Natural Metabolite Predicts Cardiovascular Events in Diabetics

The plasma concentration of asymmetric dimethyl arginine (ADMA), a naturally occurring endogenous L-arginine metabolite, predicts cardiovascular outcomes in type 1 diabetics with diabetic nephropathy, according to a report in the April Diabetes Care.

Dr. Lise Tarnow from Steno Diabetes Center, Gentofte, Denmark, stated that, "If confirmed in other studies, ADMA might in the near future turn out to be a new tool for risk-stratification and identification of type 1 diabetic individuals at particularly high risk of adverse cardio-renal outcomes and a practical tool for guidance on the need for additional intensification of treatment in this group of patients."

Dr. Tarnow and associates investigated the predictive value of circulating ADMA levels on the risk of fatal and nonfatal cardiovascular disease, progression to end-stage renal disease (ESRD), rate of decline in glomerular filtration rate and all-cause mortality in 397 type 1 diabetic patients with overt diabetic nephropathy and in 175 diabetic controls without nephropathy.

ADMA can inhibit all three isoforms of nitric oxide synthase, the authors explain. Among the type 1 diabetics with diabetic nephropathy, significantly more patients with ADMA levels above the median (43.4%) than similar patients with ADMA levels below the median (19.4%) suffered a fatal or nonfatal major cardiovascular event, the authors report.
In separate analyses, plasma ADMA significantly predicted nonfatal major cardiovascular events but was weaker in predicting cardiovascular mortality.

Patients with ADMA levels above the median experienced a rate of decline in glomerular filtration rate greater than that experienced by patients with lower ADMA levels, the report indicates. Patients with higher ADMA levels were 3.2 times as likely as patients with lower ADMA levels to develop ESRD.

Overall mortality was 67% higher among patients with higher ADMA levels than among patients with lower ADMA levels, the investigators say.

The risk of cardiovascular events was similar for patients with persistent normoalbuminuria regardless of ADMA level, but there was a strong trend toward higher mortality among normoalbuminuric patients with ADMA levels above the median.
"Plasma ADMA levels predict fatal and nonfatal cardiovascular events in patients with type 1 diabetic nephropathy," the authors conclude. "In addition, elevated ADMA levels suggest an increased risk of progressive diabetic kidney disease."
"Although not yet proven or even investigated in humans, it is likely that agents stimulating nitric oxide synthase or otherwise increasing nitric oxide levels will be protective against cardiovascular events and progressive renal disease in type 1 diabetic nephropathy," Dr. Tarnow explained.

"We are currently investigating the genetic predisposition to increased ADMA by studying the genes involved in synthesis and degradation of the compound," Dr. Tarnow said. "Furthermore, studies on the effect of antihypertensive treatment and other cardioprotective regimens on ADMA levels are in progress."

Diabetes Care 2008;31:747-752.

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