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Keywords:

  • Gout;
  • Metabolic syndrome;
  • Obesity;
  • Hypertension;
  • Insulin resistance;
  • NHANES-III

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To determine the prevalence of metabolic syndrome among patients with gout and to examine the association between the 2 conditions in a nationally representative sample of US adults.

Methods

Using data from 8,807 participants age ≥20 years in the Third National Health and Nutrition Examination Survey (1988–1994), we determined the prevalence of metabolic syndrome among individuals with gout and quantified the magnitude of association between the 2 conditions. We used both the revised and original National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) criteria to define metabolic syndrome.

Results

The prevalence (95% confidence interval [95% CI]) of metabolic syndrome according to revised NCEP/ATP III criteria was 62.8% (51.9–73.6) among individuals with gout and 25.4% (23.5–27.3) among individuals without gout. Using 2002 census data, ∼3.5 million US adults with a history of gout have metabolic syndrome. The unadjusted and age- and sex-adjusted odds ratios (95% CI) of metabolic syndrome for individuals with gout were 4.96 (3.17–7.75) and 3.05 (2.01–4.61), respectively. With the original NCEP/ATP criteria, the corresponding prevalences were slightly lower, whereas the corresponding odds ratios were slightly higher. The stratified prevalences of metabolic syndrome by major associated factors of gout (i.e., body mass index, hypertension, and diabetes) remained substantially and significantly higher among those with gout than those without gout (all P values <0.05).

Conclusion

These findings indicate that the prevalence of metabolic syndrome is remarkably high among individuals with gout. Given the serious complications associated with metabolic syndrome, this frequent comorbidity should be recognized and taken into account in long-term treatment and overall health of individuals with gout.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Metabolic syndrome, which consists of multiple interrelated conditions, increases the risk for atherosclerotic cardiovascular disease up to 3 times and increases the risk for type 2 diabetes up to 5 times (1, 2). Metabolic syndrome also increases mortality from cardiovascular disease and all causes (3, 4). The syndrome affects >50 million Americans (2, 5).

The potential link between gout, a common inflammatory arthritis, and metabolic syndrome has been repeatedly suggested (6–8), but no quantitative population data are available; therefore, the magnitude of the problem remains unclear. The proposed connection has been supported by the close association between hyperuricemia and insulin resistance syndrome (6, 9, 10). For example, a cross-sectional study of 4,053 young adults found close associations between hyperuricemia and the individual metabolic abnormalities of the syndrome including hyperinsulinemia, hypertension, dyslipidemia, and obesity (10). Renal clearance of urate is inversely related to the degree of insulin resistance (11). Therefore, the reduced renal excretion of urate among patients with metabolic syndrome may explain the increased frequency of hyperuricemia. Furthermore, recent case series reported that the prevalence of metabolic syndrome was high among patients with gout (82% in Mexican men [12] and 44% in Korean men [13] compared with 5% in the Korean general population [14]). Although these hospital-based case series (12, 13) may have included patients who are sicker than individuals from the general population, the totality of available information points toward a strong link between gout and metabolic syndrome. Because the serious implications of metabolic syndrome for overall health of individuals with gout are substantial, we determined the prevalence of the syndrome among patients with gout and examined the association between the 2 conditions based on the Third National Health and Nutrition Examination Survey (NHANES-III).

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Study population.

Conducted between 1988 and 1994, the NHANES-III included a representative sample of the noninstitutionalized US civilian population, which was selected using a multistage, stratified sampling design. Persons ≥60 years of age and African American and Mexican American persons were oversampled. After a home interview, participants were invited to attend examination sessions where blood and urine specimens were obtained. In the current study, we analyzed data for 8,807 men and nonpregnant women at least 20 years of age who attended the medical examination, had fasted at least 8 hours prior to the blood collection, and had complete information to allow definition of the metabolic syndrome (4) and gout status.

Assessment of metabolic syndrome.

We used both the revised and original National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) criteria to define the metabolic syndrome. According to the original NCEP/ATP III criteria (4, 15), participants with ≥3 of the following criteria were defined as having metabolic syndrome: abdominal obesity (waist circumference >102 cm in men and >88 cm in women), hypertriglyceridemia (≥150 mg/dl [1.69 mmoles/liter]), low high-density lipoprotein (HDL) cholesterol (<40 mg/dl [1.04 mmoles/liter] in men and <50 mg/dl [1.29 mmoles/liter] in women), high blood pressure (≥130/85 mm Hg), and high fasting glucose (≥110 mg/dl [≥6.1 mmoles/liter]). We counted participants who reported currently using antihypertensive or antidiabetic medication (insulin or oral agents) as participants with high blood pressure or diabetes, respectively (4). Because the original NCEP/ATP III criteria have recently been revised to require a lower fasting glucose level (i.e., ≥100 mg/dl [≥5.6 mmoles/liter]) (1, 16), we report results obtained using the original criteria as well as those obtained using the revised criteria in this study. Serum triglycerides were measured enzymatically after hydrolyzation to glycerol (Hitachi 704 Analyzer; Hitachi, Tokyo, Japan). HDL cholesterol was measured following the precipitation of other lipoproteins with a heparin-manganese chloride mixture (Hitachi 704 Analyzer) (17). Serum glucose concentration was measured using an enzymatic reaction (Cobas Mira assay; Roche, Basel, Switzerland). Details about the laboratory procedures of all of these tests are published elsewhere (17). Three blood pressure readings were obtained in the mobile examination center. The average of the second and third systolic and diastolic blood pressure readings was used in the analyses.

Assessment of gout.

During the home interview, all subjects were asked, “Has a doctor ever told you that you had gout?” Interviewers were instructed to emphasize the word doctor. If the respondent stated that it was another health professional who gave this diagnosis of gout, then the answer was coded as no.

Statistical analysis.

All statistical analyses were performed using survey commands of STATA, version 9 (StataCorp, College Station, TX) to incorporate sample weights and adjust for clusters and strata of the complex sample design. Prevalence of metabolic syndrome was calculated according to the presence of gout. We performed logistic regression to evaluate the association between presence of gout and presence of metabolic syndrome and calculated unadjusted odds ratios (ORs) and age- and sex-adjusted ORs. We also stratified the results by major associated factors of gout including body mass index (BMI) <26.2 kg/m2 (median value) versus ≥26.2 kg/m2, hypertension (high blood pressure as defined above or antihypertensive medication use), and diabetes (by self report of a physician diagnosis or fasting glucose ≥126 mg/dl [≥6.99 mmoles/liter]). For all measures, we calculated 95% confidence intervals (95% CIs). All P values are 2-sided.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

The mean age was 44 years, 49.7% were men, 76.5% were white, and the mean BMI was 26.4 kg/m2. The mean uric acid level was 5.42 mg/dl (95% CI 5.37–5.46 mg/dl). The cross-sectional prevalence of hyperuricemia (i.e., serum uric acid >7.0 mg/dl for men and >6.0 mg/dl for women) was 49.1% (95% CI 39.5–58.7) among individuals with gout and 18.0% (95% CI 16.9–19.1) among those without gout. A diagnosis of gout by a physician was reported by 2.4% (95% CI 2.0–2.9) of participants. The mean age of participants with gout was 57.6 years, 72% were men, 86.3% were white, and the mean BMI was 29.7 kg/m2.

The prevalence of metabolic syndrome according to the revised NCEP/ATP III criteria (1, 16) was 62.8% (95% CI 51.9–73.6) among individuals with gout and 25.4% (95% CI 23.5–27.3) among individuals without gout (Table 1). The prevalence among individuals who had gout and were exposed to allopurinol or uricosuric agents was higher (83.3%; 95% CI 71.1–95.4). The unadjusted and age- and sex-adjusted ORs of metabolic syndrome for individuals with gout were 4.96 (95% CI 3.17–7.75) and 3.05 (95% CI 2.01–4.61), respectively (Table 1). Using the original NCEP/ATP III criteria (4, 15), the corresponding prevalences were slightly lower, whereas the corresponding ORs were slightly higher. The prevalence of metabolic syndrome among individuals with gout did not appear to differ substantially between men and women. The prevalence increased from 27% among participants with gout ages 20–39 years to >71% among participants ≥40 years of age (Table 1). Application of the age-specific prevalence rates to US census counts from 2002 indicated that of the 5.9 million US adults with a history of gout, ∼3.5 million US adults have metabolic syndrome according to the revised NCEP/ATP criteria (1, 16).

Table 1. Prevalence of metabolic syndrome according to presence of gout in adults in NHANES-III*
 No. of participantsRevised NCEP/ATP III definitionOriginal NCEP/ATP III definition
Gout (n = 223)No gout (n = 8,584)UnadjustedAge/sex adjustedGout (n = 223)No gout (n = 8,584)UnadjustedAge/sex adjusted
  • *

    Values are the percentage (95% confidence interval) unless otherwise indicated. Data are presented incorporating sample weights and adjusted for clusters and strata of the complex sample design of NHANES-III. NHANES-III = Third National Health and Nutrition Examination Survey; NCEP/ATP III = National Cholesterol Education Program Adult Treatment Panel III.

  • Odds ratios (ORs) for the total participants were adjusted for age and sex; ORs for men or women were adjusted for age, ORs for age categories were adjusted for sex.

Total8,80762.8 (51.9–73.6)25.4 (23.5–27.3)4.96 (3.17–7.75)3.05 (2.01–4.61)57.8 (47.2–68.4)21.0 (19.3–22.6)5.16 (3.41–7.80)3.36 (2.25–5.01)
Men4,26160.0 (44.9–75.0)25.6 (23.0–28.2)4.35 (2.38–7.95)2.79 (1.53–5.07)58.2 (43.2–73.2)19.9 (17.8–22.0)5.61 (3.11–10.11)3.70 (2.06–6.64)
Women4,54669.9 (56.5–83.3)25.2 (23.1–27.3)6.90 (3.65–13.04)3.97 (1.95–8.10)56.8 (44.6–69.0)22.0 (20.0–24.1)4.65 (2.76–7.84)2.66 (1.41–5.03)
Age, years         
 20–393,87227.0 (1.0–53.1)12.4 (10.2–14.6)2.61 (0.72–9.44)2.39 (0.65–8.75)27.0 (1.0–53.1)9.6 (7.9–11.4)3.48 (0.97–12.44)3.56 (0.99–12.80)
 40–592,32171.8 (57.0–86.5)30.6 (27.7–33.5)5.77 (2.89–11.50)5.56 (2.76–11.21)65.5 (49.1–81.8)25.6 (22.9–28.2)5.51 (2.76–11.00)5.39 (2.68–10.84)
 ≥602,61471.0 (61.7–80.4)48.7 (45.7–51.6)3.51 (1.79–6.87)2.63 (1.66–4.17)64.9 (54.9–75.0)41.3 (38.4–44.3)2.63 (1.68–4.11)2.71 (1.73–4.24)

Prevalences of individual metabolic abnormalities according to the presence of gout are summarized in Table 2. The prevalence ranged from 33.1% for fasting glucose ≥110 mg/dl or hypoglycemic medication use to 69.1% for high blood pressure or antihypertensive medication use. All prevalence rates of individual metabolic abnormalities were substantially higher among persons with gout than those without gout. All OR estimates for the association between gout and each metabolic component were statistically significant except for the age- and sex-adjusted ORs for the more lenient insulin resistance criterion that required a fasting glucose level ≥100 mg/dl (Table 2).

Table 2. Prevalence of individual metabolic abnormalities of the metabolic syndrome according to presence of gout in NHANES-III*
 Prevalence, % (95% CI)OR (95% CI)
Gout (n = 223)No gout (n = 8,584)UnadjustedAge and sex adjusted
  • *

    Data are presented incorporating sample weights and adjusted for clusters and strata of the complex sample design of NHANES-III. NHANES-III = Third National Health and Nutrition Examination Survey; 95% CI = 95% confidence interval; OR = odds ratio; HDL = high-density lipoprotein.

Abdominal obesity62.9 (50.9–74.8)35.3 (33.7–36.9)3.10 (1.84–5.22)2.55 (1.50–4.34)
Hypertriglyceridemia53.7 (42.9–64.4)27.9 (25.5–30.3)3.00 (1.93–4.65)1.90 (1.24–2.92)
Low HDL cholesterol47.4 (37.2–57.6)36.6 (34.1–39.1)1.56 (1.03–2.36)1.60 (1.04–2.46)
High blood pressure or medication use69.1 (59.4–78.8)30.3 (28.4–32.2)5.13 (3.32–7.95)2.63 (1.67–4.13)
Fasting glucose ≥110 mg/dl or medication use33.1 (24.8–41.4)10.8 (9.9–11.8)4.07 (2.83–5.86)2.14 (1.44–3.17)
Fasting glucose ≥100 mg/dl or medication use48.4 (37.7–59.2)27.1 (25.4–28.7)2.53 (1.62–3.95)1.24 (0.81–1.88)

We stratified the prevalence of metabolic syndrome by major associated factors of gout (i.e., BMI, hypertension, and diabetes) (Table 3). As expected, the prevalence of metabolic syndrome was higher when these stratified factors were present. However, all stratified prevalence rates remained substantially and significantly higher among individuals with gout than those without gout. For example, age- and sex-adjusted ORs for the association between gout and metabolic syndrome among individuals with BMI lower than the median value (<26.2 kg/m2) was 2.11 (95% CI 1.21–3.67) according to the revised NCEP/ATP III criteria (1, 16) and 3.55 (95% CI 1.57–8.05) according to the original criteria (15). The corresponding ORs among individuals without diabetes were 5.49 (95% CI 1.85–16.28) and 2.78 (95% CI 1.90–4.09), respectively (Table 3). In addition, when we repeated our analyses after excluding persons with diuretic exposure (n = 698, including 64 persons with gout), the prevalence of metabolic syndrome according to the revised NCEP/ATP III criteria was 57.7% (95% CI 44.5–70.9) among individuals with gout and 23.2% (95% CI 21.3–25.2) among individuals without gout.

Table 3. Prevalence of metabolic syndrome according to presence of gout, stratified by major associated factors of gout in NHANES-III*
 No. of participantsRevised NCEP/ATP III definitionOriginal NCEP/ATP III definition
Gout (n = 223)No gout (n = 8,584)Unadjusted OR (95% CI)Age- and sex-adjusted OR (95% CI)Gout (n = 223)No gout (n = 8,584)Unadjusted OR (95% CI)Age- and sex-adjusted OR (95% CI)
  • *

    Values are the percentage (95% confidence interval) unless otherwise indicated. Data are presented incorporating sample weights and adjusted for clusters and strata of the complex sample design of NHANES-III. NHANES-III = Third National Health and Nutrition Examination Survey; NCEP/ATP III = National Cholesterol Education Program Adult Treatment Panel III; OR = odds ratio; 95% CI = 95% confidence interval.

  • Median value of the total study population (n = 8,807).

  • High blood pressure or antihypertensive medication use (see Subjects and Methods for details).

  • §

    Self-reported physician diagnosis of diabetes or fasting glucose ≥126 mg/dl (≥6.99 mmoles/liter).

BMI, kg/m2         
 <26.24,40739.4 (22.0–56.8)9.3 (8.0–10.5)2.84 (1.56–5.19)2.11 (1.21–3.67)34.6 (18.3–50.9)6.8 (5.7–7.9)7.30 (3.50–15.23)3.55 (1.57–8.05)
 ≥26.24,40070.3 (56.0–84.7)46.7 (43.4–50.0)2.70 (1.38–5.30)1.87 (1.01–3.44)65.3 (51.4–79.2)39.8 (36.8–42.8)6.37 (3.01–13.47)2.83 (1.22–6.60)
Hypertension         
 No5,40534.2 (10.9–57.6)11.5 (10.0–12.9)2.41 (1.38–4.19)2.44 (1.39–4.28)29.5 (7.4–51.7)8.5 (7.3–9.6)4.53 (1.55–13.22)3.78 (1.30–11.01)
 Yes3,40275.5 (64.9–86.2)57.3 (54.2–60.4)2.30 (1.26–4.21)2.26 (1.24–4.11)70.4 (59.2–81.7)49.7 (46.9–52.6)4.01 (1.41–11.39)3.06 (1.11–8.49)
Diabetes§         
 No7,97953.3 (41.2–65.5)22.0 (20.3–23.6)5.95 (2.04–17.35)5.49 (1.85–16.28)46.9 (35.8–58.1)17.4 (16.0–18.8)4.20 (2.74–6.43)2.78 (1.90–4.09)
 Yes82895.6 (91.4–99.9)80.2 (74.4–86.0)5.37 (1.83–15.73)5.09 (1.68–15.46)95.6 (91.4–99.9)78.5 (72.1–85.0)4.06 (2.53–6.50)2.51 (1.67–3.78)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

In this nationally representative sample of men and women, we found that ∼60% of US adults with gout had metabolic syndrome. Compared with adults without gout, the prevalence was nearly 3 times higher among those with gout. The prevalence of individual metabolic abnormalities was higher among persons with gout, and the link persisted across the different subgroups stratified by BMI, hypertension, and diabetes. Although these associations have been suspected, this is the first population-based study to demonstrate the strong association and quantify the high prevalence of metabolic syndrome among individuals with gout.

These data indicate that the prevalence of metabolic syndrome is very high among individuals with gout. In fact, the prevalence is substantially higher than among those who experienced myocardial infarction or stroke (41–44%) in the same NHANES study (18). These data expand on previous studies that demonstrated a close relationship between hyperuricemia and insulin resistance syndrome (6, 9, 10), and on the recent case series of gout and metabolic syndrome (12, 13), thereby supporting a pathogenetic overlap between these conditions. Higher insulin levels are known to reduce renal excretion of urate (11, 19–21). For example, exogenous insulin can reduce the renal excretion of urate in both healthy and hypertensive subjects (6, 19, 20). Insulin may enhance renal urate reabsorption via stimulation of urate-anion exchanger URAT1 (22) and/or the Na+-dependent anion cotransporter in brush border membranes of the renal proximal tubule (8). Additionally, because serum levels of leptin and urate tend to increase together (23, 24), some investigators have suggested that leptin may affect renal reabsorption (8). Finally, in insulin resistance syndrome, impaired oxidative phosphorylation may increase systemic adenosine concentrations by increasing the intracellular levels of coenzyme A esters of long-chain fatty acids (8). Increased adenosine, in turn, can result in renal retention of sodium, urate, and water (25–28). Some researchers have speculated that chronically increased extracellular adenosine concentrations may also contribute to hyperuricemia by increasing urate production (25).

There are several important clinical implications of our results. First, a diagnosis of gout should trigger a high clinical suspicion and investigation for a potential coexistence of metabolic syndrome. If present, the syndrome needs to be recognized as a potentially more life-threatening factor than gout or hyperuricemia (6) given the serious associated complications (1–4). The cornerstones of treatment for the syndrome are the management of weight and ensuring appropriate levels of physical activity (4). Recent studies demonstrated that dietary modification and enhanced physical activity may delay or prevent the transition from impaired glucose tolerance to type 2 diabetes mellitus and may provide relevant treatment paradigms for patients with metabolic syndrome (4, 29–31).

Long-term dietary recommendations for the majority of patients with gout should take into account this frequent comorbidity. For example, conventional dietary recommendations for gout have focused on restriction of purine intake, although low-purine diets are often high in carbohydrate and saturated fat (7). These macronutrients are associated with an increased risk of insulin resistance syndrome and associated major consequences (21, 32, 33). Furthermore, these macronutrients tend to lead to higher serum insulin levels, which are known to reduce renal excretion of urate (11, 19–21), thus potentially raising the serum uric acid level and the risk of gout. Given the frequent association between gout and metabolic syndrome, it is imperative to develop appropriate dietary and other lifestyle guidelines, taking into account risk of gouty attacks as well as overall long-term health effects. Our data also provide support for the value of the strategic choice of certain therapies for patients with gout and metabolic syndrome or its individual components (8). For example, the uricosuric property of fenofibrate (34) may be associated with a favorable risk-benefit ratio among patients with gout and metabolic syndrome (8). Similarly, antihypertensive agents with uricosuric properties (e.g., losartan [34] or amlodipine [35]) could have a better risk-benefit ratio than diuretics for hypertension in hypertensive patients with gout (8). In addition, the growing epidemic of obesity (36, 37) and metabolic syndrome (38) presents a substantial challenge in the prevention and management of gout (8). Because these conditions would likely also share important parts of public health and clinical management approaches, future studies may need to focus on developing the overall optimal strategies for improving these concurrent conditions.

Hyperuricemia is associated with cardiovascular disorders (CVD), but whether it is an independent risk factor with a pathogenic role in CVD or only a marker for associated CVD risk factors, such as insulin resistance, obesity, diuretic use, hypertension, and renal disease, is unclear (39, 40). Although a number of studies have investigated the relationship between serum urate levels and CVD, little information is available regarding the relationship between gout and cardiovascular outcomes. The Framingham Study reported that gout was associated with a 60% increased risk of coronary artery disease in men (41), and we are not aware of any other prospective data on this important topic. The remarkably high prevalence of metabolic syndrome observed in our study suggests that individuals with gout are likely at increased risk for atherosclerotic cardiovascular disease and type 2 diabetes (1, 2), the known complications of metabolic syndrome. Additional prospective data on these important outcomes would be valuable.

Strengths and limitations of our study deserve comment. This study was performed in a nationally representative sample of US men and women; therefore, the findings are likely to be generalizable to US men and women. The self-reported diagnosis of gout by a physician was not validated in this study. However, it is unlikely that misclassification of the diagnosis would explain the strong associations observed in this population study. It remains conceivable that the results may even be more striking with more specific case definitions of gout, as was the case in our prospective epidemiologic study of gout for suspected associated factors (42, 43). Nonetheless, confirming these results using such specific case definitions of gout would be valuable. The current study provides national estimates of the prevalence of metabolic syndrome among individuals with gout and the magnitude of the cross-sectional association between the 2 conditions, which was well served by the NHANES study design. Potential temporal relationships between these disorders should be addressed by longitudinal studies.

In conclusion, these findings from a nationally representative sample of US adults indicate that the prevalence of metabolic syndrome is remarkably high among individuals with gout. Given the serious complications associated with metabolic syndrome, this frequent comorbidity should be recognized and be taken into account in the long-term treatment and overall health of individuals with gout.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Dr. Choi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Drs. Choi and Ford.

Acquisition of data. Drs. Choi and Li.

Analysis and interpretation of data. Drs. Choi, Ford, Li, and Curhan.

Manuscript preparation. Drs. Choi, Ford, and Curhan.

Statistical analysis. Drs. Choi, Ford, and Li.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  • 1
    Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement [review] [published errata appear in Circulation 2005;112:e297 and Circulation 2005;112:e298]. Circulation 2005; 112: 273552.
  • 2
    American Heart Association. Metabolic syndrome: new guidance for prevention and treatment. URL: http://www.americanheart.org/presenter.jhtml?identifier=3033454.
  • 3
    Trevisan M, Liu J, Bahsas FB, Menotti A, and the Risk Factor and Life Expectancy Research Group. Syndrome X and mortality: a population-based study. Am J Epidemiol 1998; 148: 95866.
  • 4
    Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence [review]. Diabetes Care 2005; 28: 176978.
  • 5
    Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 3569.
  • 6
    Emmerson B. Hyperlipidaemia in hyperuricaemia and gout. Ann Rheum Dis 1998; 57: 50910.
  • 7
    Fam AG. Gout, diet, and the insulin resistance syndrome. J Rheumatol 2002; 29: 13505.
  • 8
    Choi HK, Mount DB, Reginato AM, the American College of Physicians, and the American Physiological Society. Pathogenesis of gout. Ann Intern Med 2005; 143: 499516.
  • 9
    Lee J, Sparrow D, Vokonas PS, Landsberg L, Weiss ST, and the Normative Aging Study. Uric acid and coronary heart disease risk: evidence for a role of uric acid in the obesity-insulin resistance syndrome. Am J Epidemiol 1995; 142: 28894.
  • 10
    Rathmann W, Funkhouser E, Dyer AR, Roseman JM, and the Coronary Artery Risk Development in Young Adults Study. Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: the CARDIA study. Ann Epidemiol 1998; 8: 25061.
  • 11
    Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 1991; 266: 300811.
  • 12
    Vazquez-Mellado J, Garcia CG, Vazquez SG, Medrano G, Ornelas M, Alcocer L, et al. Metabolic syndrome and ischemic heart disease in gout. J Clin Rheumatol 2004; 10: 1059.
  • 13
    Rho YH, Choi SJ, Lee YH, Ji JD, Choi KM, Baik SH, et al. The prevalence of metabolic syndrome in patients with gout: a multicenter study. J Korean Med Sci 2005; 20: 102933.
  • 14
    Lee WY, Park JS, Noh SY, Rhee EJ, Kim SW, Zimmet PZ. Prevalence of the metabolic syndrome among 40,698 Korean metropolitan subjects. Diabetes Res Clin Pract 2004; 65: 1439.
  • 15
    National Institutes of Health. Third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NIH Publication 01-3670. Bethesda (MD): National Institutes of Health; 2001.
  • 16
    Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C, the American Heart Association, and the National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition [review]. Circulation 2004; 109: 4338.
  • 17
    Centers for Disease Control and Prevention. The Third National Health and Nutrition Examination Survey (NHANES III 1988-94) reference manuals and reports [CD-ROM]. Bethesda (MD): National Center for Health Statistics; 1996.
  • 18
    Ninomiya JK, L'Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation 2004; 109: 426.
  • 19
    Ter Maaten JC, Voorburg A, Heine RJ, ter Wee PM, Donker AJ, Gans RO. Renal handling of urate and sodium during acute physiological hyperinsulinaemia in healthy subjects. Clin Sci (Lond) 1997; 92: 518.
  • 20
    Muscelli E, Natali A, Bianchi S, Bigazzi R, Galvan AQ, Sironi AM, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens 1996; 9: 74652.
  • 21
    Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J. Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis 2000; 59: 53943.
  • 22
    Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417: 44752.
  • 23
    Bedir A, Topbas M, Tanyeri F, Alvur M, Arik N. Leptin might be a regulator of serum uric acid concentrations in humans. Jpn Heart J 2003; 44: 52736.
  • 24
    Fruehwald-Schultes B, Peters A, Kern W, Beyer J, Pfutzner A. Serum leptin is associated with serum uric acid concentrations in humans. Metabolism 1999; 48: 67780.
  • 25
    Bakker SJ, Gans RO, ter Maaten JC, Teerlink T, Westerhoff HV, Heine RJ. The potential role of adenosine in the pathophysiology of the insulin resistance syndrome. Atherosclerosis 2001; 155: 28390.
  • 26
    Balakrishnan VS, Coles GA, Williams JD. Effects of intravenous adenosine on renal function in healthy human subjects. Am J Physiol 1996; 271: F37481.
  • 27
    Balakrishnan VS, Coles GA, Williams JD. A potential role for endogenous adenosine in control of human glomerular and tubular function. Am J Physiol 1993; 265: F50410.
  • 28
    Fransen R, Koomans HA. Adenosine and renal sodium handling: direct natriuresis and renal nerve-mediated antinatriuresis. J Am Soc Nephrol 1995; 6: 14917.
  • 29
    Eriksson KF, Lindgarde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise: the 6-year Malmo feasibility study. Diabetologia 1991; 34: 8918.
  • 30
    Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 53744.
  • 31
    Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 134350.
  • 32
    Fam AG. Gout in the elderly: clinical presentation and treatment [review]. Drugs Aging 1998; 13: 22943.
  • 33
    Parillo M, Rivellese AA, Ciardullo AV, Capaldo B, Giacco A, Genovese S, et al. A high-monounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients. Metabolism 1992; 41: 13738.
  • 34
    Takahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Effects of combination treatment using anti-hyperuricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis 2003; 62: 5725.
  • 35
    Chanard J, Toupance O, Lavaud S, Hurault de Ligny B, Bernaud C, Moulin B. Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients. Nephrol Dial Transplant 2003; 18: 214753.
  • 36
    Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA 2002; 288: 17237.
  • 37
    Freedman DS, Khan LK, Serdula MK, Galuska DA, Dietz WH. Trends and correlates of class 3 obesity in the United States from 1990 through 2000. JAMA 2002; 288: 175861.
  • 38
    Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care 2004; 27: 24449.
  • 39
    Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med 2003; 139: 76176.
  • 40
    Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003; 41: 118390.
  • 41
    Abbott RD, Brand FN, Kannel WB, Castelli WP. Gout and coronary heart disease: the Framingham Study. J Clin Epidemiol 1988; 41: 23742.
  • 42
    Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. New Eng J Med 2004; 350: 1093103.
  • 43
    Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004; 363: 127781.