Background: Endothelial dysfunction is recognized as an early modification involved in the pathogenesis of vascular diseases. Evidence suggests that the Mediterranean Diet (MD) is associated with endothelial function improvement and, in turn, plays an important role in atherosclerosis development and progression. Objectives: To evaluate both acute and sustained effects of the MD on endothelial function in patients with high cardiometabolic risk. Methods: A total of 25 subjects were randomly assigned to either the MD group or the Control Diet (CD) group according to a single-blind, parallel-group study design. Endothelial function was evaluated through non-invasive flow-mediated dilation (FMD) measurements at baseline (T0) and after 8 weeks (Tw8) of the MD or CD intervention, under both 12 h fast condition (fasting) and 2 h post-meal resembling the assigned diet (2 h). Assessments were conducted by a blinded sonographer. Results: FMD at T0-fasting was similar between MD and CD groups (6.11% ± 0.67 vs. 7.90% ± 1.65; p = 0.266). A significant difference in FMD between MD and CD groups was observed at T0-2h (12.14% ± 1.93 vs. 4.01% ± 1.03; p = 0.004), T8w-fasting (9.76% ± 1.18 vs. 5.03% ± 0.89; p = 0.008), and T8w-2h (8.99% ± 1.22 vs. 3.86% ± 0.52; p = 0.003). Oral glucose insulin sensitivity (OGIS) at T0 correlated with FMD percent changes from T0-fasting to T0-2h (r = 0.414, p = 0.044). After adjusting for age, gender, and OGIS, MD was an independent predictor of percent changes in FMD from T0-fasting to T0-2h (β: −0.582, p = 0.003), from T0-fasting to T8w-fasting (β: −0.498, p = 0.013), and from T0-fasting to T8w-2h (β: −0.479, p = 0.018). Conclusions: Adherence to the MD may improve endothelial function in both the short- and medium-term among patients at high cardiometabolic risk.
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