The New Worldwide Definition of Metabolic Syndrome Is Not a Better Diagnostic Predictor of Cardiovascular Disease in Japanese Diabetic Patients Than the Existing Definitions : Additional analysis from the Japan Diabetes Complications Study

The Japan Diabetes Complications Study (JDCS) has been described in detail elsewhere (1, 5). The same dataset was used for evaluation so that the new definition of metabolic syndrome could be directly compared with the WHO and NCEP definitions (1–4). A total of 1,424 Japanese patients (771 men and 653 women, age 58.4 ± 7.4 years [means ± SD]) with previously diagnosed type 2 diabetes but without known CVD were followed for 8 years for coronary heart disease (CHD) and stroke events. Fatal and nonfatal CHD and stroke were defined as previously reported (1). The new International Diabetes Federation definition (4) was used with a recommended ethnic modification for Japanese subjects in relation to waist circumference (men ≥85 cm, women ≥90 cm). Since all of the subjects had diabetes, metabolic syndrome diagnosis was made in patients who met criteria for central obesity plus one or more of the following: increased triglycerides, increased blood pressure, or reduced HDL cholesterol (see Table 1 for detailed thresholds). Incidence rates in the two groups (with and without metabolic syndrome) were estimated under the Poisson assumption using person-year methods. Cox regression analysis was used to calculate the age-adjusted hazard ratio (HR) and 95% CI of metabolic syndrome risk factors with CHD, stroke, or both. The SAS software package (version 8.0; SAS Institute, Cary, NC) was used for all analyses. P < 0.05 was considered statistically significant.

At baseline, the prevalence of metabolic syndrome, using the new definition (Table 1), was notably lower, especially in female patients, than the prevalence under the WHO (2) and NCEP (3) definitions, which was ∼50% on average (1). Diabetes duration in patients with (9.9 ± 6.9 years) or without (10.7 ± 7.3 years) metabolic syndrome did not differ significantly (P = 0.07). The proportion of patients that met the central obesity criterion (an essential component of the new definition) was 36.7% for men and 9.7% for women, such that 87% of men and 95% of women with central obesity had metabolic syndrome.

The incidence (per 1,000 patient-years) of CHD (13.5 [with metabolic syndrome] vs. 8.1 [without metabolic syndrome] in men; 5.8 vs. 5.5 in women) or stroke (8.1 vs. 7.5 in men; 8.8 vs. 7.0 in women) did not differ significantly between subjects with or without metabolic syndrome. Age-adjusted HRs were calculated to determine whether the new metabolic syndrome definition or its components could predict cardiovascular events (Table 1). Patients diagnosed as having metabolic syndrome, even when subgrouped by therapeutic contents (oral hypoglycemic agents or insulin use), did not show significantly raised HRs for CHD, stroke, or both compared with subjects without metabolic syndrome. However, male patients with raised triglyceride levels and/or having specific treatment for this condition had a significantly increased risk of CHD (HR 2.93, P < 0.001) and combined CHD and stroke (1.96, P = 0.006), regardless of whether they had metabolic syndrome (Table 1).

Our previous analysis (1) showed that HRs for CVD in patients with WHO-defined metabolic syndrome were significantly elevated compared with HRs in subjects without metabolic syndrome (although the HR for CHD in male patients was not elevated). Diagnosis of metabolic syndrome by the NCEP definition was less predictive but still associated with a significantly elevated HR for CHD in male patients. However, metabolic syndrome diagnosis by the new definition was not predictive for CVD in either male or female patients in the same prospective setting. Therefore, the new definition did not improve the prediction of adverse cardiovascular events, and its clinical usefulness in Japanese diabetic patients is rather less than that of the existing definitions or of hypertriglyceridemia alone in male patients.

The indispensability of central obesity to the new definition was a major cause of the decrease in the prevalence of metabolic syndrome observed using the new definition. The fact that most patients with central obesity were classified as having metabolic syndrome revealed that metabolic syndrome diagnosis by the new definition was highly dependent on waist circumference when applied to Japanese diabetic subjects. It also denoted that most patients with central obesity had at least one other cardiovascular risk factor, suggesting a close relationship between central obesity and other cardiovascular risk factors. However, this combination was not necessarily associated with an increased risk of CVD in our patients. This latter observation led us to further evaluate the significance of waist circumference in our patients by modifying the threshold within the 65- and 105-cm range and recalculating the HRs. Interestingly, we could not find any thresholds associated with significantly elevated HRs for cardiovascular events in either male or female subjects (data not shown). Therefore, the new definition’s lower prediction power for CVD seemed to be derived from the indispensability of the waist circumference component.

To date, prospective trials examining the significance of metabolic syndrome as a predictor of CVD in diabetic patients (1, 6–9) have been inadequate (10, 11). Many important issues remain to be resolved. 1) Is the new definition of metabolic syndrome a good predictor of CVD in diabetic patients of differing ethnicities (12)? 2) Are there any other combinations of components (or different thresholds) that are better predictors of CVD in Asian diabetic patients (13–15)? 3) Is the concept of metabolic syndrome truly applicable or relevant to diabetic patients in general? Investigations of these issues would aid the screening of diabetic patients at especially high risk of CVD, as well as inform and direct ethnic group–specific management of diabetes (16–19).

The JDCS was financially supported by the Ministry of Health, Labor, and Welfare of Japan.