High-Density Lipoprotein Cholesterol Levels and Risk of Age-Related Macular Degeneration

Purpose: To evaluate the association between high-density lipoprotein cholesterol (HDL-C) levels and incident age-related macular degeneration (AMD) in a large cohort. Methods: This retrospective cohort study used electronic health records from 70 U.S. healthcare organizations in the TriNetX network from 2005 to 2025. Adults with at least two HDL-C measurements obtained at least three months apart were classified as having high HDL-C (all values ≥60 mg/dL) or low HDL-C (all values ≤39 mg/dL). Groups were matched 1:1 on demographics, comorbidities, medications, laboratory values, and healthcare utilization. Follow-up began at the second qualifying HDL-C measurement and continued for up to 10 years. Incident nonexudative and exudative AMD were evaluated using Kaplan-Meier and Cox proportional hazards analyses, with robustness assessed through nested matching, subgroup and sensitivity analyses, and positive and negative control outcomes. Results: Over 1.29 million person-years of follow-up, high HDL-C was associated with increased risk of nonexudative AMD (hazard ratio [HR] = 1.53; 95% confidence interval [CI], 1.32-1.78) and exudative AMD (HR = 1.37; 95% CI, 1.09-1.73). For nonexudative AMD, risk was elevated across early (HR = 1.55; 95% CI, 1.26-1.91), intermediate (HR = 1.82; 95% CI, 1.42-2.33), and advanced atrophic (HR = 1.85; 95% CI, 1.16-2.97) stages. Associations for nonexudative AMD were robust across washout periods, follow-up intervals, mortality exclusion, and stepwise matching. Associations for exudative AMD were consistently positive but less stable. Control outcomes supported the specificity and internal validity of the findings. Conclusions: Higher HDL-C levels were associated with increased risk of incident nonexudative AMD and a weaker, less consistent association with exudative AMD. These findings suggest that sustained HDL-C levels may be relevant to AMD risk assessment and warrant further investigation.