Diabetes-type-specific thyroid safety of GLP-1 receptor agonists: evidence from a large real-world cohort
Hao-I Hsieh, Yu-Nan Huang, Ya-Wen Chang, Wen-Ling LiaoBackground:
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used across the glycemic spectrum, yet their thyroid safety profile remains debated. Prior studies have shown inconsistent findings, and evidence across prediabetes, type 1 diabetes (T1D), and type 2 diabetes (T2D) is lacking.
Objectives:
To evaluate diabetes-type-specific associations between GLP-1RA therapy and thyroid outcomes, including thyroid dysfunction, autoimmune thyroiditis, nontoxic goiter, and thyroid cancer.
Design:
A real-world, retrospective target-trial emulation using electronic health records (EHR) from a large multicenter network.
Methods:
We used the TriNetX US Collaborative Network to identify adults with prediabetes, T1D, or T2D initiating GLP-1RAs. Active comparators included usual care and sodium–glucose cotransporter two inhibitors (SGLT2i). Propensity score matching with extensive covariate adjustment was applied. Participants were followed for incident thyroid outcomes for up to 5 years. Sensitivity and subgroup analyses were conducted to assess robustness.
Results:
Across glycemic states, GLP-1RA therapy demonstrated distinct thyroid safety patterns. In prediabetes and T1D, GLP-1RA use was associated with reduced risks of thyroid dysfunction and all-cause mortality, suggesting potential metabolic or immunomodulatory benefits. By contrast, among individuals with T2D, GLP-1RA exposure was linked to modest increases in autoimmune thyroiditis and nontoxic goiter, particularly among those with obesity or without hypertension. Importantly, no increased risk of thyroid cancer was observed in any glycemic state, providing reassuring evidence regarding long-term endocrine safety.
Conclusion:
In this large-scale target-trial emulation, GLP-1RAs showed favorable thyroid safety profiles in prediabetes and T1D, while modestly increasing selected nonmalignant thyroid outcomes in T2D. The absence of elevated thyroid cancer risk across glycemic states supports the overall endocrine safety of GLP-1RAs. These findings highlight the importance of individualized monitoring, particularly in metabolically high-risk T2D populations.