Hyperuricemia appears to be related to metabolic syndrome (MS), but its impact on cardiovascular risk in patients with MS is unclear. We evaluated the impact of hyperuricemia on cardiovascular risk in patients with MS. Of 2,963 patients with coronary artery disease enrolled in the Bezafibrate Infarction Prevention study, 1,410 had MS, as established by the presence of ≥3 of the following 5 criteria: serum fasting glucose >110 mg/dl, triglycerides >150 mg/dl, high-density lipoprotein cholesterol <40 mg/dl in men and <50 mg/dl in women, systolic and diastolic blood pressures >130 and 80 mm Hg, respectively, and body mass index >28 kg/m 2 . The remaining 1,553 patients had no MS. Primary end points were defined as occurrence of acute myocardial infarction or sudden cardiac death. Hyperuricemia was defined as serum uric acid levels >7.0 mg/dl in men and >6.0 mg/dl in women, respectively. Higher rate of primary end point was noted in hyperuricemic patients (n = 284) versus normouricemic patients (n = 1,126) with MS (20.1% and 15.3%, respectively, p = 0.05). After adjustment for age, gender, smoking, diabetes, previous myocardial infarction, hypertension, New York Heart Association classes II to IV, estimated glomerular filtration rate, body mass index, total cholesterol, triglycerides, diuretics, antiplatelets, angiotensin-converting enzyme inhibitors, β blockers, and bezafibrate treatment, hyperuricemic patients with MS demonstrated significantly higher risk for the primary end point compared to normouricemic patients with MS (hazard ratio 1.45, 95% confidence interval 1.00 to 2.17, p = 0.05). In conclusion, hyperuricemia is associated with increased risk of myocardial infarction and sudden cardiac death in patients with MS.
The estimated prevalence of metabolic syndrome (MS) in populations of the Western hemisphere varies from 10% to 23%. MS is characterized by insulin resistance, hypertension, abdominal adiposity, and dyslipidemia and is well recognized as a high-risk factor for adverse cardiovascular outcome. Furthermore, it appears to be associated with an increase of inflammatory markers such as C-reactive protein. According to recent reports, increased serum uric acid (UA) is associated with increased risk of cardiac events in the general population and in patients with coronary artery disease. Some reports have suggested that serum UA may be higher in patients with MS or possibly be directly related to its components such as insulin resistance, hypertension, abdominal adiposity, and hypertriglyceridemia. However, whether hyperuricemia is an active component of MS or merely an epiphenomenon remains unclear. In addition, the question of whether hyperuricemia is associated with increased cardiovascular risk in patients with MS is unanswered. The aim of this study was to evaluate the association between hyperuricemia and adverse outcome in patients with MS.
Methods
This study was a retrospective analysis of 2,963 patients with coronary artery disease enrolled in the Bezafibrate Infarction Prevention study (BIP) from May 1990 to January 1993. Patients who fulfilled the following inclusion criteria were randomized to the BIP study: age 45 to 74 years, history of myocardial infarction (MI) ≥6 months but <5 years before enrollment, and/or stable angina pectoris confirmed by coronary angiography and/or radionuclear studies or standard exercise tests. In addition, a lipid profile of serum total cholesterol of 180 to 250 mg/dl, low-density lipoprotein cholesterol ≤180 mg/dl (≤160 mg/dl for patients <50 years old), high-density lipoprotein cholesterol ≤45 mg/dl, and triglycerides ≤300 mg/dl was required. Main exclusion criteria were insulin-dependent diabetes mellitus, severe heart failure, unstable angina pectoris, clinically significant hepatic or renal failure, known sensitivity to bezafibrate, or current use of lipid-modifying drugs. All patients were allocated to bezafibrate 400 mg or placebo 1 time/day. Blood samples were collected after ≥12 hours of fasting using standardized equipment and procedures. Serum analysis was carried out in a central laboratory using standard automated procedures with commercially available diagnostic kits (Boehringer-Mannheim, Mannheim, Germany). Periodic surveillance of accuracy and precision was performed by the Centers for Disease Control/National Heart, Lung, and Blood Institute’s Lipids Standardization Program and by the Wellcome-Murex Diagnostic Clinical Chemistry Quality Assessment Program. UA levels were determined by calorimetric enzymatic tests. Hyperuricemia was defined as serum UA levels >7.0 mg/dl for men and >6.0 mg/dl for women. Estimated glomerular filtration rate (eGFR) was calculated by the Cockroft-Gault equation. All study participants were followed for a mean period of 6.2 ± 0.8 years (range 4.7 to 7.6). The primary end point was defined as the first occurrence of an acute MI or sudden cardiac death.
Of the 2,963 patients, 1,410 (47.6%) with ≥3 of the following 5 risk factors characterizing MS constituted the MS + group: fasting glucose levels >110 mg/dl, triglyceride levels >150 mg/dl, high-density lipoprotein cholesterol levels <40 mg/dl in men and <50 mg/dl in women, increased systolic and diastolic blood pressures >130 and >85 mm Hg, respectively, and body mass index >28 kg/m 2 . The remaining 1,553 patients who did not fulfill these criteria were included in the MS − group. The MS + and MS − patient groups were subsequently divided into 2 subgroups based on baseline serum UA levels: hyperuricemic MS + subgroup (n = 284), normouricemic MS + subgroup (n = 1,126), hyperuricemic MS − subgroup (n = 177), and normouricemic MS − subgroup (n = 1,376).
Continuous variables were expressed as mean ± SD. Chi-square and analysis of variance were used to compare proportions and means, respectively. Two-sided p values were reported. A p value <0.05 was defined as statistically significant. Incidence of the primary end point was analyzed separately in each of the 4 subgroups. Multivariate analyses of primary end points in each subgroup were performed using Cox proportional hazard model. Adjustment for age, gender, current and former smoking, diabetes, previous MI, hypertension, New York Heart Association classes II to IV, eGFR, body mass index, total cholesterol, triglycerides, heart rate, diuretics, antiplatelet drugs, angiotensin-converting enzyme inhibitors, β blockers, and bezafibrate treatment was performed. Data were analyzed with SAS software, version 8.2 (SAS Institute, Cary, North Carolina).
Results
Incidence of hyperuricemia was significantly higher in patients with MS (n = 284, 20.1%) compared to those without MS (n = 177, 11.4%, p <0.0001). Baseline clinical characteristics, risk factors, and medical treatment in hyperuricemic versus normouricemic MS + and MS − subgroups are listed in Table 1 . There were no significant differences regarding age, previous MI, and severity of heart failure, but significantly higher rates of hypertension, higher body mass index, total cholesterol, triglycerides, and lower eGFR in hyperuricemia were noted in the hyperuricemic MS + patient subgroup compared to the normouricemic MS + subgroup. The hyperuricemic MS − subgroup was characterized by significantly higher total cholesterol and triglycerides levels, but lower high-density lipoprotein cholesterol and lower eGFR compared to the normouricemic MS − subgroup. Bezafibrate treatment was similar in all 4 subgroups.
| Clinical Characteristics | MS + | MS − | p Value | ||||
|---|---|---|---|---|---|---|---|
| Hyperuricemia | Normouricemia | p Value | Hyperuricemia | Normouricemia | p Value | ||
| (n = 284) | (n = 1,126) | (n = 177) | (n = 1,376) | ||||
| Age (years), mean ± SD | 60.5 ± 6.6 | 60.1 ± 6.6 | 0.34 | 60.5 ± 6.5 | 60.1 ± 6.9 | 0.47 | 0.34 |
| Women | 14.8% | 10.7% | 0.05 | 7.9% | 5.8% | 0.27 | 0.05 |
| Previous myocardial infarction | 80.3% | 77.4% | 0.29 | 77.3% | 78.4% | 0.74 | 0.29 |
| New York Heart Association classes II to IV | 26.5% | 27.3% | 0.79 | 27.6% | 21.3% | 0.06 | 0.79 |
| History of hypertension | 45.8% | 37.3% | 0.009 | 32.2% | 25.7% | 0.06 | 0.009 |
| Diabetes mellitus | 9.2% | 17.5% | 0.001 | 2.3% | 4.9% | 0.11 | 0.001 |
| Estimated glomerular filtration rate (ml/min), mean ± SD | 64.9 ± 10.5 | 70.4 ± 10.5 | <0.0001 | 63.8 ± 9.5 | 70.2 ± 10.2 | <0.0001 | <0.0001 |
| Current smoker | 8.1% | 14.0% | 0.008 | 8.5% | 11.2% | 0.27 | 0.008 |
| Former smoker | 62.7% | 56.2% | 0.05 | 59.9% | 59.7% | 0.97 | 0.05 |
| Total cholesterol (mg/dl), mean ± SD | 217 ± 18 | 214 ± 18 | 0.007 | 213.0 ± 19.0 | 210.2 ± 17.0 | 0.04 | 0.007 |
| High-density lipoprotein cholesterol (mg/dl), mean ± SD | 32.6 ± 4.9 | 32.9 ± 5.0 | 0.30 | 34.9 ± 6.0 | 36.1 ± 5.4 | 0.005 | 0.30 |
| Low-density lipoprotein-cholesterol (mg/dl), mean ± SD | 147.5 ± 17.1 | 147.0 ± 16.9 | 0.70 | 152.1 ± 17.2 | 149.9 ± 15.7 | 0.08 | 0.70 |
| Triglycerides (mg/dl), mean ± SD | 183.4 ± 49.6 | 168.0 ± 51.1 | <0.0001 | 130.0 ± 36.5 | 121.0 ± 38.2 | 0.003 | <0.0001 |
| Body mass index (kg/m 2 ), mean ± SD | 28.8 ± 3.6 | 27.9 ± 3.4 | <0.0001 | 25.7 ± 2.5 | 25.3 ± 2.4 | 0.06 | <0.0001 |
| β Blockers | 48.6% | 41.0% | 0.02 | 41.2% | 34.4% | 0.07 | 0.02 |
| Aspirin | 69.0% | 65.8% | 0.31 | 73.4% | 73.9% | 0.89 | 0.31 |
| Angiotensin-converting enzyme inhibitors | 18.7% | 13.1% | 0.02 | 20.3% | 9.4% | <0.0001 | 0.02 |
| Diuretics | 26.4% | 13.5% | <0.0001 | 24.3% | 10.6% | <0.0001 | <0.0001 |
| Calcium channel blockers | 46.8% | 53.4% | 0.05 | 50.8% | 44.1% | 0.09 | 0.05 |
| Bezafibrate | 48.9% | 53.3% | 0.19 | 53.7% | 49.2% | 0.26 | 0.19 |
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