Abstract / Summary
Abstract Background Type 2 diabetes mellitus (T2DM) often coexists with thyroid dysfunction. Glucagon‑like peptide‑1 receptor agonists (GLP‑1 RAs) are widely used in T2DM, but their association with thyroid hormone sensitivity remains unclear. This study aimed to compare central thyroid hormone sensitivity indices between T2DM patients treated with GLP‑1 RAs and those who were not. Methods This cross‑sectional study included 7,697 adults with T2DM from two metabolic management centers (from June 2020 to August 2025). Central thyroid hormone sensitivity was assessed using three central indices: thyroid feedback quantile index (TFQI), thyroid‑stimulating hormone index (TSHI), and thyrotroph T4 resistance index (TT4RI). Multivariable linear regression, propensity-score analyses, and multiple sensitivity analyses were performed to evaluate associations between GLP‑1 RA use and these indices. Because all variables were measured at a single visit, the analyses are reported as cross-sectional controlled associations rather than causal effects. Results GLP‑1 RA use was associated with significantly lower TFQI values (full-adjustment model β = − 0.08, 95% CI: − 0.10 to − 0.05, P < 0.001), a marker interpreted as consistent with greater central sensitivity to thyroid hormones. The association remained similar in propensity-score analyses. No significant associations were observed for TSHI or TT4RI. Subgroup analyses showed directionally consistent associations across strata. No interaction remained significant after correction for multiple testing. However, this association was not reproduced within either center after stratification by center, indicating non-negligible between-center heterogeneity. Conclusion In this large cross‑sectional study of T2DM patients, GLP‑1 RA use was associated with lower TFQI, consistent with greater central thyroid hormone sensitivity. No association was observed for TSHI or TT4RI. Whether GLP-1 RA therapy alters thyroid hormone sensitivity or levothyroxine requirements in individual patients remains to be determined and requires prospective confirmation. Because of the cross-sectional design, causality cannot be established. Prospective studies are needed to establish causality and underlying mechanisms. Larger multi-center studies are needed to verify this association.