Abstract Body (Do not enter title and authors here): Background: Prediabetes is an intermediate stage of hyperglycemia associated with an elevated risk of major adverse cardiovascular events (MACE). Vascular dysfunction is a non-traditional risk factor that worsens with hyperglycemia and elevates the risk of MACE in high-risk populations. It is currently unknown whether vascular dysfunction contributes to MACE in prediabetes. We hypothesized that vascular dysfunction would associate with an elevated risk of MACE in individuals with prediabetes independent of traditional risk factors.
Methods: We conducted an observational study (n=4557) in the Framingham Offspring and Generation III cohorts. Prediabetes status was defined by ADA criteria as fasting plasma glucose between 100-125 mg/dL or HbA1c between 5.7-6.4%. Endothelial function was determined via brachial artery flow-mediated dilation (BA-FMD), aortic stiffness via carotid-femoral pulse wave velocity (cfPWV), and coronary artery calcium (CAC) score via computed tomography. Cross-sectional general linear models were utilized with appropriate transformation of the outcome variable to evaluate if BA-FMD, cfPWV, and CAC score differed by prediabetes status. Cox regression was used to assess the association of BA-FMD, cfPWV, and CAC score with time to MACE in prediabetes. MACE was defined as coronary artery disease, stroke, and all-cause mortality. Models were adjusted for age, sex, smoking status, cardiovascular disease, and blood pressure.
Results: Median age of the prediabetes group was 55 (48,62) years and 42% were female, whereas median age of the normoglycemic control group was 45 (39,51) years and 61% were female. In unadjusted models, individuals with prediabetes had lower BA-FMD and higher cfPWV and CAC score (p<0.001). After adjustment, prediabetes remained associated with lower BA-FMD [Beta -2.1 (95% CI, -2.3,1.8; p <0.001)] and higher cfPWV [exp(Beta) 1.30 (95% CI, 1.28-1.32; p <0.001)], however the association with CAC score was abolished [OR 0.83 (95% CI, 0.67-1.01; p=0.06)]. In unadjusted analyses, BA-FMD, cfPWV, and CAC score > 100 were associated with MACE in the prediabetes group (p<0.001). After adjustment, BA-FMD [HR 0.94 (95% CI, 0.88-1.00; p=0.035)] and CAC score > 100 [HR 2.67 (95% CI, 1.26-5.64; p=0.010)] remained associated with MACE.
Conclusions: Individuals with prediabetes exhibit impaired vascular function compared with controls. Moreover, peripheral endothelial function and CAC score > 100 associate with MACE in prediabetes.