Metabolic syndrome: To be or not to be?

The metabolic syndrome (MetS), a constellation of cardiovascular risk factors, has become one of the major public‐health challenges worldwide 1. The MetS was first described by Kylin in the 1920s as the clustering of hypertension, hyperglycaemia and gout 2. Gerald Reaven was the first investigator establishing the significance of this syndrome (‘Syndrome X’) in his Banting lecture in 1988 3. According to Reaven the primary value of his syndrome (also called ‘the insulin resistance syndrome’) was to provide a conceptual framework with which to place apparently unrelated biological events into a pathophysiological construct. About 10 years later the concept took another turn when the MetS was introduced as a diagnostic category by the definitions of the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), and the National Cholesterol Education Program – Third Adult Treatment Panel (NCEP ATP III) 4–6. Recently the International Diabetes Federation (IDF) presented new criteria for the MetS 7, and also the NCEP ATP III updated its definition 8. The starting point for the IDF definition was a need for one simple definition/diagnostic tool for clinical practice which could be used in any country by any physician to identify patients at considerably increased risk of developing cardiovascular disease and/or type 2 diabetes.

All definitions of the MetS include the following components: obesity, insulin resistance or raised blood glucose, dyslipidaemia and elevated blood pressure. According to the WHO and EGIR criteria, insulin resistance was thought to be the driving force for the syndrome, whereas NCEP ATPIII introduced the significance of central obesity (large waist circumference) for cardiovascular risk factor clustering. According to the new IDF definition of the MetS, central obesity is a prerequisite for the syndrome 7. The rationale for this requirement is that central obesity is more strongly associated with the other MetS features than is any other parameter9. Furthermore, central obesity is highly correlated with insulin resistance. Recommended cut‐off points for waist circumference vary for different ethnic groups. In contrast, when the American Heart Association recently updated the NCEP ATP III criteria, no single risk factor was a requirement for the clinical diagnosis of this syndrome 8. There is no evidence or consensus on what is the predominant underlying cause (or causes) of the MetS. Insulin resistance and abdominal obesity have been assumed to be underlying causes for this syndrome, but there are no convincing data to show which one of these two (or neither) is the primary abnormality. Insulin resistance is present in the majority of subjects with the MetS, and it strongly associates with a number of other components, although the association with hypertension is weak. Therefore, the selection of abdominal obesity as a primary candidate for the MetS in the IDF definition is based more on clinical utility than on research evidence. Although none of the definitions of the MetS includes markers of thrombosis or inflammation, it is generally believed that the prothrombotic and proinflammatory state are characteristic features of the MetS 8.

About the same time as the IDF presented a new definition of the MetS this year, the American Diabetes Association and the European Association for the Study of Diabetes published a critical review of the syndrome 10. Although the authors agreed that the MetS has been a useful paradigm to describe cardiovascular risk factor clustering, they concluded that the MetS has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a cardiovascular risk marker 10. According to their opinion too much critically important information is missing to warrant its designation as a ‘syndrome’. Also Reaven has recently criticized the concept of the MetS. According to his opinion the diagnosis of the MetS does not bring with it much in the way of pathophysiological understanding or clinical utility 11,12. Other investigators have presented opposite views and claimed that the MetS represents a powerful hypothesis that unifies the metabolic factors underlying the development of both cardiovascular disease and diabetes 13.

Is the MetS a conceptual pathophysiological framework or just a diagnostic tool to identify people at high risk of developing cardiovascular disease or type 2 diabetes? This is the fundamental question without any clear answer today. More studies are needed to make progress in the understanding of this syndrome. At least the following questions are still unanswered 10,14: 1) What is the aetiology of the MetS? 2) What is the best and most predictive definition of the MetS and its components? 3) What is the value of including diabetes in the definition? 4) How is blood pressure related to the other components of the syndrome? 5) What is the relationship between different constellations of risk factors to cardiovascular outcomes? 6) Is the cardiovascular risk associated with the MetS greater than the sum of its components? and 7) What is the true impact of effective treatment of all components of the syndrome on cardiovascular risk?

This special issue of the Annals of Medicine reflects the current status of knowledge and controversies of the concept of the MetS. In the first article Dr. Paul Zimmet and his co‐workers present various definitions of the MetS, with a particular emphasis on the IDF definition. Thereafter, Dr. Ele Ferrannini and Dr. Jean‐Pierre Després review the evidence for the relative contribution of insulin resistance and abdominal obesity to the syndrome. Finally, Dr. Enzo Bonora presents the evidence that the MetS increases the risk of cardiovascular complications.