A 2022 meta-analysis evaluated the association between the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the risk of different thyroid disorders. A total of 45 randomized controlled trials (N= 94,063) were analyzed and the results indicated that the use of GLP-1 RAs was associated with a 28% increased risk of overall thyroid disorders (relative risk [RR] 1.28; 95% confidence interval [CI] 1.03 to 1.60; p= 0.027). However, when examining different GLP-1 RAs, only liraglutide, and dulaglutide showcased significant increases in the risk of overall thyroid disorders. Liraglutide increased the risk by 37% (RR 1.37; 95% CI 1.01 to 1.86; p= 0.044)), and dulaglutide showed a 96% increase (RR 1.96; 95% CI 1.11 to 3.45; p= 0.020). On the other hand, other GLP-1 receptor agonists such as semaglutide, lixisenatide, exenatide, and albiglutide, did not show significant effects on the occurrence of overall thyroid disorders. When evaluating specific types of thyroid disorders, GLP-1 RAs did not show significant effects on the occurrence of thyroid cancer (RR 1.30; 95% CI 0.86 to 1.97; p= 0.608), hyperthyroidism (RR 1.19; 95% CI 0.61 to 2.35; p= 0.608), hypothyroidism (RR 1.22; 95% CI 0.80 to 1.87; p= 0.359), thyroiditis (RR 1.83; 95% CI 0.51 to 6.57; p= 0.353), thyroid mass (RR 1.17; 95% CI 0.43 to 3.20; p= 0.759), and goiter (RR 1.17; 95% CI 0.74 to 1.86; p= 0.503). Based on these findings, it was concluded that GLP-1 RAs did not show any significant impact on the risk of thyroid cancer, hyperthyroidism, hypothyroidism, thyroiditis, thyroid mass, and goiter. However, it is important to note that the mechanism responsible for the unfavorable effects of GLP-1 RAs on thyroid disorders still remains unclear. For thyroid cancer, some of the included studies did not specify the type of thyroid cancer, which would affect the accuracy of the results and further limit the findings. Additionally, the study lacked any discussion regarding risk factors, including family history, associated with the development of thyroid cancer. Researchers emphasize the need for further prospective studies to confirm the potential effects of GLP-1 RAs on overall thyroid disorders, and specifically in thyroid cancer. [1]
Following the release of a case-control analysis, which revealed an elevated risk of thyroid cancer associated with the usage of GLP-1 RA for a duration of 1 to 3 years (adjusted hazard ratio [HR] 1.58; 95% CI 1.27 to 1.95), a commentary published in 2023 further delved into the connection between GLP-1 RAs and thyroid cancer risk. The article emphasized that well-established risk factors for thyroid cancer encompass conditions such as goiter, nodules, familial history, prior exposure to radiation, obesity, and genetic syndromes. Notably, while certain factors can be addressed through claims data, it’s important to highlight that the study was unable to account for family history in its adjustment. While it remains plausible that GLP-1 RAs may lead to a modest relative increase in thyroid cancer risk, it's important to acknowledge that the presence of detection bias cannot be outright dismissed as an alternative explanation. It's worth noting that thyroid cancer is an infrequent outcome, thereby resulting in an exceedingly marginal escalation in absolute risk. Consequently, it was recommended that healthcare practitioners and patients alike adopt a discerning approach in weighing the benefits against the potential drawbacks of treatment options while taking into account available alternatives. In populations devoid of specific risk factors associated with thyroid cancer, the favorable impacts of GLP-1 RAs are anticipated to substantially outweigh any potential adverse effects. [2], [3]
A 2022 study embarked on an investigation into the potential association between GLP-1RA and tumor development by analyzing data from the FDA Adverse Event Reporting System (FAERS) database spanning from the first quarter of 2004 to the second quarter of 2020. This comprehensive analysis revealed a total of 8,718 reported cases of tumors associated with GLP-1RA usage. Significant correlations emerged between GLP-1RA and specific tumor types, notably thyroid cancer, including medullary thyroid cancer (with a proportional reporting ratio [PRR] of 27.43) and papillary thyroid cancer (PTC, with a PRR of 8.68). Among cases of malignant thyroid neoplasms, PTC constituted 28.9% of the occurrences. However, the precise reasons behind the elevated reporting of PTC cases linked to GLP-1RA remain uncertain and multifaceted. One plausible explanation is that the awareness of GLP-1RA elevating the risk of medullary thyroid cancer could potentially lead to an attribution of PTC reports to GLP-1RA. Furthermore, studies have indicated the presence of GLP-1 receptors (GLP-1R) in PTC cells. Specifically, one study found that 32.1% of PTC cases displayed immunoreactivity to GLP-1R. Additionally, research revealed that the expression of GLP-1R was more pronounced in papillary thyroid cancer cells than in normal thyroid cells. Intriguingly, though GLP-1RA did not exhibit a significant impact on the proliferation of papillary thyroid cancer cells in vitro, the activation of GLP-1R by GLP-1RA could still hold implications for the potential development of PTC. Therefore, the relationship between GLP-1RA and PTC may require long-term observation. [4]
Due to the limited available data regarding the potential relationship between a family history of PTC and the utilization of GLP-1 RAs, we initiated communication with Novo Nordisk, the manufacturer responsible for the production of Wegovy and Saxenda. In response, the medical information correspondent conveyed that while administration of these medications is contraindicated for individuals with a family or personal history of medullary thyroid cancer, they regrettably lack sufficient data to offer a comprehensive assessment of the risk associated with their use in patients affected by PTC. [5]