Patients with the metabolic syndrome (MS) events are also more likely to develop type 2 diabetes and may have an increased risk of future cardiovascular disease (CVD) [¹].

The most commonly used guidelines for definitions of MS are those developed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) in 2001 [²], the World Health Organization (WHO) in 1999 [³], and more recently, the International Diabetes Federation (IDF) definition [⁴], and the harmonized definition [⁵]. The various components of MS do not contribute equally to CVD risk in those without frank diabetes, and the relative importance of clusters of these risk factors in the setting of established diabetes is less clear.

In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study [⁶,⁷], 9795 patients with type 2 diabetes, with or without prior CVD, were recruited and followed up for an average of 5 years. Of these, 4900 were randomized to placebo, providing a sample size sufficient to explore whether CVD event rates were influenced by the presence of MS components (hypertension, dyslipidemia, and waist circumference) or clusters, according to the 4 current definitions. This study also allowed us to assess whether various MS components affected the risk of CVD equally or differently in those with and those without prior CVD and in predefined age and sex subgroups.

In the FIELD study, 9795 patients with type 2 diabetes, aged 50 to 75 years, from Australia, New Zealand, and Finland were randomly assigned to treatment with placebo or fenofibrate for a planned duration of 5 years. The trial has been described in detail elsewhere [⁶]. To be eligible, patients had to have an initial plasma total cholesterol level of 3.0-6.5 mmol/L, plus a total cholesterol/HDL-c ratio of ≥ 4.0 or plasma triglyceride 1.0-5·0 mmol/L, with no clear indication for lipid-modifying therapy at study entry. Exclusion criteria included renal impairment (creatinine > 130 μmol/L), chronic liver disease or symptomatic gallbladder disease, and a cardiovascular event within 3 months before recruitment.

In this further study of FIELD participants, we examined whether the presence of MS, and its various components, increased cardiovascular disease events over 5 years. In addition, we examined which components of MS contributed most to cardiovascular risk. This analysis was confined to the placebo group (n = 4900, including 1833 women), who did not receive fenofibrate during the trial, and of whom 1016 had known CVD at study entry.

The prevalence at baseline of the MS components for referenced definitions (ATPIII, IDF, and WHO) was determined (Table 1). The harmonized definition data added nothing to the conclusions regarding the IDF definition, so were not considered further. High blood pressure was defined as a self-reported history of hypertension and documented use of medication for hypertension, or a mean of 3 blood pressure values at baseline above 130/85 mm Hg for the IDF, ATPIII and harmonized definitions, or above 140/90 mm Hg for the WHO definition [^3-5,⁸]. In the WHO MS definition, dyslipidemia is a single component, and patients can have either raised blood triglyceride (≥ 1.7 mmol/L) or low HDL-c levels (< 0.9 mmol/L for men and < 1.0 mmol/L for women). If both were present, this was counted as a single risk factor in all analyses using the WHO definition, whereas the other definitions allowed each to be counted individually. Thus, if HDL-c levels were low and triglyceride was high, both risk factors were counted separately for IDF and ATPIII. Type 2 diabetes was a core component for each of the definitions, and waist measurement was included as a requirement of the IDF definition.

Outcome was defined as the first CVD event over the duration of the study (CVD death, nonfatal coronary events, stroke, and coronary and carotid revascularizations).

Event rates for those meeting or not meeting MS criteria were established in subgroups based on the prespecified cut-off age of 65 years, sex, and the presence or absence of prior CVD. The effects of baseline blood pressure, waist circumference, HDL-c, and triglyceride levels on CVD event rates were analysed by quintile.

In the placebo cohort of FIELD, the absolute risk of a CVD event was higher in those with more MS components, provided they did not have prior CVD. Patients with prior CVD had a less clear risk gradient related to the presence or absence of MS features.

The WHO definition of metabolic syndrome outperformed the other definitions in predicting CVD. It does not include waist measurement, which was not a significant risk factor in any case (replaced by waist-hip ratio and also not a significant risk factor). Its hypertension cut-off is higher than that of the other definitions, and it combines the triglyceride criterion (not predictive in women) with the lower and sex-specific HDL-c criterion. Our findings are in line with those of the Strong Heart Study, also in diabetes, with the WHO definition performing best[⁹].

The prevalence of MS features, as defined by ATPIII, IDF, and WHO classifications, was high, particularly for treated hypertension or high blood pressure at study entry. Over 80% met MS criteria irrespective of definition, and 60% had at least 3 MS components, in addition to type 2 diabetes.

The protective effect of sex was strong, with women having a 30% lesser CVD risk than men, after adjustment. This is consistent with previous reports, first, that type 2 diabetes doubles in men and triples in women the relative risk of various CVD events [¹⁰,¹¹], and second, that men with MS are more likely to have a CVD event than women [¹²,¹³]. However, there are also some reports that women are at higher risk of CVD than men [¹⁴,¹⁵]. In FIELD, for every 10 years of age, at baseline, CVD risk was 74% higher in women and 21% higher in men. Although truncal obesity was prevalent, particularly in women, high waist circumference and waist-hip ratio were not significant CVD risk factors, in contrast to other studies in more general populations [¹⁶,¹⁷]. This may reflect the greater importance of this component in a prediabetes setting. Although truncal fat is an important driver of insulin resistance [¹⁸], and adjustment for WHR has been shown, for example, to influence the relationship of HOMA-index with left ventricular mass in people without diabetes [¹⁹], once diabetes is present, it is possible that excess truncal fat no longer predicts future CVD events. However, fatness, adipocytokine release and inflammation are tightly interlinked, and an effect on CVD event rates would have been predicted [²⁰,²¹]. The most important MS predictor of CVD events in the Framingham Offspring Study was blood pressure [¹³], followed by HDL-c level, and not waist measurement, consistent with the findings of this FIELD analysis. Waist circumference is a required component of the IDF definition, which may explain its lesser discrimination of risk in comparison with the harmonized version. Of interest, another group has reported an association between prevalence of MS and higher levels of within-normal-limits liver function [²²].

The presence of dyslipidemia contributed to CVD risk. All MS definitions apply sex-specific levels for HDL-c, with the triglyceride level set at 1.7 mmol/L, above which LDL particles tend to be of smaller size and greater density, properties that reflect higher atherogenicity [²³]. In the FIELD cohort, there was a gradient of risk as triglyceride levels increased above 1.5 mmol/L in men, but in women no change in risk was observed across the quintiles except for a suggestion of higher risk at levels over 2.5 mmol/L. These data support the possibility of a triglyceride risk differential by sex in diabetes, although this was not the finding of the recent meta-analysis of the Emerging Risk Factors Collaboration [²⁴]. It would appear that there is also a strong sex difference with respect to cut-offs for the HDL-c levels that escalate risk. Higher CVD risk in men was associated with HDL-c levels below 0.95 mmol/L, a value similar to that used in these definitions of MS. In women, the FIELD data suggest that the defined levels for HDL-c should be set lower than specified by ATPIII (for example, < 1.0 mmol/L) to select diabetes patients with higher CVD risk. This may partly explain why the WHO definition came out as the most predictive (although it also captured as having MS those with higher blood pressure and microalbuminuria). Thus, the most aggressive risk factor management for diabetes patients might be guided by levels of HDL-c and triglyceride that are sex-specific. For both men and women, an HDL-c level below 1.0 mmol/L seems to best identify highest risk. For triglycerides, a level above 1.5 mmol/L seems appropriate for men, but for women, a much higher value, such as > 2.5 mmol/L, might be necessary to identify higher risk.

The limitations to the study are that the analysis was based on data at study entry, and the proportion of subjects lacking MS features was relatively small. Comparisons between those with and without MS thus might have over- (or under-) estimated effects, but is consistent with other reports[²⁵]. In addition, the average rate of uptake of statins in the placebo group during follow-up was substantial (17% over 5 years) [²⁶], and those with more marked dyslipidemia were most likely to have had this treatment initiated (21%).

An increasing number of MS variables increased future CVD risk, and for all definitions, other than the IDF definition, the risk of CVD among patients defined as having MS was significantly higher than among those without. The two MS variables that contributed most to this risk were HDL-c and hypertension. Waist measurement was not a material contributor. Of current definitions of MS, the WHO definition, which includes albuminuria, was consistently the best discriminator of risk, whereas the IDF definition was not significantly predictive. These results can help guide clinicians in identifying patients with diabetes at high CVD risk.

ATP III: Adult Treatment Panel III; CVD: cardiovascular disease; FIELD: Fenofibrate Intervention and Event Lowering in Diabetes; HDL: high-density lipoprotein; IDF: International Diabetes Federation; LDL: low-density lipoprotein; MS: metabolic syndrome; NCEP: National Cholesterol Education Program; WHO: World Health Organisation.

The authors declare that they have no competing interests.

RS designed this study, wrote the manuscript, MD contributed to the discussion, analysed the data, revised the manuscript; GFW contributed to the discussion, revised the manuscript; ROB contributed to the discussion, revised the manuscript; CP contributed to the discussion, analysed the data, revised the manuscript; MRT contributed to the discussion, revised the manuscript; TMED contributed to the discussion, revised the manuscript; PGC contributed to the discussion, revised the manuscript; PM contributed to the discussion, revised the manuscript; GF contributed to the discussion, revised the manuscript; ACK designed the study, contributed to the discussion, wrote the manuscript; all authors read and approved the final manuscript.

The FIELD study was supported by a grant from Laboratoires Fournier SA, Dijon, France (now part of Abbott) and the National Health and Medical Research Council (NHMRC) of Australia, and was coordinated independently by the NHMRC Clinical Trials Centre, University of Sydney. The authors thank Rhana Pike from the NHMRC Clinical Trials Centre, for assistance with the manuscript.