Association of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists and Diabetic Retinopathy (DR) -A Systematic Review and Meta-Analysis

Hassan Alwafi^1*Sarah Saleh Al-Harbi²Ghada Ahmad Aladwani²Safaa Alsanosi^1,3Tope Oyelade⁴Fahd AlMalki¹Husna Irfan Thalib^5*Abdallah Y Naser⁶Manal Alfahmi⁷Basil AlOtaibi⁸Samra Fuad⁵Talha Zubair⁵Abdulelah Aldhahir⁹Widya N. Insani¹⁰Abdullah A. Alqarni¹¹Jaber S Alqahtani¹²Deema S. Ashoor¹³Mohammad Dairi¹

• ¹Umm Al-Qura University College of Medicine, Mecca, Saudi Arabia
• ²Umm Al-Qura University College of Pharmacy, Makkah, Saudi Arabia
• ³University of Glasgow BHF Glasgow Cardiovascular Research Centre, Glasgow, United Kingdom
• ⁴University College London Institute for Liver and Digestive Health, London, United Kingdom
• ⁵Batterjee Medical College, Jeddah, Saudi Arabia
• ⁶Department of Applied Pharmaceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman, Jordan, Amman, Jordan
• ⁷Executive Administration of Research & Innovation, King Abdallah Medical City, Makkah, Saudi Arabia, Makkah, Saudi Arabia
• ⁸Independent Researcher, Jeddah, Saudi Arabia
• ⁹Jazan University College of Nursing, Jazan, Saudi Arabia
• ¹⁰Department of Pharmacology and Clinical Pharmacy, Padjadjaran University, Indonesia, Jatinangor, Indonesia
• ¹¹Department of Respiratory Therapy, Faculty of Medical Rehabilitation Sciences, King Abdulaziz University, Jeddah, 21589, Saudi Arabia, Jeddah, Saudi Arabia
• ¹²Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia
• ¹³Al Noor Specialist Hospital, Mecca, Saudi Arabia

Word count: 302 Objectives: Previous studies have shown conflicting results on the relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and diabetic retinopathy (DR). This systematic review and meta-analysis aimed to clarify the association between GLP-1 receptor agonists use and the development or progression of DR. A comprehensive search of MEDLINE (via OVID and PubMed), Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted from inception to March 2025. We included randomized controlled trials (RCTs) and observational studies reporting on the association between GLP-1 receptor agonists and DR. Screening, data extraction, and quality appraisal were performed independently and in duplicate. We assessed study quality using the Cochrane risk-of-bias tool for RCTs and the Newcastle-Ottawa Scale for observational studies. Meta-analysis was conducted using Stata 17, following PRISMA and MOOSE guidelines. The search identified 6,922 studies. Of these, 39 articles (24 RCTs and 15 observational studies) met the inclusion criteria and 27 were included in the meta-analysis. The pooled analysis showed that GLP-1 receptor agonists were not significantly associated with the risk of DR compared with comparators (pooled RR = 0.98, 95% CI 0.71–1.35). Subgroup analyses by study design yielded similar non-significant results, with a pooled RR of 0.86 (95% CI 0.69–1.05) for randomized controlled trials and 1.86 (95% CI 0.57–6.06) for observational studies. After excluding studies with a high risk of bias, the pooled estimate remained non-significant (RR = 1.03, 95% CI 0.66–1.61), supporting the robustness of the overall findings. In conclusions, this systematic review found no significant association between GLP-1 receptor agonists and DR risk, though a non-significant trend toward lower risk was observed in randomized trials. Given the limited number of long-term studies and variations in study design, the current evidence remains inconclusive. Further high-quality studies with longer follow-up are warranted to clarify the long-term ocular safety of GLP-1 receptor agonists.