Diabetic retinopathy and mortality in adults with diabetes: causal mediation analysis of the role of HbA1c

Background

Diabetic retinopathy (DR) is a well-established risk factor for increased mortality in diabetes, but the mechanisms remain unclear. Chronic hyperglycemia, reflected by glycated hemoglobin (HbA1c), may be one pathway linking DR to adverse outcomes, yet its mediating role is not well defined.

Methods

We analyzed data from 5658 adults with self-reported diabetes in the NHANES 2001–2018 cycles. DR was assessed via questionnaire, HbA1c was measured using standardized laboratory methods, and all-cause mortality was determined through linkage to the National Death Index. Cox proportional hazards models were used to assess the association between HbA1c and mortality. Causal mediation analysis was conducted using the mediation R package.

Results

Participants with DR had a 34 % higher risk of all-cause mortality compared with those without DR (adjusted HR = 1.34; 95 % CI: 1.20–1.51; P < 0.0001). Higher HbA1c levels were also associated with increased mortality (per 1 % increase: HR = 1.07; 95 % CI: 1.04–1.10; P < 0.0001), and participants in the highest HbA1c tertile had a 30 % greater risk of death than those in the lowest tertile (HR:1.30; 95 %CI:1.14–1.48; P < 0.0001). Mediation analysis indicated that HbA1c accounted for 9.1 % of the excess mortality risk associated with DR, suggesting that DR may elevate mortality risk partly through increased glycemic burden.

Conclusions

DR is associated with an increased risk of all-cause mortality, and this excess risk appears to be partly linked through higher HbA1c levels. These findings suggest that elevated glycemic burden may serve as one pathway connecting DR to increased mortality in adults with diabetes.