GLP-1 RECEPTOR AGONISTS AND THYROID DISEASE: FROM MECHANISM TO CLINICAL PRACTICE
DOI:
https://doi.org/10.31435/ijitss.4(52).2026.6324Keywords:
Glucagon-like Peptide-1 Receptor Agonists, Thyroid Function Tests, Medullary Thyroid Carcinoma, C-cell Hyperplasia, Autoimmune Thyroid Disease, PharmacoepidemiologyAbstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are prescribed across type 2 diabetes, obesity, and cardiovascular indications (Drucker, 2024). Despite rodent C-cell hyperplasia with MTC/MEN2 black-box contraindication, clinical thyroid risk remains incompletely defined. This review addresses: cancer risk beyond the rodent signal, levothyroxine-treated patient hormone modulation, autoimmune thyroid natural history, and dual/triple incretin agonist profiles.
Methods. PubMed/MEDLINE, Embase, Web of Science, Cochrane CENTRAL were searched in 2025–2026 with no lower date restriction; pharmacovigilance and cohort studies were appraised for channeling bias (Sendor & Stürmer, 2022).
Findings. Receptor mapping finds absent GLP-1R in normal human C-cells (Waser et al., 2014); primate toxicology at ~500× maximum human dose shows no C-cell phenotype (Knudsen et al., 2010; Vahle et al., 2015). RCT meta-analysis shows composite signal (RR 1.28, 95% CI 1.03–1.60) without individual sub-domain effects (Hu et al., 2022); cancer-specific MH-OR 1.52 (1.01–2.29), fragility index 1 (Silverii et al., 2023). FAERS class ROR 21.80 (10.25–46.36) is hypothesis-generating (Makunts et al., 2023). Baxter 2025 active-comparator cohort: HR 0.81 (0.59–1.12) (Baxter et al., 2025); vs Bezin's aHR 1.58 (1.27–1.95) with non-user comparator (Bezin et al., 2022). Class-wide thyrotropic modulation: oral semaglutide increases levothyroxine exposure ~33% (Hauge et al., 2021) with weight-loss-independent TSH reduction (Konopka et al., 2024; Sencar et al., 2019; Yu et al., 2023). Autoimmune evidence is hypothesis-generating (Jung et al., 2025; Mazokopakis, 2023; Mazza, 2025; Sabudin et al., 2025; Shlomov et al., 2026; Yaribeygi et al., 2024). Tirzepatide: SURMOUNT-3 reports 1.7% vs 1.0% malignancy, no related MTC (Wadden et al., 2023); retatrutide phase 2 endpoints unreported.
Conclusion. Modest composite thyroid signal without established cancer effect; class-wide thyrotropic modulation requiring 6–8-week levothyroxine monitoring; hypothesis-generating autoimmune signals warranting informed-consent discussion. Current regulatory framework (Watts et al., 2025) is supported.
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Copyright (c) 2026 Aleksandra Milewska, Anna Bociąg, Konrad Kowalski, Rafał Marciniak, Łukasz Ptach
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