Abstract
BackgroundTo evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease.Methods200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model’s improved ability to discriminate events from non-events. rIDI quantifies the increase in separation of events and non-events on a relative scale.ResultsHigher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality.ConclusionIn persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors.
Highlights
To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease
Inclusion criteria were (1) type 2 diabetes according to WHO criteria; (2) no history of coronary artery disease or symptoms suggestive of cardiac disease; and (3) persistent urinary albumin excretion rate (UAER) >30 mg/24 h. 613 consecutive patients were invited by letter to participate in the study. 72 patients declined the invitation. 341 patients were excluded
Participants with high ADMA levels were older, with higher UAER and plasma creatinine and lower esti‐ mated glomerular filtration rate (eGFR) compared to participants with low ADMA
Summary
To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. Elevated levels of ADMA in persons with type 2 diabetes and macrovascular disease have been reported in cross sectional studies [7, 8], there are conflicting results concerning the prognostic value [9, 10]. It is unknown whether associations seen for ADMA extend to the structural isomer SDMA. A recent metaanalysis demonstrated that higher SDMA is a risk factor for cardiovascular disease and mortality in different populations, with the strongest associations observed in the general population [3] This meta-analysis did not report results for any diabetic cohorts. Studies of SDMA in type 2 diabetes are few; a cross sectional study demonstrated higher SDMA in persons with cardiovascular disease [8]
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