Understanding the risk of diabetic retinopathy from glucagon-like peptide-1 receptor agonists: a Mendelian randomization study and systematic review of European populations

• Published in: Diabetology and metabolic syndrome Vol. 17; no. 1; pp. 345 - 17
• Main Authors: Shen, Baixuan, Wang, Wanying, Guo, Yuanhui, Chen, Zilong, Liu, Chuanxin, Huang, Jiarui, Li, Ying
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.08.2025; BioMed Central; BMC
• Subjects: Chromosomes; Consortia; Diabetic retinopathy; Diabetics; Genetic aspects; Genome-wide association studies; Genomics; GLP-1R agonist; Glucagon; Liraglutide; Mendelian randomization; Single nucleotide polymorphisms; Type 2 diabetes; Europe; Diabetic retinopathy; Genome-wide association studies; Mendelian randomization; Single nucleotide polymorphisms; GLP-1R agonist
• ISSN: 1758-5996; 1758-5996
• DOI: 10.1186/s13098-025-01878-3

Background Glucagon-like peptide-1 receptor agonists (GLP-1RA) are extensively prescribed to treat obesity and diabetes. However, previous studies have debated whether GLP-1RA use induces diabetic retinopathy (DR) in diabetic populations, and the relationship between the two is unclear. Methods Cis-expressed quantitative trait locus data (Cis-eQTL) in blood tissue were used to extract single nucleotide polymorphisms (SNPs) as a genetic proxy tool. The analyses were performed using Mendelian randomisation (MR) as the primary tool and Summary-data-based Mendelian Randomization (SMR) as an auxiliary validation. Discovery cohort was obtained from a large study from the GWAS catalog database, and the FinnGen consortium DR data were used as a validation cohort. Additionally, the outcomes of the two cohorts were combined using meta-analysis. In addition, we systematically retrieved relevant cohort studies of GLP-1RA and DR for systematic review to complement the association of GLP-1RA with DR in the real world. Results A total of 9 SNPs highly correlated with the exposure were screened as tool variables to proxy for GLP-1RA. The MR method showed a significant association between GLP-1RA and reduced risk of DR (OR = 0.59, 95%CI: 0.39-0.89, P = 0.0109), in addition, similar results were also found with the SMR method (OR = 0.48, 95%CI: 0.27-0.86, P = 0.0129). Finally, a total of three eligible articles were included in the systematic review, and overall GLP-1RA reduces the incidence of DR compared with existing glucose-lowering agents, but more research is required to verify the generalisability of the findings. Conclusion Based on MR and SMR, we found that GLP-1RA can reduce the risk of DR. Systematic review showed that compared with insulin therapy, T2D patients treated with GLP-1RA had a lower incidence of DR, but compared with other hypoglycemic agents, the incidence of DR was inconsistent. Therefore, clinical trials with larger sample sizes and longer follow-up times are warranted to determine this. Keywords: GLP-1R agonist, Diabetic retinopathy, Mendelian randomization, Single nucleotide polymorphisms, Genome-wide association studies