Evaluation of the safety profile of glucagon-like peptide-1 receptor agonists: a focus on thyroid cancer-related adverse events by using the European pharmacovigilance database.
This observational pharmacovigilance study analyzed Individual Case Safety Reports (ICSRs) from the European EudraVigilance (EV) database to investigate whether GLP-1 receptor agonists (semaglutide, liraglutide, exenatide, lixisenatide, dulaglutide) and the dual GLP-1/GIP agonist tirzepatide are disproportionately associated with thyroid cancer-related adverse events. The study retrieved 34,956 ICSRs reported between January 2022 and September 2024. Most adverse events affected adult and elderly female patients, with gastrointestinal disorders being the most commonly reported category. Using disproportionality analysis (Reporting Odds Ratio, ROR), the study found that semaglutide had a statistically significantly lower probability of thyroid cancer-related adverse event reporting compared to tirzepatide (ROR = 0.54, 95% CI 0.37–0.81). The authors acknowledge key limitations inherent to pharmacovigilance databases, including reporting bias, confounding by indication, and the inability to establish causality. They conclude that findings must be interpreted cautiously and that further prospective studies are needed to clarify whether a true causal relationship exists between GLP-1 RAs and thyroid cancer risk.
Why this grade: This is a large pharmacovigilance disproportionality analysis using spontaneous reporting data, which cannot establish causality and is subject to significant reporting bias, confounding, and underreporting limitations inherent to passive surveillance databases.
Introduction The therapeutic landscape for the treatment of type 2 diabetes mellitus (T2DM) has greatly evolved with the introduction of glucagon-like peptide-1 receptor agonists (GLP-1 RAs); however, concerns regarding their potential association with thyroid cancer have emerged. The aim of this study is to analyze individual case safety reports (ICSRs) involving GLP-1 RAs, focusing on thyroid cancer-related adverse events (AEs) using the European pharmacovigilance database. Methods ICSRs reporting GLP-1 RAs (semaglutide, liraglutide, exenatide, lixisenatide, dulaglutide) or the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide as suspected drugs were retrieved from the EudraVigilance (EV) database from 1st January 2022 to 26th September 2024. A disproportionality analysis was performed to compare the probability of reporting thyroid cancer-related AEs among these drugs using the reporting odds ratio (ROR) and its 95% confidence interval (95% CI). Considering the different therapeutic indications, a sensitivity analysis was also conducted. Results A total of 34,956 ICSRs were included in the analysis. The majority of AEs were experienced by adult and elderly female patients. The most reported system organ classes (SOCs) were: "gastrointestinal disorders", "general disorders and administration site conditions", and "injury, poisoning and procedural complications". Disproportionality analysis revealed that semaglutide had a lower probability of reporting thyroid cancer-related AEs than tirzepatide (ROR = 0.54, 95% CI 0.37-0.81, p Conclusion These findings should be interpreted with caution, given the inherent limitations of pharmacovigilance databases. Further studies are recommended to better assess the potential causal relationship between GLP-1 RAs and thyroid cancer.
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