Inverted U-Shaped Relationship between HbA1c and Diabetic Retinopathy in Diabetic Patients: A Cross-Sectional Study

Abstract Background: Diabetic retinopathy (DR) is a leading cause of blindness among adults with diabetes. Glycated hemoglobin A1C (HbA1C) is a critical biomarker for long-term glycemic control and has been closely associated with the risk of developing DR. However, the relationship between HbA1C and DR remains complex and multifaceted, with limited research exploring the nonlinear aspects of this association. This study aims to investigate the nonlinear relationship between HbA1C and DR, providing insights into their association and informing clinical interventions. Objective: Many studies have indicated that HbA1C is positively correlated with DR. However, although elevated HbA1C is common in patients with DR, its relationship with DR remains controversial. Our study aimed to investigate the nonlinear relationship between HbA1c and DR, thereby accurately elucidating their association and providing a basis for clinical interventions. Methods: This study is the second analysis based on a cross-sectional studv. A total of 2,001 patients with type 2 Diabetes Mellitus (T2DM) visited the diabetic clinic in the Internal Medicine outpatient departments of two hospitals in southern Taiwan between April 2002 and November 2004 were included in this analysis. Demographic and clinical data were collected, and HbA1c levels were measured. The association between HbA1c and DR was analyzed using multivariate logistic regression, adjusting for potential confounders, and the potential nonlinear correlation was explored with a smooth curve fitting approach. Results: The fully-adjusted model showed that HbA1c positively correlated with DR (OR:1.13, 95%CI: 1.05－1.22). However, an inverted U-shaped association between them was observed by applying the smooth curve fitted method. The inflection point of HbA1c (9.4%) was calculated by utilizing the two-piecewise logistic regression model. In the subgroup analysis, the inverted U-shaped nonlinear correlation between HbA1c and DR was also found in age, sex and BMI. Conclusions: HbA1C and DR have an inverted U-shaped relationship, with a peak at an HbA1C of 9.4% in the early phase of DR. After this peak, HbA1C decreases as DR increases. These results have crucial implications for DR patients. The findings also offer insights for public health policy, highlighting the necessity of regular screening and intervention for diabetic patients. Future research should further explore the mechanisms linking HbA1c to DR and consider individualized management strategies for different populations to effectively mitigate the burden of DR.