Metabolites of Glutamate Metabolism Are Associated With Incident Cardiovascular Events in the PREDIMED PREvención con DIeta MEDiterránea (PREDIMED) Trial

Background: Glutamate metabolism may play a role in the pathophysiology of cardiometabolic disorders. However, there is limited evidence of an association between glutamate‐related metabolites and, moreover, changes in these metabolites, and risk of cardiovascular disease (CVD). Methods and Results: Plasma levels of glutamate and glutamine were measured at baseline and 1‐year follow‐up in a case‐cohort study including 980 participants (mean age 68 years; 46% male) from the PREvención con DIeta MEDiterránea (PREDIMED) randomized trial, which assessed a Mediterranean diet intervention in the primary prevention of CVD. During median 4.8 years of follow‐up, there were 229 incident CVD events (nonfatal stroke, nonfatal myocardial infarction, or CVD death). In fully adjusted models, per 1‐SD, baseline glutamate was associated with 43% (95% CI: 16% to 76%) and 81% (39% to 137%) increased risk of composite CVD and stroke alone, respectively, and baseline glutamine‐to‐glutamate ratio with 25% (6% to 40%) and 44% (25% to 58%) decreased risk of composite CVD and stroke alone, respectively. Associations appeared linear for stroke (both P linear trend≤0.005). Among participants with high baseline glutamate, the interventions lowered CVD risk by 37% compared to the control diet; the intervention effects were not significant when baseline glutamate was low (P interaction=0.02). No significant effect of the intervention on year‐1 changes in metabolites was observed, and no effect of changes themselves on CVD risk was apparent. Conclusions: Baseline glutamate was associated with increased CVD risk, particularly stroke, and glutamine‐to‐glutamate ratio was associated with decreased risk. Participants with high glutamate levels may obtain greater benefits from the Mediterranean diet than those with low levels. Clinical Trial Registration URL: www.controlled-trials.com. Unique identifier: ISRCTN 35739639