Other Tools (WHO, EGIR and AACE)

• WHO was the first major organization to produce a definition of the metabolic syndrome that focused mainly on insulin resistance, whose diagnosis requires an oral glucose tolerance test.

• WHO criteria also proposed that microalbuminuria as a marker to identify high-risk patients with the metabolic syndrome.

• In response to WHO, EGIR sought to establish criteria that would be easier to use in clinical practice. EGIR makes measuring insulin resistance mandatory.

• The AACE position does not provide a specific scoring system for diagnosing the “insulin resistance syndrome”. Insulin resistance is at the core of AACE criteria, while waist circumference is not considered a diagnosis criterion.

• These organizations acknowledge that their diagnosis tools can be refined and that further research is needed to improve diagnosis of the metabolic syndrome in clinical practice.

EGIR published its own clinical criteria for the metabolic syndrome in response to the provisional report from the WHO consultation in 1999 (Table) [7]. EGIR’s approach was described as very “glucocentric” [8]. It has the advantage of being simple for ready use in clinical practice and epidemiological studies. Since there were “non-metabolic” abnormalities included in the metabolic syndrome criteria, EGIR felt that it should be labelled the “insulin resistance syndrome.” EGIR also saw insulin resistance as the core component of this syndrome. EGIR hypothesized that the insulin resistance syndrome was a constellation of mild abnormalities that worked in conjunction to considerably increase CVD risk. To facilitate diagnosis of the insulin resistance syndrome, EGIR criteria do not require the use of the clamp technique. As fasting insulin levels are one of the best markers of insulin resistance, EGIR suggested that insulin resistance be defined as the presence of fasting hyperinsulinemia (i.e., the top 25% of the distribution of fasting insulin levels in non-diabetic individuals).

According to EGIR, the insulin resistance syndrome should be diagnosed if insulin resistance is observed with two or more of the following abnormalities: fasting plasma glucose concentrations ≥6.1 mmol/l without diabetes, blood pressure ≥140/90 mmHg or treatment for elevated blood pressure, triglyceride levels >2.0 mmol/l (177 mg/dl) or treatment for elevated triglycerides and/or HDL cholesterol levels <1.0 mmol/l (88 mg/dl) or treatment for reduced HDL cholesterol levels, or an increased waist circumference (≥94 cm for men and ≥80 cm for women). EGIR criteria for blood pressure and dyslipidemia were drawn from the report of the Second Joint Task Force of European and other Societies on Coronary Prevention, which suggested that proposed cutoff values for blood pressure, triglyceride, and HDL cholesterol levels were associated with increased coronary heart disease risk [9]. Regarding obesity criteria, EGIR did not incorporate BMI in its diagnosis variables because the association between BMI and insulin resistance is not very clear, obesity being heterogeneous and not always associated with insulin resistance [10]. In addition, waist-to-hip ratio was omitted and waist circumference included since it is a better correlate of visceral adiposity than waist-to-hip ratio [5]. EGIR also excluded microalbuminuria from its criteria since the relationship between microalbuminuria and insulin resistance is not clear.

The American Association of Clinical Endocrinologists (AACE) presented its official position on the “insulin resistance syndrome” in 2003 (Table) [11]. Unlike WHO and EGIR, AACE deliberately chose not to provide a specific definition of the insulin resistance syndrome, suggesting instead that diagnosis should depend on individual clinical judgement. AACE’s decision was based on the fact that the field is evolving rapidly and that it did not feel comfortable making a firm decision on proposed criteria cutoff values until more data was available. Regarding criteria to be included, AACE adopted the same clinical criteria as 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) for blood pressure and lipid criteria (which were also endorsed by the International Diabetes Federation). Blood pressure above 130/85 mmHg, triglyceride concentrations above 1.7 mmol/l (150 mg/dl), and HDL cholesterol concentrations below 1.04 mmol/l (40 mg/dl) for men and below 1.29 mmol/l (50 mg/dl) for women are therefore abnormalities of the insulin resistance syndrome. AACE also stated that fasting plasma glucose concentrations between 6.1 mmol/l (110 mg/dl) and 6.9 mmol/l (125 mg/dl) and plasma glucose concentrations between 7.8 (140 mg/dl) and 11.1 mmol/l (200 mg/dl) after a two-hour glucose challenge should be considered another syndrome abnormality. The two-hour oral glucose tolerance test is recommended for at-risk individuals who do not meet the proposed criteria for the insulin resistance syndrome. The Task Force appointed by AACE suggested that other criteria should be added or revised for assessment of the syndrome.

These modifications include recognition of the limitations of fasting glucose values and recognition of the merits of the oral glucose tolerance test. In describing syndrome etiology, the Task Force remarked that obesity should not be seen as a consequence of insulin resistance, but more akin to a physiological factor affecting insulin sensitivity. Obesity should therefore be considered a causal risk factor of the insulin resistance syndrome. The Task Force also recommended adding BMI as a measure of obesity. It felt that waist circumference did not provide sufficient additional information on overall risk, though it does view abdominal obesity as a prevalent form of insulin resistance. The Task Force also called for obesity cutoffs to be adjusted for ethnicity and ethnicity per se to be considered a risk factor. Moreover, the Task Force suggested expanding the list of at-risk individuals and the list of associated disorders, such as familial history of type 2 diabetes, hypertension, CVD, personal history of CVD, polycystic ovary syndrome, gestational diabetes, and acanthosis nigricans. The AACE report also noted that physical inactivity is closely tied to insulin resistance and recommended early and more aggressive lifestyle interventions aimed at improving fitness and nutritional status to prevent the harmful effects of the insulin resistance syndrome. In addition, the report identified pharmacotherapy as an important option although very few pharmacological compounds have been proven to prevent, delay, or treat insulin resistance syndrome. Given this, thiazolidinedione compounds should benefit from further research to establish their clinical utility in targeting the insulin resistance syndrome. Special focus should be placed on their cardiovascular safety.

Although NCEP-ATP III clinical criteria are the most widely used in studies evaluating metabolic syndrome-related CVD risk, some studies have investigated whether WHO, EGIR, and AACE criteria also indicate increased CVD and type 2 diabetes risk. The most relevant studies are summarized in the Comparison of Screening Tools section.

None of the NCEP-ATP III, IDF, WHO, EGIR, and AACE working groups claimed that their criteria were best at defining and classifying individuals with the metabolic syndrome (or insulin resistance syndrome). Each of them called for further research to improve assessment and recommended the use of criteria that take into account obesity, dyslipidemia, insulin resistance, blood pressure, and the pro-inflammatory and pro-thrombotic state. They also agreed that the most promising treatment for the metabolic syndrome is lifestyle therapy because it works on both abdominal obesity and insulin sensitivity.