Increase in Serum Uric Acid Is Selectively Associated With Stroke in Type 2 Diabetes

Hyperuricemia has previously been described as a strong predictor of well-defined cerebrovascular complications (stroke) in a Finnish cohort of patients with type 2 diabetes (1). To evaluate whether serum uric concentration would be selectively associated with presence of stroke as compared with transient ischemic attack (TIA) in a group of hospitalized diabetic patients, we studied 835 patients (220 affected with type 2 diabetes and 615 nondiabetic subjects), who were consecutively admitted to and subsequently discharged from our hospital for TIA (n = 386) or stroke (n = 449) during the period 1 January 1998 to 31 December 1999. Stroke was classified by means of computerized tomography as ischemic (thromboembolic) in 363 cases (81%) and hemorrhagic in 86 (19%). TIA was defined as an acute loss of focal cerebral function lasting <24 h presumed to be due to ischemic vascular disease and without clinical or biochemical evidence of hypoglycemia. Those who were determined to be affected with TIA were chosen as control subjects because patients with stroke and with TIA appeared homogeneously exposed to previous chronic drug therapy or to hospitalization and, moreover, because they were characterized by co-presence of about the same risk factors for cardiovascular disease.

Regardless of whether they were affected with diabetes, there was no difference in serum creatinine among the groups of patients, and the percentage of those chronically taking drugs (at home) potentially able to modify serum uric acid was similar. The serum uric acid values (means ± SD) were similar in groups with and without diabetes (340.8 ± 99.9 vs. 343.8 ± 96.9 μmol/l, P = NS). In the diabetic group, serum urate was significantly higher in patients with stroke (n = 138, 354.5 ± 118.4 μmol/l) than in those with TIA (n = 82, 318.8 ± 88 μmol/l, P = 0.001), whereas no difference was observed in the group of nondiabetic patients (343.8 ± 100.5 μmol/l in 304 patients with TIA vs. 343.8 ± 104.1 μmol/l in 311 subjects with stroke, P = NS). These findings were confirmed after also excluding patients with hemorrhagic stroke, and the relative risk for stroke was linearly related to serum urate concentration in the diabetic group, since the odds ratio (adjusted for sex, age, blood pressure, serum creatinine, plasma glucose, and lipids for the presence of coronary heart disease and of atrial fibrillation) in the fourth urate quartile was significantly higher than in the first quartile (1 vs. 1.32 [95% CI 1.07–1.41], P < 0.05).

From these findings, it is impossible to recognize whether an increase in serum urate is a predisposing risk factor or can instead be considered the effect of stroke itself, or both. Serum uric acid is a soluble antioxidant scavenger (2), and oxidative stress is a hallmark of tissues’ hyperglycemic milieu (3). In addition, the increase in serum uric acid is a feature of the metabolic syndrome (4). Furthermore, serum uric acid may be considered as a marker of acute endothelial dysfunction, since hyperuricemia has been observed to be associated with raised endothelin levels (5), and there is evidence of uric acid involvement, via purine metabolism, in the process of thrombus formation (6). In conclusion, our data suggest a selective relationship between serum uric acid and stroke in type 2 diabetes. Whether treatment aimed at reducing serum uric acid can be useful to prevent acute cerebrovascular events in these patients remains to be ascertained.