Among men enrolled in the National Health and Nutrition Examination Survey (NHANES) for the years 1988-1994 and 1999-2007, there was a 33% increase in all-cause mortality for those whose serum urate was below 4 mg/dL, compared with those whose serum urate was 5 to 6 mg/dL (HR 1.33, 95% CI 1.17-1.51), said Kristin D’Silva, MD, of Massachusetts General Hospital in Boston.

And for men whose serum urate was above 8 mg/dL, there was a 52% increase in all-cause mortality (HR 1.52, 95% CI 1.37-1.69).

“Uric acid has antioxidant properties and there is an inverse association between serum urate and the risk of Alzheimer’s dementia and Parkinson’s disease. Based on this, the latest EULAR recommendations for gout management have advised against maintaining serum urate less than 3 mg/dL for prolonged periods,” D’Silva said.

A U-shaped relationship also has been noted between serum urate and cardiovascular events, but the relationship between urate levels and mortality has not been determined.

To examine this, D’Silva and her colleagues analyzed data from NHANES, which is a nationally representative sample of the U.S. general population, focusing on individuals who were 18 and older who had a serum urate level taken at baseline.

Their multivariable analysis adjusted for NHANES cycle, age, race, body mass index (BMI), education, alcohol use, smoking, hypertension, total cholesterol, and estimated glomerular filtration rate (eGFR).

The male cohort included 19,954 participants, with 5,714 deaths during a median follow-up of 13.7 years. With higher serum urate at baseline, the percentage of patients with hypertension increased, while the lowest serum urate was associated with the highest percentage of participants with diabetes. In addition, as serum urate increased, the eGFR decreased and total cholesterol increased.

In the multivariable analysis of cause-specific mortality, the hazard ratio for diabetes-related mortality among men was 3.39 (95% CI 1.89-6.09) for a serum urate level below 4 mg/dL. With a serum urate level above 8 mg/dL, there was a 22% increase in cardiovascular death (HR 1.22, 95% CI 1.00-1.49) and a 91% increase in mortality related to chronic lower respiratory disease (HR 1.91, 95% CI 1.18-3.10).

Of note, D’Silva said, the multivariable hazard ratio for Alzheimer’s-related mortality with the highest serum urate level among men was 0.23 (95% CI 0.05-0.99), which is in agreement with previous studies.

“In men with low serum urate, the increased mortality was driven primarily by diabetes, which may be explained by the uricosuric effect of uncontrolled hyperglycemia,” she said.

However, the same pattern was not observed for women in the NHANES cohort. The analysis of women included 21,853 individuals with 4,901 deaths over a median follow-up of 14.6 years. At the time of enrollment, serum urate increased with greater age, higher BMI, higher percentages of hypertension and diabetes, higher total cholesterol, and lower eGFR.

“Unlike what was observed in men, at low serum urate, there was no higher risk of all-cause mortality in women,” she said. But at high levels, above 7 mg/dL, there was a 45% higher risk of all-cause mortality (HR 1.45, 95% CI 1.31-1.61) and a 66% higher risk of mortality related to diabetes (HR 1.66, 95% CI 1.02-2.71).

The finding of no increased risk for mortality with low serum urate among women was in contrast to what has been seen in prior studies from Asian cohorts, which showed higher mortality for both men and women at low serum urate levels. “This suggested that there are perhaps differences in the relationship between uric acid and mortality in different races,” she said.

Further research will be needed to identify potential causality for these findings, D’Silva concluded.