Abstract

BACKGROUND: Prediabetes is a growing public health concern that increases the risk of major adverse cardiovascular events (MACE). Vascular dysfunction worsens with hyperglycemia and is associated with MACE in several high-risk populations. However, it is unknown whether vascular dysfunction contributes to MACE in prediabetes. We hypothesized that vascular dysfunction is associated with elevated risk of MACE in prediabetes. METHODS: We conducted an observational study of 5742 adults (age 54.9 ± 11.5 years, 54% female) in the Framingham Offspring and Generation III cohorts. Prediabetes was defined using the ADA criteria. 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. Stepwise selection models evaluated BA-FMD, cfPWV, and CAC score by prediabetes status. The association of BA-FMD, cfPWV, and CAC score with time to MACE was assessed via Cox proportional hazards regression. RESULTS: Individuals with prediabetes had lower BA-FMD and higher cfPWV and CAC score (p < 0.001). In stepwise selection models, age, sex, smoking history, systolic blood pressure, triglycerides, high-density lipoprotein, low-density lipoprotein, and fasting glucose related to vascular dysfunction. After adjusting for traditional cardiovascular risk factors, BA-FMD (HR [95% CI], 0.93 [0.90,0.97]; p < 0.001) and CAC score >100 [HR [95% CI], 4.15 [2.24, 7.70]; p < 0.001)] were associated with MACE in prediabetes while cfPWV was not (p = 0.051). CONCLUSIONS: Vascular dysfunction measured by BA-FMD independently associates with MACE in prediabetes. Therapies that target vascular dysfunction may reduce CVD risk in prediabetes.