Controversial Links Between Cardiometabolic Factors and Age-Related Macular Degeneration: Methodological Perspectives...

Epidemiological studies yielded conflicting results regarding the relationship between cardiometabolic factors and age-related macular degeneration (AMD). However, the methodological characteristics of these studies, which may partly explain this controversy, are not currently addressed. This narrative review aimed to examine current evidence between the six most studied cardiometabolic factors and AMD, focusing on identifying key methodological shortcomings and discussing analytical approaches currently available to address them.

We conducted a rigorous, nonsystematic literature search using targeted MeSH terms and keywords in MEDLINE (PubMed), EMBASE, Web of Science and Scopus, with no language restrictions, up to June 2025. We identified and reviewed epidemiological (cross-sectional, case-control, cohort) studies reporting original data on the six targeted cardiometabolic factors: blood pressure, antihypertensive medications, lipid levels, lipid-lowering medications, diabetes mellitus and antidiabetic treatments. A quantitative synthesis of studies was conducted to describe their methodological characteristics and reported associations.

Across the 116 reviewed associations, prospective cohorts (41%) and cross-sectional designs (37%) predominated. Most originated from America (35%) and Europe (32%). Lipids (21%) and lipid-lowering agents (20%) were the most frequently studied exposures, while advanced AMD was the predominant outcome (56%). Logistic regression was the main analytic approach (70%), and association conclusions were most often null (42%), followed by increased (36%) and decreased (22%) risk. The most common methodological limitations included cross-sectional study designs, static modeling of dynamic exposures, unaddressed interval censoring, not controlling for confounding by indication, and unstandardized selection of confounders, which are likely to bias the reported associations.

Future studies should prioritize robust methodological frameworks, including longitudinal designs, survival bias mitigation, standardized and repeated exposure assessments, distinction between AMD subtypes, propensity scores for medications use, and advanced causal inference techniques wherever feasible. Such an effort is foundational to strengthening the validity and reproducibility of findings linking cardiometabolic factors to AMD, thereby improving AMD prevention strategies.