Limitations

• The underlying cause(s) of the metabolic syndrome are not fully understood. Visceral obesity and insulin resistance are thought to be the driving forces behind the development of the metabolic syndrome.
• Although the metabolic syndrome is associated with incident CVD and diabetes, it is not clear whether it enhances CVD and diabetes risk on top of currently available algorithms for assessing CVD and diabetes risk.
• Further research and work is needed to eventually harmonize metabolic syndrome diagnosis criteria and develop new modelling approaches to take into account the linear relationship between the features of the metabolic syndrome and CVD and diabetes risk.
• For the moment, it is unclear whether the metabolic syndrome is a clinical entity that increases CVD and diabetes risk more than the sum of its individual components. It is also unclear whether the metabolic syndrome should be treated differently than its individual components.

The usefulness of diagnosing the metabolic syndrome in clinical practice is the subject of an ongoing debate. It is well accepted that certain individuals without traditional cardiovascular disease (CVD) risk factors are at risk if they have visceral obesity or insulin resistance (or both). This population at risk for CVD and type 2 diabetes needs to be identified and treated to lessen the burden associated with features of the metabolic syndrome. Twenty years ago, these individuals were largely undiagnosed. However, the identification by Reaven [1] in 1988 of a cluster of metabolic abnormalities associated with insulin resistance (syndrome X) paved the way for a plethora of metabolic, clinical, and epidemiological studies aimed at defining, diagnosing, treating, and identifying the underlying causes of the metabolic syndrome. These abnormalities have also been identified as a target for pharmacotherapy, a topic that has sparked criticism and heated debate [2].

Faced with widespread interest in the metabolic syndrome by the medical field and lay press, in 2005 the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a joint statement calling for caution in diagnosing the metabolic syndrome and questioning its clinical relevance. These two organizations also jointly stated that much more research was needed before this cluster of abnormalities could rightly be called a “syndrome” [3].

The underlying causes of the metabolic syndrome are another topic of contention. The rationale behind using screening tools and cutoff values is also discussed. With the exception of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III or ATP III), every organization has suggested a mandatory criterion for either insulin resistance or abdominal obesity. Both European Group for the Study of Insulin Resistance (EGIR) and World Health Organization (WHO) criteria rely on an index of insulin resistance or on impaired glucose tolerance, while the IDF believes that abdominal obesity (estimated by waist circumference) is at the core of metabolic syndrome complications. Although abdominal obesity is the most prevalent form of the metabolic syndrome in clinical practice [4], insulin resistance certainly plays a critical role in the pathogenesis of the metabolic syndrome, as it is clearly associated with elevated blood pressure, dyslipidemia, and the pro-inflammatory and pro-thrombotic state, even in the absence of clinical obesity [2,5].

As described in previous sections, there are no gold standard criteria for clinical diagnosis of the metabolic syndrome. Since proposed criteria differ between organizations and, more importantly, in their underlying rationale, the same individuals are not consistently identified with the metabolic syndrome when different screening tools are used. For instance, both NCEP-ATP III and IDF criteria include waist circumference. However, while NCEP-ATP waist circumference criteria are 102 cm for men and 88 cm for women, IDF criteria use much lower cutoffs that are also ethnic-specific (both organizations focused on the relationship between body mass index (BMI) and waist circumference to determine waist circumference cutoffs [6]). For example, waist circumference cutoff values for Europid men and women are 94 cm and 80 cm, respectively. As described in the Comparison of Screening Tools section, screening tools for clinical diagnosis of the metabolic syndrome vary from one organization to another. This in turn provides individuals/organizations with fodder to criticize the use of the metabolic syndrome as a clearly defined condition [7]. For instance, with NCEP-ATP III metabolic syndrome criteria, there are 10 different combinations of criteria for diagnosing the metabolic syndrome. It is reasonable to believe that not all these combinations carry equivalent CVD risk.

The joint statement from the ADA and EASD also questioned the clarity of existing criteria. According to initial NCEP-ATP III and WHO criteria, the respective cutoff values for elevated blood pressure were ≥130/85 mmHg and ≥140/90 mmHg.

With respect to meeting NCEP-ATP III elevated blood pressure criterion, it was initially unclear whether one had to have systolic blood pressure ≥130 mmHg and diastolic blood pressure ≥85 mmHg or whether either condition was sufficient. This confusion has been clarified in later publications [8]. Furthermore, treatment for hypertension also qualifies as a metabolic syndrome criterion, irrespective of blood pressure values.

Several questions have also been raised regarding the measurement of waist circumference, which, unlike BMI, requires validation. To address this issue, the IDF’s scientific statement fortunately provided a waist circumference measurement guide. Yet discrepancies may still exist among health professionals who assess this critically important clinical criterion. In order to address this issue, the International Chair on Cardiometabolic Risk solicited a panel of experts who reviewed the literature and concluded that the waist circumference measurement protocol did not substantially affect the association between waist circumference with all-cause and CVD mortality, CVD and diabetes [9]. In addition, as the measurement at the iliac crest is more precise and reliable over time because it implies a bony landmark, the International Chair on Cardiometabolic Risk recommended to measure the waist circumference at the top of the iliac crest [9].

Some have also criticized the cutoff values of the respective features of the metabolic syndrome, stating that they are arbitrary and not based on their ability to optimally discriminate CVD and type 2 diabetes risk [3]. Further research is clearly required to generate optimal cutoff values for the various metabolic syndrome criteria.

Thus, various diagnostic criteria have been proposed by different organizations over the years. It must be acknowledged that this situation has generated some confusion among healthcare professionals. Several international and influent organizations (IDF Task Force on Epidemiology and Prevention, NHLBI, AHA, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity) have gathered to reach a consensus in order to propose unified diagnosis criteria [10]. They agreed that waist circumference should not be a mandatory component, but that waist measurement would continue to be a useful preliminary screening tool. They also suggested that 3 out of 5 clinical criteria (waist circumference, triglycerides, HDL cholesterol, blood pressure and fasting glucose) would qualify a person for the metabolic syndrome. A single set of cutoff values would be used except for waist circumference which requires further validation according to sex and ethnicity.

One of the major criticisms levelled against the concept of the metabolic syndrome is that it is progressive. The metabolic markers included in metabolic syndrome clinical criteria represent a set of continuously distributed variables, and it is very difficult to draw a line over a certain cutoff value to identify, for example, an individual with elevated triglyceride concentrations (high or low). Similarly, to be diagnosed with the metabolic syndrome using NCEP-ATP III criteria (which are widely accepted in the literature), one should have three or more out of five risk markers. Diagnosis of the metabolic syndrome therefore provides a “yes” or “no.” However, metabolic syndrome-related CVD and type 2 diabetes risk increases progressively based on the severity of the criteria. The current “all or none,” 3 out of 5 metabolic syndrome clinical criteria do not adequately address this linear relationship between components of the metabolic syndrome and CVD or type 2 diabetes risk.

Of course, the metabolic syndrome is a progressive disorder, and it is reasonable to believe that patients with many metabolic abnormalities are more likely to develop cardiovascular outcomes than subjects with fewer or less severe features of the metabolic syndrome. However, individuals with two or less features of the metabolic syndrome are not necessarily at lower CVD risk. Indeed, if these individuals have traditional risk factors, they are at increased CVD risk even though they were not diagnosed with the metabolic syndrome. Wilson et al. [11] tested this hypothesis in the Framingham Offspring Study and reported that participants with three metabolic traits were not necessarily at greater CVD risk than participants with two features of the metabolic syndrome.

This suggests that the presence of even a few metabolic traits might reflect ongoing abnormalities that increase CVD risk and need to be treated aggressively.

To address this issue, Macchia et al. [12] sought to generate a diagnostic score to predict late-onset diabetes in the metabolic syndrome by assigning the appropriate weight to individual components of the metabolic syndrome. Data came from the GISSI-Prevenzione Study that included 11,323 patients with prior myocardial infarction followed for 3.5 years. This global assessment risk score assigned each component of the metabolic syndrome a proportion based on its association with diabetes (β coefficients). The metabolic syndrome score was found to have stronger ties to incident diabetes than NCEP-ATP III criteria, with an area under the receiver operating characteristic curve of 0.650 and 0.587 for the score and NCEP-ATP III criteria, respectively. The ability of the metabolic syndrome score to predict incident type 2 diabetes has been confirmed in another study which also reported its usefulness to predict myocardial infarction and coronary and cardiovascular mortality [13]. Accordingly, this global approach to diagnosing the metabolic syndrome may be a better predictor of diabetes and CVD than any other current screening tool.

Several prospective studies have shown that all metabolic syndrome criteria enhance CVD and type 2 diabetes risk [7,14,15]. However, given the fact that each individual component of the metabolic syndrome increases risk, these observations are not very surprising. When the individual components are combined, the risk is likely greater. This raises the question whether the metabolic syndrome as a whole is more closely linked to CVD and type 2 diabetes risk than its individual components. Many specialists hold opposing views on the issue, which is being debated in the literature. In the Hoorn Study, investigators described a linear relationship between metabolic syndrome components and CVD risk and stated that the number of components provided more information in assessing CVD risk than diagnosis of the metabolic syndrome itself [7]. With the findings of the Framingham Offspring Study, Wilson et al. [11] stated that diagnosing the metabolic syndrome is clinically relevant, especially for patients with modestly elevated risk factors who are not necessarily insulin resistant. In the Strong Heart Study, de Simone et al. [16] concluded that both NCEP-ATP III and WHO screening tools predicted CVD independent of their individual components, while this was not the case for IDF criteria. These authors therefore suggested that diagnosis of the metabolic syndrome is clinically relevant, especially for non-diabetic individuals at increased CVD risk.

Another important question is whether diagnosis of the metabolic syndrome influences treatment: is treating the metabolic syndrome really different than treating each underlying abnormality? There seems to be a consensus surrounding both the treatment of the metabolic syndrome and the treatment of its components. Lifestyle interventions aimed at increasing physical activity/exercise and improving nutritional habits have been shown to reduce waist girth and underlying metabolic markers of dyslipidemia, namely insulin resistance and blood pressure [17,18]. However, lifestyle modification as a treatment of obesity has been shown to be unsuccessful and disappointing in clinical practice [19]. In light of this, the pharmaceutical industry is now keenly interested in pharmacotherapies targeting abdominal obesity as the underlying cause of the metabolic syndrome.

In summary, numerous groups have called for further research to resolve several unanswered questions regarding the relationship of metabolic syndrome diagnosis criteria to CVD and type 2 diabetes. At issue is the concordance between various guidelines, the criteria to be included in the clinical diagnosis of the metabolic syndrome, the “continuous” nature of the metabolic syndrome (create a scoring system rather than make a “yes” or “no” diagnosis in order to consider the linear relationship between the metabolic syndrome and CVD and diabetes risk), and the medical value of diagnosing the metabolic syndrome beyond current screening tools. Further research is obviously needed to shed light on the pathophysiological processes that underpin the metabolic syndrome and enhance our understanding of its clustering abnormalities and clinical relevance. More work is also required to develop new therapeutic targets for treatment of the metabolic syndrome and determine whether it is better to treat the metabolic syndrome as a single entity or focus our efforts on its individual components.