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Others
Key Points
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.

WHO Definition and Criteria

In 1998, the World Health Organization (WHO) was the first major
organization to propose a definition of the metabolic syndrome (Table) (1). In
accordance with the syndrome X concept introduced by Reaven (2) (a
combination of elevated fasting triglyceride and insulin concentrations,
reduced HDL cholesterol levels, and raised blood pressure, with insulin
resistance as a common denominator), the WHO definition also identified
insulin resistance as the most common etiological factor behind the clustering
abnormalities of the metabolic syndrome (2). An index of glucose intolerance,
impaired glucose tolerance, or diabetes and/or insulin resistance (insulin Table: Criteria proposed
sensitivity measured under euglycemic-hyperinsulinemic conditions) was for clinical diagnosis of
therefore a necessary WHO criterion for clinical diagnosis of the metabolic the metabolic syndrome
syndrome. Insulin resistance also had to be accompanied by at least two other
criteria from among the following: raised blood pressure (≥140/90 mmHg),
increased plasma triglyceride (≥1.7 mmol/l (150 mg/dl) and/or reduced HDL cholesterol levels (<0.9 mmol/l
(35 mg/dl) for men and < 1.0 mmol/l (39 mg/dl) for women), obesity as estimated by waist-to-hip ratio
(>0.90 for men and >0.85 for women) and/or body mass index (BMI) >30 kg/m2 for both genders, and
microalbuminuria (urinary excretion rate ≥ 20 μg/min or albumin-creatinine ratio ≥30 mg/g).

The original WHO recommendations were intended to serve as working guidelines for research purposes.
They were not designed to provide an exact definition for clinical diagnosis. The initial recommendations
have remained controversial for a number of reasons. First, debate continues as to whether microalbuminuria
is a necessary component of the metabolic syndrome. Although microalbuminuria is a marker of endothelial
dysfunction and a predictor of increased cardiovascular risk, its relationship with the other components of the
metabolic syndrome and the need to include this criterion in the clinical diagnosis of the metabolic syndrome
are not firmly established (3, 4). Controversy also surrounds the use of waist-to-hip ratio versus waist
circumference alone. It has been shown that waist circumference better indicates absolute intra-abdominal
(visceral) adipose tissue accumulation (as measured with computed tomography, the gold standard method)
than waist-to-hip ratio which is an index of relative abdominal fat deposition (5). In addition, insulin
resistance must be assessed for the metabolic syndrome to be properly diagnosed using WHO criteria. The
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preferred method is the clamp technique. Because this technique requires time and technical expertise, it was
acknowledged that the euglycemic-hyperinsulinemic clamp would never be used by health professionals in
clinical practice to screen for the presence of the metabolic syndrome in asymptomatic individuals.
Moreover, apart from the European Group for the Study of Insulin Resistance (EGIR), very few
epidemiological studies have measured subject insulin sensitivity with the clamp technique. It is therefore
hard to develop large databases to generate population-based data on insulin resistance assessed with this
technique (6). In its 1998 statement, WHO stressed that the metabolic syndrome could be present for up to
10 years before any measurable glycemic disorders were detected, underlining the fact that individuals with
normal glycemic control could still be at increased cardiovascular disease (CVD) or type 2 diabetes risk if
they show other features of the metabolic syndrome. WHO called for the early detection and aggressive
management of the metabolic syndrome to prevent related chronic diseases. The WHO group also called for
future research in this area in order to understand and integrate the relevance of each component of the
metabolic syndrome.

EGIR Definition and Criteria

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 cut-off 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 intra-abdominal 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.

AACE
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 cut-off 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

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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 cut-offs 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 section Comparison of
Screening Tools.

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-
thromobotic 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.

References
1. Alberti KG and Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO
consultation. Diabet Med 1998; 15: 539-53.
2. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607.
3. Chugh A and Bakris GL. Microalbuminuria: what is it? Why is it important? What should be done
about it? An update. J Clin Hypertens (Greenwich) 2007; 9: 196-200.
4. Toft I, Bonaa KH, Eikrem J, et al. Microalbuminuria in hypertension is not a determinant of insulin
resistance. Kidney Int 2002; 61: 1445-52.
5. Pouliot M-C, Després JP, Lemieux S, et al. Waist circumference and abdominal sagitttal diameter: best
simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related
cardiovascular risk in men and women. Am J Cardiol 1994; 73: 460-8.
6. Hills SA, Balkau B, Coppack SW, et al. The EGIR-RISC STUDY (The European group for the study
of insulin resistance: relationship between insulin sensitivity and cardiovascular disease risk): I.
Methodology and objectives. Diabetologia 2004; 47: 566-70.
7. Balkau B and Charles MA. Comment on the provisional report from the WHO consultation. European
Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999; 16: 442-3.
8. Alberti KG, Zimmet P and Shaw J. The metabolic syndrome--a new worldwide definition. Lancet
2005; 366: 1059-62.
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9. Wood D, De Backer G, Faergeman O, et al. Prevention of coronary heart disease in clinical practice.
Summary of recommendations of the Second Joint Task Force of European and other Societies on
Coronary Prevention. Blood Press 1998; 7: 262-9.
10. Farin HM, Abbasi F and Reaven GM. Body mass index and waist circumference both contribute to
differences in insulin-mediated glucose disposal in nondiabetic adults. Am J Clin Nutr 2006; 83: 47-
51.
11. Einhorn D, Reaven GM, Cobin RH, et al. American College of Endocrinology position statement on
the insulin resistance syndrome. Endocr Pract 2003; 9: 237-52.

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