Abstract Body (Do not enter title and authors here): Introduction
A substantial risk gradient for incident cardiovascular disease has been seen across glycated hemoglobin (HbA_1c) levels below diabetic and pre-diabetic thresholds, highlighting the need for better risk prediction across the glycemic spectrum. Glycemia is associated with greater non-calcified plaque, limiting the predictiveness of calcium scores in this population. Generalizable data on the association between HbA_1c, semiquantitative CAD burden, and high-risk plaque (HRP) features in pre and nondiabetics is limited. We hypothesized that higher HbA_1c is associated with a higher comprehensive CCTA risk (Leiden) score and HRP.

Methods
Patients undergoing clinically indicated CCTA were prospectively enrolled (2021-2023, N=419) in a study of blood biomarkers predictive of CAD, of whom 347 were nondiabetic. CCTAs were independently analyzed using a 17-segment model and comprehensively phenotyped by two experts in consensus to derive the Leiden score, determine HRP. HbA_1c, measures of insulin resistance and comorbidities were compared across those with or without ≥1 coronary segment with HRP and CAD severity groups [Leiden scores 0-5 (low), 6-20 (moderate) and >20 (high)]. Multivariable logistic regression assessed the association between HbA_1C groups and presence of HRP. Receiver operating characteristic (ROC) analysis and Youden index were used to define an optimal HbA_1c cutoff predictive of HRP.

Results
Patients with HRP (93, 26.8%), were older (64±10 years), more hypertensive (HTN, 69%) and dyslipidemic (79%). HRP was associated with more severe CAD (mean Leiden score 17.62 vs. 7.35, P<0.001). Median HbA_1c was significantly higher in those with HRP [5.55, IQR 5.3-5.7 vs. 5.6, IQR 5.5-5.8, P<0.001] (Table 1), but did not vary significantly by CAD severity (Table 2). HbA_1c was associated with a greater risk of HRP in age, sex adjusted models [OR 2.54; 95% CI 1.24-5.35, per unit increase]. An optimal HbA_1c threshold of 5.55 had modest predictive performance for HRP (c-statistic 0.62). HbA_1c ≥ 5.55 was independently predictive of HRP in models adjusted for age, sex, race, smoking, HTN, statin use, and Leiden score [OR 1.79; 95% CI 1.19–2.71].

Conclusion
Higher HbA_1c is independently associated with high-risk plaque in pre- and nondiabetics undergoing clinically indicated CCTA. Further prospective evaluation of prediabetic HbA_1c thresholds predictive of subclinical and incident CAD in larger populations, and their preventive implications is warranted.