Enzo Bonora, M.D., Ph.D., Endocrinology and Metabolic Diseases, University of Verona, Medical School, Verona, Italy It has been known for a long time that metabolic disorders like obesity, type 2 diabetes, dyslipidemia, hyperuricemia, and hypertension often occur together [1-3]. The cluster has been named with various terminology (Syndrome X, Insulin Resistance Syndrome, Cardiometabolic Syndrome, Atherometabolic Syndrome, etc.), but the most commonly used term is now Metabolic Syndrome. This name is currently included in the ninth edition of the International Codes of Diseases (ICD-9). Although a consensus does exist in considering dysglycemia (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or type 2 diabetes [T2DM]), hypertension, high triglycerides, low HDL cholesterol, and central obesity (high waist or waist/hip ratio) as members of the metabolic syndrome, different sets of diagnostic criteria have been issued by groups of experts appointed by different institutions, including the World Health Organization (WHO), the National Cholesterol Education Program (NCEP), and the International Diabetes Federation (IDF) [4-6]. This generated some confusion in the definition of the epidemiology, the pathogenesis, and the outcome of subjects affected. Most disappointingly, some authorities have recently raised several concerns about the metabolic syndrome and have challenged its true existence [7].

The metabolic syndrome, regardless of the diagnostic criteria used, is very common in the general population: it is observed in 20-30% of subjects [8,9]. The prevalence and incidence of the syndrome are thought to increase in the future, paralleling the increase in the prevalence and incidence of obesity. A fraction of individuals affected has a fully blossomed syndrome, with most or all of the constituting components well expressed (e.g., diabetes); others have only a cluster of mild abnormalities (e.g. IFG), with a variety of possible clinical/biochemical phenotypes and with a phenotype in continuous evolution, depending on changes in life-style, menopausal state, aging, co-morbidity, use of drugs, and other factors. In this regard, it is important to emphasize that all clinical and biochemical features used for diagnosing the syndrome (e.g. waist circumference and plasma glucose) are continuous variables and that being just above or just below the diagnostic threshold could make a substantial difference from a nosologic but not from a biological and clinical standpoint. Also being just above the threshold or definitely above the threshold of any given component of the syndrome is thought to make a substantial difference. However, no data are currently available on the outcome in sub-phenotypes of the metabolic syndrome.

Most components of the metabolic syndrome (i.e. T2DM, hypertension, low HDL cholesterol, and hypertriglyceridemia) are classic cardiovascular risk factors [10-13]. There is also good evidence that obesity, mainly excess of central fat, and insulin resistance (which is a diagnostic criterion of the syndrome according to WHO) convey an increased cardiovascular risk [14-16]. Interestingly, the latter two abnormalities have been indicated as the principal underlying disorders of the syndrome [17,18]. Moreover, a panel of novel (non-traditional) risk factors turned out to be somewhat related to the metabolic syndrome. They include biomarkers of chronic mild inflammation (e.g. C-reactive protein, CRP, white blood cells, WBC, erythrocyte sedimentation rate, ESR), increased oxidant stress (e.g. oxidized LDL, reactive exigent species, ROS), thrombophilia (e.g. fibrinogen, plasminogen activator inhibitor-1, PAI-1), endothelial dysfunction (e.g. E-selectin, intercellular adhesion molecule-1, ICAM-1, vascular cell adhesion molecule-1, VCAM-1), and adipose tissue derangement (e.g. adiponectin, leptin, resistin) [19,20]. Therefore, for the concomitant presence of a wide spectrum of classic and non-classic cardiovascular risk factors, subjects with the metabolic syndrome are potentially at very high risk of developing atherosclerosis and clinical cardiovascular events.

In recent years several longitudinal studies have confirmed that subjects with the metabolic syndrome present with atherosclerosis and suffer from myocardial infarction and stroke at rates higher than subjects without the syndrome [21-34]. On average, the risk of cardiovascular disease (CVD) is 2-fold higher in subjects affected, when data are adjusted for sex, age, smoking, and LDL cholesterol. Interestingly, the CVD risk seems to be higher in women with the syndrome (RR around 4) than in men with the syndrome when compared to sex-matched individuals without the syndrome. The risk conveyed by the syndrome is also higher in subjects with pre-existing diabetes (RR around 5) or pre-existing CVD (RR around 10). Interestingly, an high CVD risk is clearly present also in subjects with a cluster of multiple mild abnormalities (e.g. IFG, low HDL cholesterol, central obesity), as we observed in the Bruneck Study (RR around 4) [23].

Some authorities claimed that the risk of CVD in subjects with the metabolic syndrome is not particularly high (RR of around 2) and is similar to that observed in those with diabetes or hypertension [7]. However, it should be underlined that the vast majority of subjects with T2DM and a large fraction of subjects with hypertension indeed have the metabolic syndrome and that the CVD risk of subjects with isolated T2DM and isolated hypertension is not high. Moreover, in all studies carried out so far focusing on CVD risk in the metabolic syndrome, the reference category was composed of subjects without the syndrome and not of subjects without any trait of the syndrome. The latter seems a more logical reference category. In fact, among subjects without the metabolic syndrome, many have 1-2 traits of the syndrome (including diabetes and/or hypertension) and this is expected to attenuate the risk. Interestingly, in the few studies in which secondary analyses were run and subjects with multiple disorders (3 or more, i.e. with the metabolic syndrome were compared to subjects without any traits, the former showed a risk of CVD several fold higher (and not just 2-fold higher) [24,29,31]. Unpublished data from the Bruneck Study confirm that, when compared to an appropriate reference category, subjects with the metabolic syndrome have a CVD risk 6- to 12-fold higher. Therefore, the metabolic Syndrome is certainly a high risk condition but the true risk of subjects affected can be underestimated when a dichotomous categorization is made (metabolic syndrome yes versus no). Thus, the use of an appropriate reference category is warranted.

A major issue in this area of discussion is that the "metabolic syndrome approach" is valid because it provides a nosologic dignity to a very common clinical condition which is often neglected when it is composed of multiple minor disorders (central adiposity, IFG, etc.). The clustering of these minor disorders, however, still is a risk condition. Another key issue is that the “metabolic syndrome approach” points out the existence of underlying pathogenic disorders of the cluster, i.e. central obesity and insulin resistance. These underlying disorders can be targeted by specific interventions in order to prevent the metabolic syndrome in those not affected yet and CVD in those already affected. Great emphasis should be placed on the notion that treating the underlying disorders, i.e. obesity and/or insulin resistance, with lifestyle changes or medications results in an amelioration of several classic and ancillary components of the metabolic syndrome and, therefore, in a substantial reduction of the cardiovascular risk.

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Please address correspondence to:
Prof. Enzo Bonora
Endocrinologia e Malattie del Metabolismo
Ospedale Maggiore
Piazzale Stefani, 1
37126 Verona, Italy
Tel: +39 045 8073113 – 8073110
Fax: +39 045 917374
E-mail: enzo.bonora@univr.it – enzobonora@virgilio.it