EBM Tools for Practice: Metabolic Syndrome Guidelines for Populations Around the World. How Do Screening Tools Differ?

Definition of Metabolic Syndrome
Metabolic syndrome is considered a "multiplex" cardiovascular risk factor, in that each component of the cluster of abnormalities is a risk factor in its own right. Metabolic syndrome is recognized clinically by the findings of abdominal obesity, elevated triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, high blood glucose and/or insulin resistance.¹ Metabolic syndrome is characterized by a pro-thrombotic and a pro-inflammatory state. When introduced as Syndrome X by Reaven in 1988 and also called insulin resistance syndrome,surprisingly obesity was omitted.² The term “metabolic syndrome” was formerly adopted by the World Health Organization (WHO) in 1999³ and soon after by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) in 2001⁴ and then by other major organizations, such as the International Diabetes Federation (IDF)⁵ American Association of Clinical Endocrinologists (AACE)(6) and European Group for the study of Insulin Resistance (EGIR)⁷. Table 1 summarizes the clinical tools used to diagnose metabolic syndrome identified by different professional organizations.

How Do Screening Tools Differ?
Although similar, some organizations put special emphasis on certain variables by using different cut-off values. Most organizations have criteria for obesity (mostly abdominal), insulin resistance, dyslipidemia and blood pressure. The proposals put forward by the NCEP expert panel on dietician evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III or ATP III)⁴ and the International Diabetes Federations (IDF)⁵ use virtually the same criteria and cut-off values. The exception is waist circumference, for which the IDF cut-off value is lower. The IDF also has proposed different waist-circumference cut-offs for various regions of the world to address the question of ethnicity. In addition, the IDF makes waist circumference a mandatory criterion. To be diagnosed with metabolic syndrome, one should have a waist circumference above the proposed IDF waist cut-off plus two other components of metabolic syndrome. In a given population, metabolic syndrome prevalence can be expected to be higher when IDF criteria are applied. Moreover, since the AACE⁶ did not propose a working definition, its criteria can hardly be tested in population studies unless investigators decide to specify their criteria/cut-offs in advance. Therefore, when comparing the criteria for metabolic syndrome and incident cardiovascular disease (CVD) or diabetes, investigators can choose from the clinical criteria of NCEP ATP III, IDF, WHO or EGIR. The hypertriglyceridemic waist also has been launched as an approach for metabolic syndrome, though the component of blood pressure has not been considered in this approach and, therefore, will not further be discussed within the scope of cardio-metabolic syndrome.⁸ (Table 2)

Metabolic Syndrome and CVD Risk or Cardiometabolic Syndrome
A few prospective studies have compared metabolic syndrome criteria in assessing CVD risk. Although most criteria have a similar relationship to CVD risk, NCEP ATP III criteria seem to have the strongest ties to CVD. Independent of the clinical criteria studied, metabolic syndrome better predicts type 2 diabetes risk than CVD risk. During the past year there has been debate about whether one should consider metabolic syndrome to be a cluster of different metabolic components leading to additive CVD risk prediction or if it more directly relays to CVD risk as a cardiometabolic syndrome.¹

1. The Insulin-Resistance Atherosclerosis Study (IRAS)
One of the few prospective population studies to compare NCEP ATP III, IDF, WHO and hypertriglyceridemic waist criteria is the Insulin-Resistance Atherosclerosis Study (IRAS)⁹. This study followed 822 subjects ages 40 to 69 without diabetes for 5.2 years. A total of 148 people developed type 2 diabetes. The best predictor of incident diabetes was impaired glucose tolerance. The prevalence of metabolic syndrome was 27.5%, 34.4%, 39.5% and 18.4% with NCEP ATP III, WHO, IDF and hypertriglyceridemic waist criteria, respectively. NCEP ATP III criteria showed the strongest association with incident diabetes, with an odds ratio (OR) of 4.14 (95% CI, 2.79-6.16). The population attributable risk (PAR), which is an estimate of the proportion of CVD in a population attributable to metabolic syndrome, was very similar between NCEP ATP III, WHO and IDF criteria (46.3%, 48.0% and 48.7%,respectively) and lower with hypertriglyceridemic waist criteria (21.7%). The authors of the IRAS concluded that IDF and NCEP ATP III criteria predicted diabetes at least as well as WHO criteria.

2. The San Antonio Heart Study
Lorenzo, et al.¹⁰, used data from the San Antonio Heart Study (SAHS) to compare NCEP ATP III, IDF and WHO screening tools in predicting CVD and diabetes incidence. SAHS recruited 2,559 Mexican American and non-Hispanic white individuals and followed them for an average of 7.4 years. Metabolic syndrome prevalence was higher when IDF criteria were used and lower when WHO criteria were used. During the follow-up, 93 men and 63 women developed CVD events and 195 subjects developed diabetes. NCEP ATP III, IDF and WHO clinical criteria yielded an OR for CVD events of 2.00 (95% CI, 1.33-3.01), 1.69 (95% CI, 1.13-2.54) and 1.73 (95% CI, 1.12-2.67), respectively. The authors found that metabolic syndrome was better able to predict CVD in men ages 45 and older and in women ages 55 and over. They also suggested that, for both men and women, adding the diagnosis of metabolic syndrome to traditional risk factors included in the Framingham risk score could enhance CVD prediction.

3. The DECODE Study
The Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study compared the ability of NCEP ATP III, WHO and IDF criteria to predict CVD deaths.¹¹ A total of 4,715 men and 5,554 women ages 30 to 89 were followed for a period ranging from 7 to 16 years. Metabolic syndrome prevalence using WHO criteria was 27.0% in men and 19.7% in women. using NCEP ATP III criteria, it was 32.2% in men and 28.5% in women. With IDF criteria, it was 35.9% in men and 34.1% in women. With respect to CVD deaths, the Hazard Ratios (HR) s for WHO clinical criteria were 2.09 (95% CI, 1.59-2.76) in men and 1.60 (95% CI, 1.01-2.51) in women; with NCEP ATP III criteria, the corresponding HRs were 1.72 (95% CI, 1.31-2.26) and 1.09 (95% CI, 0.70-1.69). They were correspondingly 1.51 (95% CI, 1.15-1.99) and 1.53 (95% CI, 0.99-2.36) using IDF criteria. In the DECODE study, WHO clinical criteria seemed to predict CVD death risk the best, and this association generally was stronger in men than in women.

Does Ethnicity Matter?
In the past, most cardiovascular risk factors have been derived from findings in Caucasian populations. Obesity and diabetes are on the rise in other ethnicities as well. A more tailored definition for metabolic syndrome may be more useful here. There was an attempt in 2005 to determine that the waist circumference cut-off value for the definition of metabolic syndrome as dependent on ethnicity.¹² One key question is whether the same criteria should be applied to someone of a particular ethnic group, regardless of his or her country of residence. IDF waist-circumference recommendations for metabolic syndrome are the same for women everywhere, owing in part to the paucity of good data, but they are somewhat higher for men of European origin (Europids) than for those of Asian origin. Levels for Asian populations are based on WHO recommendations. Fewer data are available for other regions, but Europid male recommendations also are currently applied to men of the Middle East, Eastern Mediterranean region and Sub-Saharan Africa, pending the provision of new data.¹³

Conclusion
The growing epidemic of obesity has led to a cluster of risk factors – abdominal obesity, pre-hypertension, pre-diabetes and dyslipidemia – defined as metabolic syndrome. The syndrome is associated with inflammation and insulin resistance. There have been several definitions of metabolic syndrome in the past. With the universal definition of metabolic syndrome and a high associated risk for CVD and diabetes, greater efforts have been put forth to individualize the definition of metabolic syndrome in relation to ethnicity (especially for the waist circumference component).

Future study is necessary to determine the optimal treatment cut off values of individual risk factors and for the global treatment of metabolic syndrome beyond lifestyle changes to reduce cardiovascular disease.

Disclosure statement: Dr. Godishala and Dr. Duprez have no disclosures to report.

References are listed on page 27.