The study adhered to the Declaration of Helsinki and all federal laws in the country, and its protocol was approved by the Institutional Review Board of Yonsei University, Severance Hospital (approval number 9-2023-0224). The UK Biobank cohort consists of 502,656 UK residents between the ages of 40 and 69, who were registered with UK National Health Service. This community-based cohort was examined between April 2007 and October 2010 at 22 study assessment centers. The overall study protocol ( http://www.ukbiobank.ac.uk/resources/ ) and protocols for individual tests ( http://biobank.ctsu.ox.ac.uk/crystal/docs.cgi ) are available online. Between 2009 and 2010, eye examinations were performed, which include visual acuity, autorefraction/keratometry (TomeyRC5000; Erlangen-Tennenlohe), Goldmann-corrected intraocular pressure (IOP), and cornea-corrected IOP (Ocular Response Analyzer; Reichert) in 110,573 participants. High-resolution spectral-domain retinal optical coherence tomography (OCT; Topcon 3D OCT 1000 Mk2, Topcon Inc) measurements were also completed in 62,321 participants in the same period, as described in detail by Ko et al, in compliance with the APOSTEL guidelines. The criteria for study population selection are illustrated in Figure 1 .

A flowchart of study population selection. From 68,510 participants with spectral domain OCT scans initially available for analysis, those with a history of ocular disease, neurodegenerative disease or congenital cardiac/renal diseases were excluded. A total of 17,082 participants were included in the present study.

The diagnosis and staging of CKM syndrome were conducted in accordance with the advisory published by the AHA. Stage 0 was defined as the absence of risk factors; stage 1 as the presence of (1) body mass index (BMI) ≥ 25 kg/m2; (2) waist circumference (WC) ≥ 88 cm in women or ≥ 102 cm in men; and (3) prediabetes; stage 2 as the presence of moderate to high-risk CKD and at least one of metabolic risk factors; stage 3 as individuals exhibiting subclinical cardiovascular disease (CVD), as indicated by a high predicted CVD risk; and stage 4 as clinical CVD. The detailed definitions are outlined in Table S1. Advanced CKM syndrome was defined as those in stages 3 and 4 because these individuals either had or were at significantly high risks for CVD.

The primary outcome of this study was RNFL thickness, ganglion cell-inner plexiform layer (GCIPL thickness), overall macular thickness and total macular volume, as measured by the retinal OCT. In accordance with the OSCAR-IB criteria, scans of poor quality, visual acuity less than 6 of 7.5, IOP over 21 mmHg or 5 mmHg or lower, self-reported history of ocular disorders or trauma, or neurodegenerative disease were excluded. If both eyes of 1 participant were eligible for inclusion, 1 eye was chosen at random. The participants were divided into even individual-sized quintiles for comparisons according to the distribution of 4 types of OCT measurements: Q1 (18.5-24.6 µm), Q2 (>24.6-26.9 µm), Q3 (>26.9-28.9 µm), Q4 (>28.9-31.6 µm), and Q5 (>31.6-41.2 µm) for RNFL thickness; Q1 (61.7-69.9 µm), Q2 (>69.9-73.0 µm), Q3 (>73.0-75.6 µm), Q4 (>75.6-78.6 µm), and Q5 (>78.6-86.1 µm) for GCIPL thickness; Q1 (246-266 µm), Q2 (>266-274 µm), Q3 (>274-280 µm), Q4 (>280-287 µm), and Q5 (>287-305 µm) for overall macular thickness; and Q1 (6.97-7.55 mm³), Q2 (>7.55-7.77 mm³), Q3 (>7.77-7.94 mm³), Q4 (>7.94-8.14 mm³), and Q5 (>8.14-8.63 mm³) for total macular volume.

Descriptive statistics were used to summarize baseline characteristics of the study population. Continuous variables were expressed as means ± SDs (SD), and categorical variables were presented as frequencies and percentages. Group comparisons were conducted using analysis of variance (ANOVA) for continuous variables, and Pearson’s chi-square tests for categorical variables. Logistic regression analysis was used to estimate odd ratios (OR) and 95 % CIs (CI) for having advanced CKM syndrome for each 1 unit reduction of OCT measurement. Advanced CKM syndrome was defined as stages 3 or higher, in order to include the onset of subclinical or clinical cardiovascular disease. Multivariable regression modeling was performed to adjust for potential confounders. Based on previous literature, age, sex, ethnicity, economic status and educational attainment were considered potential covariates. For missing covariates, complete-case analysis was employed. All statistical analyses were performed using R software (version 4.4.0; R foundation for Statistical Computing; Vienna, Austria). A two-sided P value < 0.05 was considered statistically significant.