What is the relationship between GLP-1 (Glucagon-like peptide-1) receptor agonists and the risk of thyroid cancer?

From the Guidelines

The relationship between GLP-1 receptor agonists and thyroid cancer risk appears minimal in humans, though precautions are warranted for certain patients. GLP-1 receptor agonists like semaglutide, liraglutide, dulaglutide, and tirzepatide carry a boxed warning for medullary thyroid carcinoma based on animal studies where these medications caused thyroid C-cell tumors in rodents 1. However, human relevance remains uncertain as humans have fewer GLP-1 receptors on thyroid C-cells than rodents. Current clinical data from large trials and post-marketing surveillance have not demonstrated a clear increased risk in humans. Some key points to consider:

• These medications are contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 1.
• Patients should be informed about the theoretical risk but reassured that human evidence of increased thyroid cancer is lacking.
• Any symptoms like hoarseness, difficulty swallowing, neck mass, or persistent throat pain while taking these medications should prompt immediate medical evaluation.
• The benefits of GLP-1 agonists for diabetes management and weight loss typically outweigh this theoretical risk for most eligible patients without personal or family history of these specific thyroid conditions. It's also worth noting that GLP-1 receptor agonists have been associated with other benefits, such as reducing albuminuria and slowing eGFR decline in patients with chronic kidney disease 1. Overall, the most recent and highest quality study 1 suggests that the benefits of GLP-1 receptor agonists outweigh the theoretical risk of thyroid cancer for most patients.

From the FDA Drug Label

In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0. 75 mg/kg/day liraglutide groups A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups

The relationship between GLP-1 receptor agonists, such as semaglutide and liraglutide, and the risk of thyroid cancer is uncertain.

• Key points:
  • Animal studies have shown an increased incidence of thyroid C-cell tumors with GLP-1 receptor agonists.
  • Human relevance of these findings is unknown.
  • Postmarketing reports of medullary thyroid carcinoma (MTC) in patients treated with liraglutide are insufficient to establish a causal relationship.
  • GLP-1 receptor agonists are contraindicated in patients with a personal or family history of MTC or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 2, 3. The use of GLP-1 receptor agonists may be associated with an increased risk of thyroid C-cell tumors, although the human relevance of this finding is uncertain. Patients should be counseled on the potential risks and monitored for symptoms of thyroid tumors.

From the Research

Relationship Between GLP-1 Receptor Agonists and Thyroid Cancer Risk

• The relationship between GLP-1 receptor agonists and the risk of thyroid cancer has been investigated in several studies, with conflicting results 4, 5, 6, 7, 8.
• A large multisite cohort study found no evidence that GLP-1 receptor agonist use is associated with an increased risk of thyroid cancer, with a pooled weighted hazard ratio of 0.81 (95% CI 0.59-1.12) 4.
• A narrative review of the literature found that while there is biological plausibility supporting an association between GLP-1 receptor agonists and medullary thyroid cancer in rodents, the evidence in humans is less clear, and clinical trials have not shown a consistent increase in risk 5.
• A nested case-control analysis found an increased risk of thyroid cancer associated with GLP-1 receptor agonist use, particularly after 1-3 years of treatment, with an adjusted hazard ratio of 1.58 (95% CI 1.27-1.95) 6.
• An analysis of spontaneous reports in the European pharmacovigilance database found a signal of increased reporting of thyroid cancer in patients treated with GLP-1 receptor agonists, with proportional reporting ratios of 27.5 (95% CI 22.7-33.3) for liraglutide and 22.5 (95% CI 17.9-28.3) for exenatide 7.
• A target trial emulation of a comparative effectiveness study found an increased risk of thyroid cancer within the first year of GLP-1 receptor agonist initiation, with a hazard ratio of 1.85 (95% CI 1.11-3.08), but the absolute risk was low 8.

Study Findings

• The studies had varying findings, with some showing no increased risk of thyroid cancer associated with GLP-1 receptor agonist use 4, 5, while others found an increased risk, particularly with longer duration of use or within the first year of treatment 6, 7, 8.
• The evidence suggests that the relationship between GLP-1 receptor agonists and thyroid cancer risk is complex and may depend on various factors, including the specific medication, duration of use, and individual patient characteristics.

Implications

• The findings of these studies have implications for the use of GLP-1 receptor agonists in patients with type 2 diabetes, and highlight the need for continued monitoring and research into the potential risks and benefits of these medications 4, 5, 6, 7, 8.