Uric acid and mortality from all-causes and cardiovascular disease among adults with and without diagnosed diabetes: Findings from the National Health and Nutrition Examination Survey III Linked Mortality Study

doi:10.1016/j.diabres.2011.05.012

Diabetes Research and Clinical Practice

Volume 93, Issue 2, August 2011, Pages e84-e86

https://doi.org/10.1016/j.diabres.2011.05.012 Get rights and content

Abstract

Using data from the National Health and Nutrition Examination Survey III Linked Mortality Study, uric acid concentration was significantly related to mortality from all-causes (978 diabetic participants: hazard ratio per mg/dl, 1.14; 95% confidence interval, 1.01–1.28; 12,824 nondiabetic participants: hazard ratio, 1.06; 95% confidence interval, 1.02–1.11) but not major CVD.

Introduction

Uric acid, an end product of the metabolism of the purines adenine and guanine, is well known for its role in gout, but the possible contribution of this compound to the pathogenesis of conditions such as coronary heart disease and stroke remains unresolved [1], [2], [3], [4]. Some evidence has also linked concentrations of uric acid to all-cause mortality [5]. In people with diabetes, however, a limited number of prospective studies of uric acid and all-cause mortality have generated inconsistent results [6], [7], [8], [9], [10]. Therefore, the objective of this study was to examine the relationships between concentrations of uric acid and mortality from all-causes and major cardiovascular disease (CVD) in a national sample of adults with diabetes.

Section snippets

Materials and methods

The analyses for this study were conducted by using public data files for the 2006 follow-up of the National Health and Nutrition Examination Survey III Linked Mortality Study [11]. From 1988 through 1994, a representative sample of the noninstitutionalized civilian US population was selected by using a multistage, stratified sampling design. Participants were interviewed at home and invited for a clinical examination [12]. The study received approval from the Centers for Disease Control and

Results

A total of 16,562 participants aged ≥20 years attended the mobile examination center. After excluding participants who used allopurinol or colchicine and those with missing values for the study variables, 13,802 participants remained in the analytic sample: 978 with diagnosed diabetes (550 total deaths; 249 from major CVD) and 12,824 without diagnosed diabetes (2669 total deaths; 1146 from major CVD). The mean and median survival times were 11.4 years and 13.2 years, respectively, among

Discussion

In this study, uric acid was a moderate and independent predictor of mortality from all-causes but not major CVD, which comprises the vast majority of deaths among people with diabetes. Mechanisms that help to explain the purported link between uric acid and risk for CVD include effects on endothelial function, platelet adhesiveness, and inflammation [2]. In contrast, its role as an antioxidant has been cited as an argument against a causative role for uric acid in CVD [13], [14].

The present

Conflict of interest statement

There are no conflicts of interest.

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Uric acid and cardiovascular risk
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Hyperuricemia and risk of stroke: a systematic review and meta-analysis
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Serum uric acid, mortality and glucose control in patients with Type 2 diabetes mellitus: a PreCIS database study
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Cited by (17)

On the non-linear association between serum uric acid levels and all-cause mortality rate in patients with type 2 diabetes mellitus
2017, Atherosclerosis
Citation Excerpt :
Along the same line, high SUA levels are associated with increased mortality risk, mainly of cardiovascular origin, in the general population [9–13]. Contrasting results about the relationship between mortality risk and SUA are available in people with diabetes [15–22]. Furthermore, whether the relationship in patients with T2DM, if any, applies across all serum uric acid levels (linear relationship) it is still uncertain [15].
High levels of serum uric acid (SUA) are associated with increased mortality risk in the general population. Contrasting results are available in people with diabetes. The aim of our study was to investigate the association and its functional form between SUA and all cause-mortality in patients with type 2 diabetes mellitus (T2DM).
We studied three cohorts of patients with T2DM: Gargano Mortality Study, Foggia Mortality Study, Pisa Mortality Study. All-cause mortality rate was the end point of this study.
The most reliable relationship between SUA levels and all-cause mortality rate was quadratic, with such model being well approximated by SUA tertiles. Both tertiles 1 and 3 were at higher risk of mortality as compared to tertile 2: Hazard Ratio (HR) [95% Confidence Interval (CI)] = 1.34 (1.07–1.68) and 1.61 (1.29–1.99), respectively. In the pseudo-sample, created from the real pooled sample, the best relationship between SUA and all-cause mortality rate was quadratic. In a tree-based Recursive Partitioning and Regression Tree analysis two subgroups at increased risk of mortality were identified, namely those with SUA levels ≥7.28 mg/dl and with SUA levels <4.16 mg/dl as compared to patients with intermediate SUA levels (i.e. 4.16–7.28), thus providing further evidence on the J-shaped relationship between SUA levels and mortality rate.
SUA was not linearly associated with all-cause mortality rate in patients with T2DM.
For clinical and public health purposes such association is J-shaped.
Mortality Predictive Role of Serum Uric Acid in Diabetic Hemodialysis Patients
2014, Journal of Renal Nutrition
It is controversial to what extent serum uric acid (SUA) is associated with mortality in patients with chronic kidney disease undergoing hemodialysis (HD). We analyzed the predictive role of SUA in the mortality of diabetic and nondiabetic chronic kidney disease patients starting on maintenance HD therapy.
SUA was measured at the initiation of HD therapy in 319 patients (137 females and 193 diabetic patients) with mean age of 60 ± 14 years and mean estimated glomerular filtration rate of 7.5 ± 3.8 mL/min/1.73 m². The patients were divided into 2 groups, hyperuricemia (HUA; n = 165) and non-HUA (n = 154) groups based on laboratory limit for normal SUA. Mortality was recorded during 31.5 ± 24.8 months.
Among the 193 diabetic patients, but not among the whole group of 319 patients, survival was significantly lower in HUA than in non-HUA patients. Among diabetic patients 2-year patient survival was worse in patients with HUA and cardiovascular disease (CVD; 52.3%; n = 30) than in non-HUA patients with CVD (81.1%; n = 36), HUA without CVD (88.6%; n = 62), and non-HUA without CVD (93.9%; n = 65). Cox analysis in all 319 patients showed that, old age, CVD, other comorbidity, and low serum albumin but not high SUA predicted mortality. Among diabetic patients, predictors of increased mortality risk were old age, CVD, other comorbidity but also high SUA with adjusted hazard ratio of 1.12 (95% confidence interval 1.02-1.22) per 1 mg/dL increase in SUA. In diabetic patients with HUA and CVD, adjusted hazard ratio for mortality was 5.98 times that of diabetic non-HUA patients without CVD.
High SUA is associated with poor survival in diabetic patients undergoing HD but not in nondiabetic patients undergoing HD. High SUA was found to be a risk marker especially in diabetic HD patients with concurrent CVD.
Relationship between serum uric acid and all-cause and cardiovascular mortality in patients treated with peritoneal dialysis
2014, American Journal of Kidney Diseases
Citation Excerpt :
Whether elevated serum uric acid concentration is an independent risk factor for mortality and CV risk or it represents a surrogate marker for decreased kidney function, hypertension, and/or CVD has been a matter of some debate. This controversy persists regarding those in the general population7-15 and patients with specific conditions such as diabetes26-28 and hypertension.22,29 Conflicting results also exist regarding the role of serum uric acid level as a risk factor in patients with ESRD.18-21
Although serum uric acid level appears to be associated with mortality in individuals treated with hemodialysis, the relationship between serum uric acid level and death is uncertain in patients treated with peritoneal dialysis (PD).
Cohort study.
985 patients from a single PD center in South China followed up for a median of 25.3 months.
Serum uric acid level.
The association of baseline sex-specific uric acid level with all-cause and cardiovascular mortality was evaluated. Models were adjusted for age, body mass index, comorbidity score, residual kidney function, total Kt/V, allopurinol and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, and laboratory test results, including hemoglobin, serum albumin, creatinine, calcium, phosphorus, triglycerides, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein.
Mean age was 48.3 ± 15.4 (SD) years, and 23% had diabetes. Mean uric acid level was 7.0 ± 1.3 (range, 3.8-19.8) mg/dL. During follow-up, 144 deaths were recorded, of which 64 were due to cardiovascular events. In multivariable models, the highest sex-specific tertile of uric acid level was associated with increased risk of all-cause mortality (HR, 1.93; 95% CI, 1.27-2.93; P = 0.004) and cardiovascular mortality (HR, 3.31; 95% CI, 1.70-6.41; P < 0.001) compared to the lowest tertile. Adjusted Cox regression models showed that the HRs per 1-mg/dL higher uric acid level for all-cause and cardiovascular mortality were 1.33 (95% CI, 1.14-1.56; P < 0.001) and 1.44 (95% CI, 1.17-1.77; P = 0.001) for men and 1.03 (95% CI, 0.86-1.24; P = 0.8) and 1.16 (95% CI, 0.97-1.38; P = 0.1) for women, respectively. A formal test for interaction indicated that the association of uric acid level with all-cause and cardiovascular mortality differed by sex (β = −0.06 [P = 0.02] and β = −0.10 [P = 0.02], respectively).
Single measurement of uric acid at baseline. Cause of death determined by death certificates and expert consensus.
Elevated serum uric acid level is an independent risk factor for all-cause and cardiovascular mortality in men treated with PD.
Impact of diabetes on uric acid and its relationship with the extent of coronary artery disease and platelet aggregation: A single-centre cohort study
2014, Metabolism: Clinical and Experimental
Citation Excerpt :
However, coronary atherosclerosis was not evaluated by angiography and moreover, patients with renal impairment could have represented a population with further increased risk, displaying higher levels of SUA than patients included in our study. Present results potentially explain the previous lack of association between SUA and cardiovascular outcome reported by Ong et al. [19] and the Casale Monferrato Study [20] and also by the National Health and Nutrition Examination Survey III Linked Mortality Study (NHANES III) [44], that however, showed a relationship between UA and all-cause mortality, but not with the occurrence of cardiovascular events. Similarly, Storhaug et al. recently reported SUA to be associated with all-cause mortality and with increased risk of stroke in men, even after adjustment for drug intake and traditional cardiovascular risk factors, however, no independent associations were observed with MI [53].
Serum uric acid (SUA) elevation has been associated with the main determinants of atherosclerosis and metabolic syndrome, although an independent relationship between SUA and coronary artery disease (CAD) has never been confirmed. Recent reports suggested a central role of SUA in diabetic patients, possibly being an early marker of impaired glucose metabolism and best predicting the risk of cardiovascular events in these patients. Aim of current study was to evaluate the relationship between diabetes and uric acid and its association with the extent of CAD and platelet aggregation among diabetics.
In diabetic patients undergoing coronary angiography, fasting samples were collected for uric acid levels assessment. Coronary disease was defined for at least 1 vessel stenosis > 50% as evaluated by QCA.
Diabetes was observed in 1173 out of 3280 (35.7%) diabetes was related to age, hypercholesterolemia, hypertension, BMI, renal failure, previous MI or coronary revascularization (p < 0.001, respectively) and smoking (p = 0.001). Diabetics were more frequently treated with ACE-inhibitors, ARBs, b-blockers, calcium-antagonists, diuretics, statins (p < 0.001, respectively), and ASA (p = 0.004). Diabetics displayed higher glycemia and HbA1c (p < 0.001), higher creatinine and triglycerides (p < 0.001) but lower total and HDL cholesterol (p < 0.001) and haemoglobin (p < 0.001).
No significant difference was found in SUA levels between diabetic and non diabetic patients (p = 0.09). In fact, we identified age, renal failure, hypertension, smoking, BMI, use of diuretics, statins, haemoglobin, triglycerides and HDL cholesterol levels as independent predictors of higher levels of uric acid (3rd tertile, ≥ 6.7 mg/dl or 0.39 mmol/l).
Among diabetic patients, no relationship was found between uric acid and the extent of coronary artery disease (p = 0.27; adjusted OR [95%CI] = 0.93 [0.76-1.1], p = 0.48), or severe (LM-trivessel) CAD (P = 0.05; adjusted OR [95%CI] = 1.01 [0.86-1.18], p = 0.94). Furthermore, SUA levels did not influence platelet aggregation.
Ageing, BMI, renal failure, hypertension, smoking, use of statins and diuretics, haemoglobin, HDL cholesterol and tryglicerides levels but not diabetes or glycemic control are independent predictors of hyperuricemia. Among diabetic patients, higher SUA is not independently associated with the extent of CAD or with platelet aggregation.
Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: A meta-analysis of prospective studies
2013, Atherosclerosis
Citation Excerpt :
In a cross-sectional population-based study [30], with each 59.48 μmol/L increase in SUA level, the HR of cardiovascular mortality was 1.09 (95% CI 1.02–1.18) for men and 1.26 (95% CI 1.16–1.36) for women. Apart from the general population, SUA is also a significant independent predictor for individuals with gout [31], diabetes [32], chronic kidney disease [33], obstructive coronary artery disease [34] or CVD [35] and overweight/obese individuals [36]. The U-shaped association was evident, as the risk of mortality was higher in patients with high or very low SUA levels.
Serum uric acid (SUA) levels have been used to predict cardiovascular and all-cause mortality event, but the data have yielded conflicting results. We investigated whether SUA was an independent predictor for cardiovascular or all-cause mortality with prospective studies by meta-analysis.
Pubmed and Embase were searched without language restrictions for publications available till April 2013. Only prospective studies on cardiovascular or all-cause mortality related to SUA levels were included. Pooled adjust relative risk (RR) and corresponding 95% confidence intervals (CI) were calculated separately for the highest vs. lowest category or the lowest vs. middle category.
For the highest SUA, eleven studies with 172,123 participants were identified and analyzed. Elevated SUA increased risk of all-cause mortality (RR 1.24; 95% CI 1.09–1.42) and cardiovascular mortality (RR 1.37; 95% CI 1.19–1.57). Subgroup analyses showed that elevated SUA significantly increase the risk of all-cause mortality among men (RR 1.23; 95% CI 1.08–1.42), but not in women (RR 1.05; 95% CI 0.79–1.39). Risk of cardiovascular mortality appeared to be more pronounced among women (RR 1.35; 95% CI 1.06–1.72). The association between extremely low SUA and mortality was reported in three studies; we did not perform a pooled analysis because of high degree of heterogeneity in these studies.
Baseline SUA level is an independent predictor for future cardiovascular mortality. Elevated SUA appears to significantly increase the risk of all-cause mortality in men, but not in women. Whether low SUA levels are predictors of mortality is still inconclusive.
Uric acid levels, even in the normal range, are associated with increased cardiovascular risk: The Guangzhou Biobank Cohort Study
2013, International Journal of Cardiology
Citation Excerpt :
The authors suggested that serum UA level may not be prognostically useful in patients with type 2 diabetes. In contrast, results from the National Health and Nutrition Examination Survey III Linked Mortality Study (NHANES III) showed that baseline serum UA level significantly predicted all-cause mortality in patients with self-reported diabetes, but not in those without diabetes or for CVD events [10]. A more recent study from the Casale Monferrato Study also showed that baseline serum UA level predicted all-cause, but not CVD mortality in 1540 older subjects with diabetes after a follow-up of 15 years [12].
To examine the association between serum uric acid (UA) levels and cardiovascular risk factors in subjects without diabetes or hyperuricemia.
6172 women and 2662 men aged 50 + years without diabetes from Phase 1 of the Guangzhou Biobank Cohort Study were included. Data on personal history, physical examination and biochemical parameters were collected. Subjects were categorized by serum UA concentration, and the association between UA levels and cardiovascular risk factors was examined using generalized linear models.
In both men and women with normouricemia (UA < 420 μmol/l in men and < 360 μmol/l in women), tertiles of UA levels were adversely associated with body mass index, waist circumference, waist-to-hip ratio, total- and HDL-cholesterol, apolipoprotein A1, systolic and diastolic blood pressures, pulse pressure, fasting plasma glucose and white blood cell count (P value for trend ranged from 0.04 to < 0.001), and also consistently associated with metabolic disorders including obesity, hypertension, hypertension treatment, dyslipidemia, waist circumference increased since the age of 18 years and the metabolic syndrome (P value for trend ranged from 0.02 to < 0.001).
Increasing UA levels, even in subjects with normouricemia and without diabetes, were associated with increasing prevalence of cardiovascular risk factors, suggesting that clinically dichotomous definition of hyperuricemia may be inadequate and high-normal value of UA may warn of metabolic disorders.

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^☆: Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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Brief reportUric acid and mortality from all-causes and cardiovascular disease among adults with and without diagnosed diabetes: Findings from the National Health and Nutrition Examination Survey III Linked Mortality Study☆

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conflict of interest statement

J Clin Epidemiol

Serum uric acid and coronary heart disease in 9458 incident cases and 155,084 controls: prospective study and meta-analysis

PLoS Med

Uric acid and cardiovascular risk

N Engl J Med

Hyperuricemia and risk of stroke: a systematic review and meta-analysis

Arthritis Rheum

Hyperuricemia and coronary heart disease: a systematic review and meta-analysis

Arthritis Care Res (Hoboken)

Serum uric acid shows a J-shaped trend with coronary mortality in non-insulin-dependent diabetic elderly people. The CArdiovascular STudy in the ELderly (CASTEL)

Acta Diabetol

Serum uric acid, mortality and glucose control in patients with Type 2 diabetes mellitus: a PreCIS database study

Diabet Med

Brief report
Uric acid and mortality from all-causes and cardiovascular disease among adults with and without diagnosed diabetes: Findings from the National Health and Nutrition Examination Survey III Linked Mortality Study☆