Abstract
Keywords
Anti-Vascular-Endothelial-Growth-Factor (VEGF) therapies have revolutionized the treatment of major neovascular retinal diseases, such as age-related macular degeneration, diabetic macular edema 1 and retinal vein occlusion—three leading causes of vision loss worldwide). 2 The common pathogenic denominator in these conditions is the overexpression of VEGF. 2
Among the main intravitreal agents used in clinical practice are bevacizumab (off-label), ranibizumab, aflibercept, brolucizumab, and faricimab. In recent years, growing scientific attention has been directed toward sex-based differences in drug response, in terms of both efficacy and safety. 3 However, few studies have specifically addressed sex-related differences in ophthalmologic treatments, despite the differing epidemiological burden of retinal diseases and pharmacological responses between men and women.
An analysis of data extracted from the FDA-adverse-event-reporting-system (FAERS) Public Dashboard 4 clearly reveals a predominance of female-reported adverse events (AEs) associated with the main anti-VEGF agents (Table 1). Of a total of 54.193 AE reports related to these therapies, 33.5% concerned female patients and 23% male patients. In terms of age distribution, the most represented categories were 65–85 years and over 85 years. Notably, 55.3% and 65.2% of reports in these respective age groups were associated with female patients.
Number of suspected adverse event reports by sex for Bevacizumab (off-label use in macular degeneration), Brolucizumab, Aflibercept, Ranibizumab, and Faricimab, without time restriction, based on the most recent consultation dated May 1, 2025.
Source. FDA Adverse Event Reporting System (FAERS) Public Dashboard.
Analysis by System-Organ-Class (SOC) reveals notable differences. The most frequently reported SOC was “Eye disorders,” which accounted for the largest proportion of total events. Of these, 38% were reported in women and 26.2% in men. The SOC “Injury, poisoning and procedural complications,” which include events related to intravitreal administration techniques or therapeutic errors, was the second most reported category, with 28.2% of cases involving women and 23.9% men. In the SOC “General disorders and administration site conditions,” women accounted for 35% of cases, compared to 25.4% in men. Similarly, in “Infections and infestations,” female reports made up 44.8% of cases, versus 29.6% in males. Lastly, in the SOC “Nervous system disorders,” 37.9% of reports were from women, while 22.9% were from men.
This pharmacovigilance analysis has inherent limitations, including reliance on spontaneous reporting, which may be incomplete or biased due to underreporting, and the absence of control groups, making it difficult to establish a definitive causal relationship between the drug and the AEs. 5
These findings support the view that sex is a significant biological variable in the response to anti-VEGF treatments. It is well established that pharmacokinetic and pharmacodynamic differences between sexes may influence both the efficacy and safety of therapies. 6 Age-stratified data also confirm that most AE reports involve elderly patients, in line with the epidemiology of retinal diseases. 7 In particular, the higher incidence of complications in women is primarily attributable to the higher female prevalence of age-related macular degeneration. 8
Nevertheless, ophthalmologic research has historically underestimated the importance of integrating sex as an analytical variable in clinical trials.
In light of these findings, there is a pressing need for prospective, sex-stratified studies. As personalized medicine continues to evolve, systematically recognizing and investigating sex differences is essential to improving therapeutic safety—particularly in women, who represent the majority of individuals affected by degenerative retinal diseases.
