European Heart Journal Supplements (2008) 10 (Supplement B), B1–B3 doi:10.


Metabolic syndrome: the dysmetabolic state of dysfunctional adipose tissue and insulin resistance
´ Jean-Pierre Despres and H. Bryan Brewer
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The current world epidemic of obesity represents a tremendous medical and public health challenge. A major consequence of obesity has been a rapid acceleration in the prevalence of type 2 diabetes;1 however, it is now recognized that even before the development of diabetes, many individuals have the constellation of atherothrombotic inflammatory abnormalities characteristic of type 2 diabetes.2 Thus, the cluster of metabolic abnormalities is not the consequence of the hyperglycaemic state of type 2 diabetes but is rather pathophysiologically related to insulin resistance, the most prevalent form of insulin resistance being present in individuals with excess visceral as well as ectopic fat.3 Thus, even in the absence of hyperglycaemia, abdominally obese patients with an excess of visceral and ectopic fat deposition are likely to have the clustering of risk factors associated with insulin resistance. In this regard, the pivotal role of insulin resistance in the pathophysiology of the cluster of risk factors was first reported by Reaven4 and designated syndrome X. Since his seminal paper, numerous groups have utilized the term insulin resistance syndrome in the description of this cluster of athero-thrombotic inflammatory abnormalities.5,6 In 2001, the guidelines developed by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) committee considered abdominal obesity as central in the pathophysiological development of the insulin resistance syndrome.7 Since the measurement of insulin resistance was not practical in the context of primary care clinical practice, the guidelines provided clinicians with simple diagnostic criteria, including waist circumference, triglycerides, high-density lipoprotein (HDL) cholesterol, blood glucose, and blood pressure to identify patients with the cluster of risk factors, resulting in an increased risk of diabetes and cardiovascular disease (CVD). The cluster of athero-thrombotic inflammatory risk factors was
The opinions expressed in this article are not necessarily those of the Editors of the Eurpean Heart Journal Supplement or of the European Society of Cardiology.

designated as the metabolic syndrome. Many groups have confused the NCEP-ATP III five criteria to diagnose the metabolic syndrome in the context of clinical practice with the conceptual definition of the syndrome. The definition of the metabolic syndrome has a pathophysiological basis3,8 and places insulin resistance and abdominal obesity at the core of the cluster of abnormalities. The NCEP-ATP III five criteria should not be considered as the definition of the metabolic syndrome but rather as simple screening tools. Refining the discriminating capabilities of these tools is work in progress. For instance, the International Diabetes Federation (IDF)9 has placed more emphasis than NCEP-ATP III on the importance of abdominal obesity and recognized the important ethnic differences in susceptibility to visceral adiposity and related metabolic abnormalities.

Diagnosis of the metabolic syndrome in clinical practice: does it matter?
Although many studies have shown that patients meeting the NCEP-ATP III criteria for the metabolic syndrome are at increased risk of cardiovascular events,10,11 the joint position paper published by the American Diabetes Association-European Association for the Study of Diabetes (ADA–EASD)12 has appropriately pointed out that a clinical diagnosis of the metabolic syndrome is not sufficient to assess CVD risk and that attention should be first paid to classical risk factors such as age, male gender, blood pressure, smoking, low-density lipoprotein (LDL) cholesterol and HDL-cholesterol, and diabetes. These two organizations have even questioned the relevance of a clinical diagnosis of the metabolic syndrome and emphasized that attention should be first given to assessment and management of classical risk factors. Therefore, although our toxic lifestyle characterized by lack of physical activity and an energy-dense diet has led to an epidemic of abdominal obesity and of the metabolic syndrome,3 whether its diagnosis in clinical

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Figure 1 The building blocks of global cardiometabolic risk. In this model, the metabolic syndrome as its most prevalent form (visceral obesity/ectopic fat) is one more modifiable risk factor affecting global risk of cardiovascular disease. From Despres and Lemieux.3 ´

Figure 2 Assessment and management of global cardiometabolic risk. This illustration emphasizes the notion that in addition to assessing and managing ‘traditional’ risk factors, targeting excess visceral adiposity/ectopic fat could lower the risk of CVD through its effects on several determinants of cardiometabolic risk.

practice would lead to different therapeutic management is a question frequently raised.13 To address this issue, additional prospective data with hard CVD end points and a comprehensive set of morphometric and metabolic markers are needed to sort the key predictors of risk beyond what is currently assessed by physicians. At present, there is evidence14–17 that markers of

inflammation (e.g. C-reactive protein), insulin resistance (insulin), an atherogenic dyslipidaemia (apolipoprotein B and LDL particle size), and possibly select cytokines derived from adipose tissue (e.g. adiponectin and interleukin-6) may be useful in risk assessment but their added value in global risk assessment, is frequently debated due to the lack of adequate data. Furthermore,


B3 Cardiometabolic Risk which is supported by an unrestricted grant from Sanofi-Aventis awarded to Universite Laval. ´ Conflict of interest: none declared.

there are no data available on whether visceral adiposity and ectopic fat predict CVD beyond or independently from classical CVD risk factors. Studies are underway to address these issues. An additional limitation that has not been adequately addressed with our current approach to diagnose the metabolic syndrome is that it is an all or none diagnosis (present vs. absent) rather than containing graded components assessing severity. In addition, because of this dichotomized classification, a diagnosis of the metabolic syndrome (absent or present) cannot be used to assess efficacy of therapy.18 Thus, the metabolic syndrome, at least as assessed in clinical practice under current guidelines cannot be considered as a target of therapy. In this supplement issue, the importance of visceral adiposity as the most common component of the metabolic syndrome is emphasized. However, although visceral adiposity increases relative CVD risk and risk of the development of diabetes through its cluster of abnormalities, it is again important to point out that its diagnosis is not sufficient to assess global CVD risk. How the risk of visceral adiposity/metabolic syndrome adds to global CVD risk is at present not clear. However, to provide a conceptual framework for further studies, global CVD risk resulting from the presence of classical risk factors as well as the metabolic consequences of visceral adiposity has been referred to as global cardiometabolic risk3 (Figure 1). In this conceptual model, the metabolic syndrome is an additional modifiable CVD risk factor and should not be confused with global cardiometabolic risk as it is only one of its components. Global cardiometabolic risk also stresses the importance of assessing and targeting all known established CVD risk factors currently used in global risk assessment algorithms. However, due to the major impact of visceral adiposity on the development of the atherogenic dyslipidaemia, insulin resistance, inflammation, and increased blood pressure, a substantial reduction in global cardiometabolic risk could be achieved by targeting excess visceral adiposity, especially in the specific subgroup of viscerally obese patients (Figure 2). Such a possibility will have to be tested in randomized clinical trials with ‘hard’ CVD end points. However, to be successful, such trials will have to focus on the selection of the right patient and, therefore, not just study the effect of pharmacotherapy-induced weight loss among patients with ‘general’ obesity. Visceral obesity/ectopic fat is a major driver of cardiometabolic risk and it should be effectively diagnosed and optimally managed. This is a substantial conceptual change. Weight loss per se may not be the most important clinically relevant end point when evaluating a ‘weight loss’ drug.

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Dr. Despres is the Scientific Director whereas Dr. Brewer is a ´ member of the Executive Board of the International Chair on

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