Bilirubin Is Negatively Associated With A1C Independently of Fasting Plasma Glucose, Age, Obesity, Inflammation, Hemoglobin, and Iron in Apparently Healthy Japanese Men and Women

It has been reported that fasting plasma glucose (FPG) is not significantly associated with risks of cardiovascular disease (CVD) and death from any cause adjusting for A1C, but A1C was significantly associated with risks of CVD and death from any cause adjusting for FPG in nondiabetic adults (1). A1C levels appear to increase with age, and any condition that changes red cell turnover, such as hemolytic anemia, chronic malaria, major blood loss, or blood transfusions, will influence A1C levels (2). Other than age and iron deficiency, some cardiovascular risk factors related with inflammation and oxidant stress may have independent associations with A1C. Although oxidation of LDL cholesterol is critical for atherosclerotic vascular changes, bilirubin suppresses the oxidation of lipid more than α-tocopherol (3) and increased serum levels of bilirubin are associated with reduced risk for CVD in some epidemiological studies (4,5). Thus, I hypothesized that the association of A1C with CVD beyond FPG in nondiabetic adults may at least partly be mediated by the association between A1C and bilirubin in nondiabetic subjects and examined the cross-sectional association between A1C and serum total bilirubin (TB) adjusting for FPG, age, obesity, inflammatory parameters, hemoglobin, and iron in apparently healthy Japanese men and women. Multivariate linear regressions using A1C as a dependent variable and FPG, age, BMI, TB, hemoglobin, iron, white blood cell count (WBC), and high-sensitivity C-reactive protein (hs-CRP) and logistic regressions using the highest quartile (≥5.6 National Glycohemoglobin Standardization Program [NGSP] unit%) and the highest decile (≥5.8 NGSP%) of A1C as a dependent variable and FPG, age, BMI, TB, hemoglobin, iron, WBC, hs-CRP, and smoking status as independent variables were performed in apparently healthy Japanese 1,803 men and 1,150 women who had no history of CVD and were with no antihypertensive, antidiabetic, or antihyperlipidemic medication. FPG (P < 0.0001), age (P < 0.0001), TB (P = 0.0003), BMI (P = 0.02), hemoglobin (P < 0.0001), and WBC (P = 0.001) in men and FPG (P < 0.0001), age (P < 0.0001), TB (P = 0.002), and iron (P = 0.004) in women were significantly associated with A1C in multivariate linear regressions. FPG (P < 0.0001), age (P < 0.0001), TB (P < 0.01), BMI (P < 0.05), hemoglobin (P < 0.05), and WBC (P < 0.05) in men and FPG (P < 0.0001), age (P < 0.0001) and TB (P < 0.01) in women were significantly associated with both the highest quartile and the highest decile of A1C in multivariate logistic regressions. Thus, bilirubin was significantly negatively associated with A1C independently of FPG, age, obesity, inflammation, hemoglobin, and iron in apparently healthy Japanese men and women. Therefore, the association of A1C with CVD beyond FPG in nondiabetic adults may at least partly be mediated by the association between A1C and bilirubin in nondiabetic subjects.