The Metabolic Syndrome

On a global scale, there are approximately 314 million people with impaired glucose tolerance (IGT), and this number is predicted to rise to 500 million cases by 2025.[1] Declining levels of physical activity, increasing caloric intake, and consequent rises in the rate of obesity are leading to increases in the number of people with IGT from most ethnic and cultural backgrounds.

Countries in the Middle East and Gulf States have a high prevalence of IGT, as does India and China. The Congress participants heard that more than 50% of people with diabetes will come from Asia over the next decade. In developed countries, the major increase in the number of people with diabetes will be among the young and middle-aged.


The term prediabetes (which embraces IGT and impaired fasting glucose [IFG]) has had a checkered history. It was included in the classification of glucose tolerance in the 1965 World Health Organization (WHO) Expert Committee Report on Diabetes Mellitus, which stipulated the following:
"This is a term that can be used retrospectively when reviewing a case." In recent years, the term prediabetes was reintroduced in the United States to describe people with IGT and IFG who are at high risk of developing diabetes in the future. On the one hand, it may be inappropriate to use the term prediabetes when there is only a 50% chance of developing diabetes in the 10 years following diagnosis. Moreover, the definition of prediabetes does not include some people at risk of developing diabetes, such as those with a family history of diabetes or other normoglycemic risk groups of certain ethnic origins. On the other hand, the American Diabetes Association (ADA) and other national organizations recognize the difficulty of communicating to the general public the concept of a high-risk situation, and the term prediabetes is certainly easier to promote than IGT and/or IFG. Certainly, the WHO and ADA usage of the term is mutually exclusive!

The Metabolic Syndrome

The concept of the metabolic syndrome has been in existence for at least 80 years. This constellation of metabolic disturbances -- all CVD risk factors -- was first described in the 1920s by Kylin, a Swedish physician, as the clustering of hypertension, hyperglycemia, and gout. In 1947, Vague[2] drew attention to upper body adiposity (android or male-type obesity) as the obesity phenotype that was commonly associated with metabolic abnormalities associated with type 2 diabetes and CVD. The more modern era of the metabolic syndrome started with a publication by Avogaro and Crepaldi[3] in 1967. In recent years, a number of expert groups have attempted to develop a unifying definition for the syndrome. The most widely accepted were those of the WHO,[5] the European Group for the Study of Insulin Resistance (EGIR),[6] and the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP ATP III).[7] All of these groups agreed on the core components of obesity, insulin resistance, dyslipidemia, and hypertension, yet they provided different clinical criteria to identify the constellation of components. From a clinical perspective, the ATP III definition was probably the most useful. However, the existence of multiple definitions caused much confusion, apart from a seemingly futile new industry of publications seeking to compare their utility in different populations. A consensus on a worldwide definition of the metabolic syndrome was urgently needed, and was reached under the auspices of the IDF by its Task Force on Epidemiology. Its first public presentation in Berlin, Germany, was the highlight of the Congress.

New definitions of waist circumference (measuring visceral obesity) for Europid men and women and ethnic-specific values for other groups, such as Asians, have been suggested. Professor Scott Grundy has presented additional metabolic criteria that appear to be related to the metabolic syndrome but are not currently included in its core definition, such as abnormal body fat distribution, atherogenic dyslipidemia, endothelial dysfunction, and proinflammatory and prothrombotic states.[8] Future research into these components will allow further modification of the definition, if necessary.

Table. The 2005 International Diabetes Federation (IDF) Definition of the Metabolic Syndrome
According to the new IDF definition, for a person to be defined as having the metabolic syndrome, they must have:

Central obesity (defined as waist circumference >/= 94 cm for Europid men and >/= 80 cm for Europid women, with ethnicity specific values for other groups) plus any 2 of the following 4 factors

* Raised TG level:≥ 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality

* Raised BP: systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg, or treatment of previously diagnosed hypertension

* Reduced HDL-cholesterol: < 40 mg/dL (1.03 mmol/L)
in men and < 50 mg/dL (1.29 mmol/L) in women, or specific treatment for these lipid abnormalities


* Raised fasting plasma glucose: FPG≥ 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes
If above 5.6 mmol/L or 100 mg/dL, an OGTT is strongly recommended, but is not necessary to define the presence of the syndrome.


TG = triglycerides; HDL = high-density lipoprotein; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test

IDF definition addresses both clinical and research needs and:
  • Provides a simple entry point for primary care physicians to diagnose the metabolic syndrome;
  • Provides an accessible diagnostic tool suitable for worldwide use, taking into account ethnic differences in waist circumference and associated type 2 diabetes and CVD risk;
  • Establishes a comprehensive "platinum standard" list of additional criteria that should be included in epidemiologic studies and other research into the metabolic syndrome. 

The Metabolic Syndrome and CVD Risk For every 1% rise in glycosylated hemoglobin (A1C) in people with diabetes, there is an 18% rise in the risk of cardiovascular events. Similarly, for every 1% rise in A1C, there is a 28% increase in peripheral arterial disease in people with diabetes. In addition, people who have had a cardiovascular event very often have diabetes or prediabetes. People with the metabolic syndrome have at least a 2-fold increase in the risk of CVD events, and a much poorer prognosis following the event. High levels of triglycerides and of small, dense low-density lipoprotein (LDL) particles and low levels of high-density lipoprotein cholesterol (HDL-C) are both components of the metabolic syndrome and risk factors for CVD. The metabolic syndrome more strongly predicts congestive heart failure and CVD mortality than its individual components.

The results of the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) studies are generally accepted as demonstrating improved cardiovascular outcomes with tight glycemic control in the peri-MI or peri-ACS period. Whereas the first DIGAMI study seemed to show a benefit of intensive glucose control, the DIGAMI 2 study did not confirm this conclusion. The jury is still out on this important question. People with diabetes and prediabetes also fail to enjoy the full benefits available from modern cardiological and surgical procedures.

Treatment of the Metabolic Syndrome

Because current knowledge does not identify a single, common mechanism for the syndrome, no single treatment agent is available, and the individual components of the syndrome, such as central obesity, dyslipidemia, dysglycemia, and hypertension, should be treated separately. There have been demonstrated positive results of intervention studies in populations at high risk for CVD using fibrates, which correct the dyslipidemic components of the metabolic syndrome.

There is a major impact of lifestyle changes, such as diet and exercise, in preventing the development of diabetes as well as reducing the CVD risk-factor components of the metabolic syndrome. Intervention studies from the United States, Finland, China, and India all showed the beneficial effects of lifestyle interventions. Diabetes prevention studies with the antidiabetic medications metformin, acarbose, and glitazones have shown promising results. New investigational pharmacologic agents, such as glucagon-like peptide (GLP)-1, dipeptidyl peptidase (DPP)-IV inhibitors, and the endocannabinoid receptor blocker rimonobant, have also demonstrated promising results.


A better definition and intense study of prediabetes and the metabolic syndrome have led to some important insights in the past decade:

  • Prediabetes and the metabolic syndrome are extremely prevalent;
  • People with prediabetes and the metabolic syndrome are at high risk for diabetes and CVD;
  • Intensive lifestyle changes are effective and should be encouraged; and
  • Effective pharmacologic therapies must also be identified.