetic predisposition for papillary or follicular thyroid cancer.

GLP-1 DRUGS ARE WIDELY USED

The glucagon-like peptide 1 (GLP-1) receptor agonists are widely used to treat type 2 diabetes mellitus. The currently available drugs of this class—exenatide (Byetta), liraglutide (Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity), and extended-release exenatide (Bydureon)—are popular because they lower glucose levels, pose a low risk of hypoglycemia, can induce weight loss,1 and, in the case of extended-release exenatide and albiglutide, are given once weekly. They are currently recommended as add-on therapy to metformin. These drugs mimic the action of GLP-1, an endogenous hormone released by the intestine in response to food. They bind to receptors on beta cells, stimulating insulin production.1

FOUR TYPES OF THYROID CANCER

There are four types of thyroid cancer: medullary (a contraindication to GLP-1 agonists), papillary, follicular, and anaplastic.

Medullary thyroid cancer is extremely rare in humans, with 976 cases diagnosed from 1992 to 2006 in the United States, compared with 36,583 cases of papillary and 4,560 cases of follicular cancer. Anaplastic cancer is also rare (556 cases).2 The highest incidence rates of medullary thyroid cancer are in people of Hispanic descent (0.21 per 100,000 woman-years and 0.18 per 100,000 man-years).2

EXPERIMENTAL EVIDENCE

Pancreatic beta cells are not the only cells in the body that can express GLP-1 receptors. Notably, the parafollicular cells (also called C cells) of the thyroid, which secrete calcitonin and which are the cells involved in medullary thyroid cancer, also sometimes express these receptors if cancer develops.

GLP-1 receptor agonists are contraindicated in patients with medullary thyroid cancer or multiple endocrine neoplasia 2

In experiments in mice and rats, the incidence of thyroid C-cell tumors was higher in animals given GLP-1 analogues. Liraglutide, exenatide, taspoglutide, and lixisenatide potently activated GLP-1 receptors in thyroid C cells, increasing calcitonin gene expression and stimulating calcitonin release in a dose-dependent manner.3 Moreover, sustained activation of these receptors caused C-cell hyperplasia and resulted in medullary thyroid cancer. However medullary thyroid cancer also occurred in rodents receiving placebo.

C cells in monkeys and humans express fewer GLP-1 receptors than those in rodents; in fact, healthy human C cells do not express them at all.3,4 In rats with C-cell hyperplasia or medullary thyroid cancer, GLP-1 receptors are present in 100% of cases (and in increased density), compared with 27% of human medullary thyroid cancers.4

In addition to medullary thyroid cancer, various other human tumors have been shown to express GLP-1 receptors.5 Based on limited data, KÖrner et al5 found that these receptors are also present in various other human tumors, eg:

  • Pheochromocytoma (60%)
  • Paraganglioma (28%)
  • Meningioma (35%)
  • Astrocytoma (25%)
  • Glioblastoma (9%)
  • Ependymoma (16%)
  • Medulloblastoma (25%)
  • Nephroblastoma (22%)
  • Neuroblastoma (18%)
  • Ovarian adenocarcinoma (16%)
  • Prostate carcinoma (5%).

Madsen et al6 reported that liraglutide binding to the GLP-1 receptor on murine thyroid C cells led to C-cell hyperplasia. However, prolonged administration of liraglutide at very high doses did not produce C-cell proliferation in monkeys.3

Gier et al7 looked at GLP-1 receptor expression in normal human C cells, hyperplastic C cells, and medullary thyroid cancer cells, as well as in papillary thyroid cancer cells, which do not arise from C cells. They demonstrated concurrent calcitonin and GLP-1 receptor immunostaining, not only in those with C-cell hyperplasia (9 of 9 cases) and medullary thyroid cancer (11 of 12 cases), but also in 3 (18%) of 17 patients with papillary thyroid cancer and 5 (33%) of 15 with normal thyroid follicular cells. However, the choice of polyclonal anti­bodies and radioligands used and concerns about methodology have led investigators to interpret these results cautiously.8–10

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