Associations Between HbA1c Across the Normal Range, Diagnosed, and Undiagnosed Diabetes and Retinal Layer Thickness in UK Biobank Cohort

PURPOSE: The purpose of this study was to investigate the association between glycated hemoglobin (HbA1c) levels and retinal sub-layer thicknesses in people with and without diabetes. METHODS: We included 41,453 UK Biobank participants aged 40 to 69 years old. Diabetes status was defined by self-report of diagnosis or use of insulin. Participants were categorized into groups: (1) those with HbA1c <48 mmol/mol were subdivided into quintiles according to normal range of HbA1c; (2) those previously diagnosed with diabetes with no evidence of diabetic retinopathy; and (3) undiagnosed diabetes: >48 mmol/mol. Total macular and retinal sub-layer thicknesses were derived from spectral-domain optical coherence tomography (SD-OCT) images. Multivariable linear regression was used to evaluate the associations between diabetes status and retinal layer thickness. RESULTS: Compared with participants in the second quintile of the normal HbA1c range, those in the fifth quintile had a thinner photoreceptor layer thickness (−0.33 µm, P = 0.006). Participants with diagnosed diabetes had a thinner macular retinal nerve fiber layer (mRNFL; −0.58 µm, P < 0.001), photoreceptor layer thickness (−0.94 µm, P < 0.001), and total macular thickness (−1.61 µm, P < 0.001), whereas undiagnosed diabetes participants had a reduced photoreceptor layer thickness (−1.22 µm, P = 0.009) and total macular thickness (−2.26 µm, P = 0.005). Compared to participants without diabetes, those with diabetes had a thinner mRNFL (−0.50 µm, P < 0.001), photoreceptor layer thickness (−0.77 µm, P < 0.001), and total macular thickness (−1.36 µm, P < 0.001). CONCLUSIONS: Participants with higher HbA1c in the normal range had marginally thinner photoreceptor thickness, whereas those with diabetes (including undiagnosed diabetes) had meaningfully thinner retinal sublayer and total macular thickness. TRANSLATIONAL RELEVANCE: We showed that early retinal neurodegeneration occurs in people whose HbA1c levels are below the current diabetes diagnostic threshold; this might impact the management of pre-diabetes individuals.