Statin Use and the Risk of Developing Graves' Orbitopathy in Patients With Graves' Disease: A Systematic Review and Meta-Analysis With Regional and Gender-Stratified Analyses.

Graves' orbitopathy (GO) is a clinically significant extrathyroidal manifestation of Graves' disease (GD), often resulting in functional and cosmetic morbidity. Preventive strategies remain limited. Statins, widely prescribed for cardiovascular disease, possess anti-inflammatory and immunomodulatory properties that may also mitigate the risk of GO. This systematic review and meta-analysis aimed to evaluate the association between statin use and GO risk in GD, with subgroup analyses by geographic region and sex to capture potential differential effects. This study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed, the Excerpta Medica database (Embase), and the Cochrane Library were systematically searched from database inception through May 2025 using a predetermined strategy. Eligible observational studies (cohort or case-control) assessing the effect of statin use on incident GO were included. Where feasible, pooled hazard ratios (HRs) or odds ratios (ORs) were estimated using random-effects models (Western cohorts). For Asian populations, effect estimates were synthesized narratively due to heterogeneity in effect measures. Two reviewers independently performed study selection, data extraction, and risk of bias assessment using the ROBINS-I tool. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD420251032246). Five studies (n = 156,926) met the inclusion criteria. In Asian populations (n = 113,628), statin use was associated with a significantly reduced risk of GO (HR = 0.56; 95% CI: 0.46-0.68; p < 0.001). In Western populations (n = 43,298), pooled analysis suggested a non-significant trend toward risk reduction (HR = 0.76; 95% CI: 0.53-1.10; p = 0.14), with substantial heterogeneity (I² = 60.8%). Among Asian females (n = 83,997), statin use consistently demonstrated protective associations (HRs 0.37-0.66), while male subgroup estimates, derived from a single study, were not statistically significant. Across all studies, risk of bias was rated as moderate, primarily due to confounding and variability in outcome measurement. Statin use appears to reduce the risk of GO among patients with GD, with the strongest protective effect observed in Asian women. Although Western data suggested a protective trend, findings did not reach statistical significance and were limited by heterogeneity. These results highlight the importance of region- and sex-specific investigations. Large-scale prospective cohort studies and randomized controlled trials (RCTs) are warranted to confirm the potential preventive role of statins in GO and to clarify dose-response relationships.