The Risk of Hypothyroidism With the Use of GLP ‐1 Receptor Agonists in Saudi Arabia

AIM: Preclinical studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may induce thyroid gland hyperplasia, raising concerns about potential thyroid-related risks. Given their increasing use and the limited evidence on thyroid safety, this study assessed the association between GLP-1RA use and the incidence of hypothyroidism using real-world data. METHODS: We conducted an active-comparator, new-user cohort study using the Real-World Evidence Research Network (SRWEN) (2016-2023). Adults (≥ 18 years) initiating GLP-1RAs or dipeptidyl peptidase-4 inhibitors (DPP-4is) were followed from first prescription until hypothyroidism, treatment discontinuation, switching, death, or study end. Hypothyroidism was identified through ICD-10 codes or levothyroxine prescriptions. Inverse probability of treatment weighting was applied to adjust for confounding, and weighted Cox proportional hazards models were used to estimate hazard ratios (HRs). RStudio 4.4.0 was used for analyses. RESULTS: A total of 47 017 patients were included (6800 GLP-1RA users; 40 217 DPP-4i users). GLP-1RA users were younger (mean age 50 vs. 58 years) and more often female. The incidence rate of hypothyroidism was 128 per 10 000 person-years in GLP-1RA users compared to 150 per 10 000 person-years in DPP-4i users. GLP-1RA use was not associated with a statistically significant risk of hypothyroidism (adjusted HR 1.04, 95% CI 0.69-1.57). Sensitivity analyses extending follow-up by 30 and 60 days yielded consistent findings. CONCLUSION: In this real-world analysis, GLP-1RA use was not associated with an increased incidence of hypothyroidism compared to DPP-4is. Findings were consistent across sensitivity and subgroup analyses. Although findings do not suggest a short-term risk, longer-term studies are warranted to further evaluate thyroid safety.