GLP ‐1 Receptor Agonists and Risk of Age‐Related Macular Degeneration in Older Adults With Obesity: A Target Trial Emulation

AIMS: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older adults. Whilst glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for obesity management, their potential impact on AMD risk in individuals without diabetes remains unclear. This study aimed to evaluate the association between GLP-1RA initiation and the risk of incident AMD in obese adults without diabetes. MATERIALS AND METHODS: We conducted a target trial emulation using the TriNetX global health research network (January 2014-June 2025). Eligible participants were adults aged ≥ 60 years with obesity but without diabetes mellitus. New users of GLP-1RAs were compared with new users of other weight-loss medications. Following 1:1 propensity score matching, Cox proportional hazards models estimated hazard ratios (HRs) for incident AMD over a maximum 7-year observation window (median follow-up: 1.11 years IQR: 1.48 in the GLP-1RA group versus 2.56 years IQR: 3.89 in the comparator group). RESULTS: In 157 880 matched patients (78 940 per group), GLP-1RA use was associated with a significantly lower risk of incident AMD (HR 0.82; 95% CI 0.68-0.98) compared with other weight-loss medications. Subtype analyses revealed reduced risk for unspecified AMD (HR 0.70; 95% CI 0.52-0.93) and a potential trend towards a lower risk of nonexudative AMD (HR 0.78; 95% CI 0.60-1.00; p = 0.050). Subgroup analyses suggested stronger effects in women and adults aged 60-69 years; all subgroup findings should be interpreted as exploratory. CONCLUSIONS: GLP-1RA use is associated with a reduced risk of incident AMD-statistically significant for unspecified AMD, with a potential trend towards a lower risk of nonexudative AMD-in obese adults without diabetes. Whether this reflects direct GLP-1RA neuroprotective mechanisms, greater weight-loss magnitude or both remains to be determined. Further mechanistic research and prospective clinical trials are warranted.