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

Cleveland Clinic Journal of Medicine. 2015 March;82(3):142-144 | 10.3949/ccjm.81a.13066

References

Samson SL, Garber A. GLP-1R agonist therapy for diabetes: benefits and potential risks. Curr Opin Endocrinol Diabetes Obes 2013; 20:87–97.
Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS. Thyroid cancer incidence patterns in the United States by histologic type, 1992–2006. Thyroid 2011; 21:125–134.
Bjerre Knudsen L, Madsen LW, Andersen S, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010; 151:1473–1486.
Waser B, Beetschen K, Pellegata NS, Reubi JC. Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology 2011; 94:291–301.
Körner M, Stöckli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007; 48:736–743.
Madsen LW, Knauf JA, Gotfredsen C, et al. GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology 2012; 153:1538–1547.
Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh MW. Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab 2012; 97:121–131.
Drucker DJ, Sherman SI, Bergenstal RM, Buse JB. The safety of incretin-based therapies—review of the scientific evidence. J Clin Endocrinol Metab 2011; 96:2027–2031.
Gagel RF. Activation of G-protein-coupled receptors and thyroid malignant tumors: the jury is still out. Endocr Pract 2011; 17:957–959.
Nauck MA. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care 2013; 36:2126–2132.
Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab 2011; 96:853–860.
Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011; 141:150–156.
Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract 2012; 98:271–284.
Parks M, Rosebraugh C. Weighing risks and benefits of liraglutide—the FDA’s review of a new antidiabetic therapy. N Engl J Med 2010; 362:774–777.

STUDIES OF GLP-1 AGONISTS IN HUMANS

Several prospective clinical studies showed no increase in calcitonin levels during therapy with GLP-1 receptor agonists in patients with type 2 diabetes.^3,11 Long-term use of liraglutide in high doses (up to 3 mg per day) did not lead to elevations in serum calcitonin levels.¹¹

In a retrospective Adverse Event Reporting System database review, the incidence rate of thyroid cancer in patients treated with exenatide was higher—with an odds ratio of 4.7 (30 events)—than with a panel of control drugs (3 events).¹² However, this study did not differentiate between types of thyroid cancer, and the inherent limitations of retrospective databases complicate its interpretation. Such a high odds ratio would imply a significant increase in the incidence of medullary thyroid cancer, but this does not seem to be true.

These studies are hypothesis-generating and do not prove that GLP-1 receptor agonists cause medullary thyroid cancer

Alves et al¹³ performed a meta-analysis of randomized controlled trials and long-term observational studies. None of the studies evaluating exenatide reported cases of thyroid cancer, whereas five of the studies evaluating liraglutide did. In total, nine patients treated with liraglutide were diagnosed with thyroid cancer, compared with one patient on glimepiride. The odds ratio for thyroid cancer occurrence associated with liraglutide treatment was 1.54, but that was not statistically significant (95% confidence interval 0.40–6.02, P = .53, I² = 0%).

These studies are hypothesis-generating and do not prove that GLP-1 receptor agonists cause medullary thyroid cancer. Given the extremely low incidence of medullary thyroid cancer, to prove or disprove a causal relationship would require an enormous number of patients, who would need to be followed for several years.

OFFICIAL RECOMMENDATIONS

Considerable differences in the biology of the rodent vs human thyroid GLP-1 receptor systems have led regulatory authorities to conclude that the risk for development of medullary thyroid cancer with GLP-1 therapy in humans is difficult to quantify, but low.¹⁴ Consequently, the US Food and Drug Administration recommends neither monitoring of calcitonin levels nor ultrasound imaging as a screening tool in patients taking GLP-1 agonists.¹⁴

BENEFITS OUTWEIGH RISKS

At present, the benefits of using GLP-1 receptor agonists to treat type 2 diabetes mellitus outweigh the risks, and there seems to be little reason to withhold this effective therapy except in patients who have a personal or family history of medullary thyroid cancer or MEN-2. Until the effects of GLP-1 agonists are systematically studied in follicular-cell-derived thyroid cancer, we also recommend caution when considering their use in patients with familial thyroid cancer and those with a genetic predisposition for papillary and follicular thyroid cancer—eg, patients with familial adenomatous polyposis, phosphate and tensin homolog hamartoma tumor syndrome, Carney complex type 1, Werner syndrome, or familial papillary thyroid cancer.

Methodologically superior studies and careful long-term monitoring of patients treated with GLP-1 agonists are required to clarify the risk vs benefit of these therapies.

References

Samson SL, Garber A. GLP-1R agonist therapy for diabetes: benefits and potential risks. Curr Opin Endocrinol Diabetes Obes 2013; 20:87–97.
Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS. Thyroid cancer incidence patterns in the United States by histologic type, 1992–2006. Thyroid 2011; 21:125–134.
Bjerre Knudsen L, Madsen LW, Andersen S, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010; 151:1473–1486.
Waser B, Beetschen K, Pellegata NS, Reubi JC. Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology 2011; 94:291–301.
Körner M, Stöckli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007; 48:736–743.
Madsen LW, Knauf JA, Gotfredsen C, et al. GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology 2012; 153:1538–1547.
Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh MW. Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab 2012; 97:121–131.
Drucker DJ, Sherman SI, Bergenstal RM, Buse JB. The safety of incretin-based therapies—review of the scientific evidence. J Clin Endocrinol Metab 2011; 96:2027–2031.
Gagel RF. Activation of G-protein-coupled receptors and thyroid malignant tumors: the jury is still out. Endocr Pract 2011; 17:957–959.
Nauck MA. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care 2013; 36:2126–2132.
Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab 2011; 96:853–860.
Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011; 141:150–156.
Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract 2012; 98:271–284.
Parks M, Rosebraugh C. Weighing risks and benefits of liraglutide—the FDA’s review of a new antidiabetic therapy. N Engl J Med 2010; 362:774–777.

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

References

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