Asymmetric Dimethylarginine Predicts Cardiovascular Events in Patients With Type 2 Diabetes

OBJECTIVE: Circulating concentrations of an endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are elevated in patients with increased cardiovascular risk. We hypothesized that ADMA predicts cardiovascular events and enhances risk prediction independent of established risk markers in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This prospective cohort study included 125 patients with type 2 diabetes. ADMA, L-arginine, high-sensitivity C-reactive protein (CRP), and routine clinical parameters were determined at baseline. First occurrence of cardiovascular events (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, carotid revascularization, or all-cause mortality) was defined as a composite end point. RESULTS: During a median follow-up of 21 (interquartile range 11-27) months, 84 events occurred in 48 patients. According to multivariate Cox regression analysis, patients with baseline ADMA or CRP in the highest tertile had a significantly increased hazard ratio for incident cardiovascular events compared with those with ADMA or CRP in tertile 1 (2.37 95% CI 1.05-5.35, P = 0.038, and 3.63 1.59-8.28, P = 0.002). Assessing the joint effect of ADMA and CRP revealed that patients with either ADMA or CRP or both in the highest tertile had increased hazard ratios for cardiovascular events compared with patients with neither ADMA nor CRP in the highest tertile before and after adjustment for possible confounders (hazard ratio 4.59 95% CI 2.07-10.15, P < 0.001). CONCLUSIONS: ADMA predicted cardiovascular events and enhanced the predictive role of CRP in patients with type 2 diabetes. ADMA therefore could improve cardiovascular risk assessment in patients with type 2 diabetes.