Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for type 2 diabetes and obesity management, yet their effects on thyroid function tests remain inadequately characterized. Preclinical rodent studies demonstrating C-cell hyperplasia have raised safety concerns, while clinical evidence regarding thyroid hormone dynamics is sparse and inconsistent. This systematic review aimed to synthesize available evidence on the effects of GLP-1 receptor agonists on thyroid function tests, explicitly acknowledging that direct evidence is limited and that characterizing this evidence gap is a primary objective. A comprehensive search of PubMed, Scopus, Web of Science, and ClinicalTrials.gov was conducted for studies published between January 2021 and December 2025. Eligible studies included randomized controlled trials and observational studies evaluating thyroid function parameters in adult patients receiving GLP-1 receptor agonists. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool for randomized trials and the Risk Of Bias In Non-randomized Studies of Interventions tool for observational studies. A narrative synthesis was performed due to substantial methodological heterogeneity precluding meta-analysis. Six studies encompassing 900,225 participants met the inclusion criteria, including three randomized controlled trials, two retrospective cohort studies, and one combined Mendelian randomization and cohort study. Only one study directly assessed thyroid function tests, reporting a mild decrease in free thyroxine and slight thyroid nodule progression after 12 months of therapy, though Mendelian randomization analysis revealed no significant causal effect. The remaining five studies did not systematically evaluate thyroid function parameters, focusing instead on thyroid malignancy outcomes or weight loss efficacy. The large-scale cohort studies demonstrated no increased risk of thyroid tumors or thyroid cancer with GLP-1 receptor agonist use. Risk of bias was low for two observational studies and moderate for one due to potential residual confounding, while two randomized trials demonstrated low risk of bias and one raised some concerns regarding outcome measurement. This systematic review aims to critically evaluate the available evidence - and, more explicitly, to characterize the substantial evidence gap - concerning the effects of GLP-1 receptor agonists on thyroid function tests. While only one of six included studies directly addressed this outcome, and available data suggest no increased thyroid malignancy risk, definitive conclusions regarding functional thyroid effects cannot be drawn due to the absence of systematic thyroid function assessments in most included studies, particularly the major randomized controlled trials. Future research should incorporate systematic thyroid hormone monitoring to clarify the clinical significance of GLP-1 receptor agonist therapy on thyroid axis regulation.
