Glycated Hemoglobin and Subclinical Atherosclerosis in People Without Diabetes

Abstract

Background: The metabolic injury caused by protein glycation, monitored as the level of glycated hemoglobin (HbA1c), is not represented in most risk scores (i.e., Systematic Coronary Risk Estimation or atherosclerotic cardiovascular disease risk scale). Objectives: The purpose of this study was to assess the association between HbA1c and the extent of subclinical atherosclerosis (SA) and to better identify individuals at higher risk of extensive SA using HbA1c on top of key cardiovascular risk factors (CVRFs). Methods: A cohort of 3,973 middle-aged individuals from the PESA (Progression of Early Subclinical Atherosclerosis) study, with no history of cardiovascular disease and with HbA1c in the nondiabetic range, were assessed for the presence and extent of SA by 2-dimensional vascular ultrasound and noncontrast cardiac computed tomography. Results: After adjusting for established CVRFs, HbA1c showed an association with the multiterritorial extent of SA (odds ratio: 1.05, 1.27, 1.27, 1.36, 1.80, 1.87, and 2.47 for HbA1c 4.9% to 5.0%, 5.1% to 5.2%, 5.3% to 5.4%, 5.5% to 5.6%, 5.7% to 5.8%, 5.9% to 6.0%, and 6.1% to 6.4%, respectively; reference HbA1c ≤4.8%; p < 0.001). The association was significant in all pre-diabetes groups and even below the pre-diabetes cut-off (HbA1c 5.5% to 5.6% odds ratio: 1.36 [95% confidence interval: 1.03 to 1.80]; p = 0.033). High HbA1c was associated with an increased risk of SA in low-risk individuals (p < 0.001), but not in moderate-risk individuals (p = 0.335). Relative risk estimations using Systematic Coronary Risk Estimation or atherosclerotic cardiovascular disease predictors confirmed that inclusion of HbA1c modified the risk of multiterritorial SA in most risk categories. Conclusions: Routine use of HbA1c can identify asymptomatic individuals at higher risk of SA on top of traditional CVRFs. Lifestyle interventions and novel antidiabetic medications might be considered to reduce both HbA1c levels and SA in individuals without diabetes.