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OBJECTIVE--We compared A1C and fasting plasma glucose (FPG) in predicting cardiovascular disease (CVD) in a population with widespread obesity and diabetes. RESEARCH DESIGN AND METHODS--A total of 4,549 American Indian adults underwent the Strong Heart Study (SHS) baseline examination (1989-1991). Data from 3,850 individuals (60% women) with baseline measurements of FPG and A1C and no prevalent CVD were analyzed; 1,386 had known diabetes. CVD events were ascertained over a median of 15 years. RESULTS--A1C ≥6.5% had a 44.3% sensitivity and 98.9% specificity to identify participants with FPG ≥ 126 mg/dL Increases in A1C were associated with adverse CVD risk factor profiles; individuals with known diabetes had worse profiles. For A1C < 5, 5 to < 5.5, 5.5 to < 6, 6-6.5, or ≥6.5% or known diabetes, the multivariate-adjusted hazard ratio (HR) [95% CI] for coronary heart disease (CHD) was significant only for individuals with known diabetes (2.76 [2.17-3.51]). Similarly, the adjusted HRs for total CVD were significant only for individuals with A1C ≥6.5% or known diabetes (1.50 [1.10-2.04] and 2.52 [2.06-3.08], respectively). Similar results were observed for FPG. CONCLUSIONS--Individuals with known or newly diagnosed diabetes had increased risk for CVD. Although A1C is more convenient than FPG in diagnosing diabetes, neither test adds to conventional CVD risk factors in predicting CHD or total CVD. [ABSTRACT FROM AUTHOR]