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, followup 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.