Low Hemoglobin A(1c) in Nondiabetic Adults: An elevated risk state?

OBJECTIVE: To identify predictors of low hemoglobin A(1c) (HbA(1c)) (<5.0%) and to investigate the association of low HbA(1c) with cause-specific mortality and risk of liver disease hospitalization. RESEARCH DESIGN AND METHODS: Prospective cohort study of 13,288 participants in the Atherosclerosis Risk in Communities Study. Logistic regression was used to identify cross-sectional correlates of low HbA(1c), and Cox proportional hazards models were used to estimate the association of low HbA(1c) with cause-specific mortality. RESULTS: Compared with participants with HbA(1c) in the normal range (5.0 to <5.7%), participants with low HbA(1c) were younger, less likely to smoke, had lower BMI, lower white cell count and fibrinogen levels, and lower prevalence of hypercholesterolemia and history of coronary heart disease. However, this group was more likely to have anemia and had a higher mean corpuscular volume. In adjusted Cox models with HbA(1c) of 5.0 to <5.7% as the reference group, HbA(1c) <5.0% was associated with a significantly increased risk of all-cause mortality (hazard ratio [HR]: 1.32, 95% CI: 1.13–1.55) and of cancer death (1.47, 95% CI: 1.16–1.84). We also noted nonsignificant trends toward increased risk of death from cardiovascular causes (1.27, 95% CI: 0.93–1.75) and respiratory causes (1.42, 95% CI: 0.78–2.56). There was a J-shaped association between HbA(1c) and risk of liver disease hospitalization. CONCLUSIONS: No single cause of death appeared to drive the association between low HbA(1c) and total mortality. These results add to evidence that low HbA(1c) values may be a generalized marker of mortality risk in the general population.