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Efficacy and Safety of IGF-1 Receptor Inhibitors for Thyroid Eye Disease: Systematic Review and Meta-analysis of
Haiyang Zhang1, Zixiang Zhang1, Ting Lu1
1Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China.
Background And Objective:
Insulin-like growth factor-1 receptor (IGF-1R) inhibitors represent the first and currently only US Food and Drug Administration (FDA)-approved disease-modifying therapy for thyroid eye disease (TED). Understanding their efficacy and safety is essential for treatment decision-making. A comprehensive analysis of randomized controlled trial (RCT) data of these drugs is necessary for defining reliably improved outcomes and commonly observed treatment-related adverse events. In this study, we aimed to evaluate the efficacy and safety profiles of IGF-1R inhibitors for treatment of TED as evidenced by RCTs.
Methods:
This systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251141789) and conducted according to Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) guidelines. PubMed, Embase, Web of Science, Cochrane Library, and EBSCO were searched through 10 December 2025. Eligible studies were RCTs comparing IGF-1R inhibitors with placebo in TED. Two reviewers independently performed study selection, data extraction, and quality assessment using the Cochrane risk of bias tool. Fixed- or random-effects models, selected according to the degree of statistical heterogeneity, were used to estimate pooled risk ratios (RRs) and mean differences (MDs), with subgroup, meta-regression, and sensitivity analyses exploring heterogeneity.
Results:
A total of 669 patients participating in 7 RCTs were included from 957 articles screened. These include studies evaluating teprotumumab, IBI311, and veligrotug. Regarding primary outcomes, IGF-1R inhibitors improved proptosis significantly (RR = 7.71, 95% CI 5.04-11.79, P < 0.001) and increased overall response (RR = 8.74, 95% CI 5.61-13.62, P < 0.001). Secondary outcome analysis revealed a significant improvement with IGF-1R inhibitors versus placebo, including achieving clinical activity score (CAS) of 0 or 1 (RR = 3.19, 95% CI 2.40-4.24, P < 0.001), diplopia (RR = 1.95, 95% CI 1.52-2.50, P < 0.001), least squares mean (LSMean) change in proptosis (MD = - 2.22 mm, 95% CI - 2.45 to - 1.99 mm, P < 0.001) and LSMean change in quality of life (MD = 10.48, 95% CI 6.95-14.00, P < 0.001). Pooled adverse-event rate was higher in the active treatment group (RR = 1.15, 95% CI 1.06-1.24, P < 0.001). Subgroup analysis and meta-regression identified disease activity as a significant predictor of proptosis reduction, with greater efficacy in acute active TED, while an exploratory subgroup difference in diplopia response was observed between trials conducted in predominantly white and predominantly East Asian populations (P(Qint) = 0.027).
Conclusions:
IGF-1R inhibitors outperformed placebo across multiple efficacy outcomes. These findings confirm their robust efficacy in TED, particularly in active disease. Given the increased adverse event risk, IGF-1R inhibitors warrant vigilant monitoring, including baseline and on-treatment glycemic and audiometric assessments, to ensure optimal safety.
