Association of GLP-1 Receptor Agonist Use with Thyroid Outcomes in Adults with Type 2 Diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used to treat type 2 diabetes mellitus, but their associations with thyroid disorders remain uncertain. We evaluated whether initiating a GLP-1 RA, compared with initiating a dipeptidyl peptidase-4 inhibitor (DPP-4i), was associated with newly recorded autoimmune thyroiditis and other thyroid outcomes.

This new-user, active-comparator cohort study emulated a target trial using the TriNetX Collaborative Network. Adults with type 2 diabetes who initiated a GLP-1 RA or DPP-4i between January 1, 2018, and December 31, 2022, and had no prior use of either drug class were eligible. Patients with pre-existing thyroid disease, any neoplasm, immunosuppressant or immunostimulant use, transplantation, or end-stage kidney disease or dialysis were excluded. Propensity score matching yielded 107,912 patients per group. The primary outcome was newly recorded autoimmune thyroiditis; secondary outcomes were nontoxic uninodular goiter, nontoxic multinodular goiter, and thyroid malignancy. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with false discovery rate adjustment. Follow-up extended from 1 day after treatment initiation to 4 years.

Autoimmune thyroiditis occurred in 524 GLP-1 RA users (0.49%) and 417 DPP-4i users (0.39%). GLP-1 RA initiation was associated with a higher risk of autoimmune thyroiditis (HR, 1.26; 95% CI, 1.11-1.43; FDR-adjusted P = 0.002). Modestly higher risks were also observed for nontoxic uninodular goiter (HR, 1.07; 95% CI, 1.01-1.13) and nontoxic multinodular goiter (HR, 1.11; 95% CI, 1.03-1.19). The risk of thyroid malignancy did not differ significantly (HR, 0.93; 95% CI, 0.77-1.12). Findings were generally consistent across sensitivity and subgroup analyses, although heterogeneity was observed across body mass index strata.

Among adults with type 2 diabetes, GLP-1 RA initiation was associated with small increases in newly recorded autoimmune thyroiditis and benign nodular thyroid disease, but not with thyroid malignancy. Given the small absolute differences and the potential for residual confounding and surveillance bias, these findings require validation in future studies.