Interplay of glycated hemoglobin and traditional risk factors for the risk of atherosclerotic cardiovascular disease and all-cause mortality in people without diabetes

BACKGROUND: To assess the impact of glycated hemoglobin A1c (HbA1c) in individuals without diabetes and at the extremes of cardiovascular risk factor (CVRF) burden on the incidence of atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality. METHODS: We studied 20,360 U.S. adults, initially free of diabetes and ASCVD from the CARDIA, MESA, ARIC, and FOS cohorts, all with available HbA1c data. The mean (standard deviation) age was 57.1 (9.1) years 56.2% women and 21.9% Black. Using multivariable Cox proportional hazard regression, ASCVD and all-cause mortality were analyzed over a median 16.7-year follow-up across categories of CVRF burden (0, 1, 2, or 3 of dyslipidemia, smoking, and hypertension) and HbA1c levels (< 5.0%, 5.0-5.4% reference, 5.5-5.9%, and 6.0-6.4%). RESULTS: During follow-up, 3592 ASCVD events (17.6%) and 6627 deaths (32.6%) occurred. The hazard ratios (HRs) and 95% confidence intervals (CIs) for HbA1c levels of 5.5-5.9% and 6.0-6.4% for ASCVD were 1.17 (1.09-1.26) and 1.59 (1.42-1.78), respectively. The corresponding HRs for mortality were 1.14 (1.07-1.20) and 1.35 (1.24-1.47). HbA1c < 5.0% was also associated with an elevated mortality risk (HR, 95% CI 1.17, 1.07-1.28). Among individuals with 0 CVRFs, the HRs for ASCVD risks ranged from 1.26 (1.02-1.55) for HbA1c 5.5-5.9% to 1.68 (1.12-2.54) for HbA1c 6.0-6.4%. For those with 3 CVRFs, the corresponding HRs were 1.22 (0.88-1.69) and 2.00 (1.35-2.97). Similar findings were observed for all-cause mortality. Subgroup analysis revealed that HbA1c ≥ 5.5% was associated with an increased mortality risk in non-Black individuals but did not reach statistical significance in Black individuals (P interaction < 0.001). CONCLUSIONS: HbA1c testing in individuals without diabetes may help identify those at higher risk for ASCVD and mortality, even at the extremes of CVRF burden.