The concept of the metabolic syndrome has existed for at
least 80 years.1
This constellation of metabolic
disturbances, all risk factors for cardiovascular disease,
was first described in the 1920s by Kylin, a Swedish
physician, as the clustering
hyperglycaemia, and gout.2Later, in 1947, Vague 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 cardiovascular disease.3
Over the past two decades, a striking increase in the
number of people with the metabolic syndrome
worldwide has taken place. This increase is associated
with the global epidemic of obesity and diabetes.4With
the elevated risk not only of diabetes but also of
cardiovascular disease from the metabolic syndrome,5
there is urgent need for strategies to prevent the
emerging global epidemic.4The metabolic syndrome is a
master of disguise since it can present in various ways
according to the different components that constitute
The metabolic syndrome is also known as syndrome
X,6the insulin resistance syndrome,7and the deadly
quartet.8The constellation of metabolic abnormalities
includes glucose intolerance (type 2 diabetes, impaired
glucose tolerance, or impaired fasting glycaemia),
insulin resistance, central obesity, dyslipidaemia, and
hypertension, all well documented risk factors for
cardiovascular disease. These conditions co-occur in an
individual more often than might be expected by chance.
When grouped together, they are associated with
increased risk of cardiovascular disease.9,10Lemieux and
have suggested the importance of
abdominal obesity and the so-called hypertrigly-
ceridaemic waist phenotype as a central component.11
Although some strong positions have been taken, the
cause of the syndrome is still not settled,12as discussed
in more detail later.
Defining the metabolic syndrome
While the concept of the metabolic syndrome was
accepted, and even while controversies have raged about
its cause, it was not until 1998 that there was an initiative
to develop an internationally recognised definition. In an
attempt to achieve some agreement on definition, and to
provide a tool for clinicians and researchers, a WHO
consultation proposed a set of criteria.13Subsequently,
the National Cholesterol Education Program’s Adult
Treatment Panel III (NCEP: ATP III)14and the European
Group for the Study of Insulin Resistance15have
formulated definitions. These definitions agree on the
essential components—glucose intolerance, obesity,
hypertension, and dyslipidaemia—but do differ in the
detail and criteria (table 1).
The WHO definition and that of the European Group
for the Study of Insulin Resistance agree in that they
both include either glucose intolerance or insulin
resistance as an essential component.13,15However, for
the NCEP:ATP III definition,14this criterion is not
included. Additionally, the cut-off points for criteria of
each component of the cluster and the way of combining
them to define the metabolic syndrome differ between
the definitions of the WHO and European Group for the
Study of Insulin resistance and the definition of the
The WHO proposal was designed as a first attempt to
define the syndrome. The report clearly stated that the
definition would be modified as new information
became available about the components and their
predictive power.13In retrospect, it is apparent that the
WHO definition was better suited as a research tool
whereas the NCEP:ATP III definition14was more useful
for clinical practice. Clinicians prefer simple tools with
which to assess patients
management, and it is generally agreed that the
NCEP:ATP-III definition is simpler for practice. It
requires only a fasting assessment of blood glucose,
whereas the WHO definition can require an oral glucose
tolerance test. Furthermore, because an accurate
assessment of insulin resistance requires a more
complicated test (eg, the hyperinsulinaemic euglycaemic
and improve their
Lancet2005; 365: 1415–28
Division of Endocrinology,
Metabolism and Diabetes,
University of Colorado at
Denver and Health Sciences
Center, PO Box 6511, MS 8106,
Aurora, CO 80045, USA
(Prof R H Eckel MD); University
of Texas Southwestern Medical
Center at Dallas, Dallas, TX,
USA (S M Grundy MD); and
Institute, Melbourne, Australia
(Prof P Z Zimmet MD)
Professor Robert H Eckel
www.thelancet.com Vol 365 April 16, 2005 1415
The metabolic syndrome
Robert H Eckel, Scott M Grundy, Paul Z Zimmet
The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The
disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The
pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated.
A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and
cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight
reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and
cardiovascular disease risk reduction.
Search strategy and selection criteria
We searched PubMed with the terms “metabolic syndrome”,
“insulin resistance”, “coronary heart disease”,
“diabetesmellitus”, “inflammation”, “hypertension”,
“insulinsecretion”, “CRP”, “cytokines”, and “adiponectin”.
clamp technique), its application in an epidemiological
or clinical setting is impractical, although the
Homeostasis Model Assessment (HOMA) model could
be used as an alternative method.16
Yet another attempt at a definition came from the
American Association of Endocrinology,17who have
referred to the cluster as the insulin resistance
syndrome. They suggest that four factors should be the
“identifying abnormalities” of the syndrome. These are
elevated triglycerides, reduced HDL cholesterol, elevated
blood pressure, and elevated fasting and postload (75 g)
glucose. Obesity is not a component of their definition.
Given the mounting evidence that central obesity is a
major risk factor for type 2 diabetes and cardiovascular
disease,11,14this omission is rather surprising.
Since several definitions of the syndrome are in use, it
is difficult to compare prevalence and impact between
countries. Fortunately, there is now a chance for a more
rational approach. In May, 2004, a group of experts was
convened by the International Diabetes Federation (IDF)
to attempt to establish a unified definition for the
metabolic syndrome and to highlight areas where more
research into the syndrome is needed. A similar process
has been initiated jointly by the National Heart, Lung
and Blood Institute (NHLBI) and the American Heart
Association. Further consideration of the definition by
the ATP III panel is expected to follow. Ultimately, the
combined efforts of the IDF and NHLBI–American
Heart Association will result in a new definition(s) of the
metabolic syndrome that will be suitable for use in
clinical practice worldwide.
A major issue for the IDF consensus consultation was
the fact that criteria used for obesity in Asian and other
populations could be different from those used in the
west. The importance of obesity as a risk factor for
several diseases including type 2 diabetes, cardiovascular
disease, hypertension, gallstone disease, and certain
cancers, is well documented.18Yet, the amount of obesity
associated with increased risk differs between
populations. The WHO criteria that define overweight
and obesity in terms of comorbidities are not necessarily
appropriate for Asian populations. This issue was
addressed in 2000 by a group convened by the
International Association for the Study of Obesity and
supported by WHO (Western Pacific Region) and the
International Obesity Task Force. They redefined
overweight as body-mass index (BMI) ?23 and obesity
as ?25 in Asians. Central obesity was defined as ?80 cm
for women and ?90 cm in men.19
More recently, a working party with representation
from WHO (Geneva), the International Society for the
Study of Obesity, and the International Obesity Task
Force re-emphasised the fact that obesity-associated risk
is a continuum and that there are interethnic differences
in the relations between various obesity indices and the
risks of cardiovascular disease.20They noted that in
urban Asians, the BMI range of 23–24 has an equivalent
risk of type 2 diabetes, hypertension, and dyslipidaemia
as a BMI of 25–29·9 in white people. This finding will
probably be taken into account when the new IDF
definition is published.
Comparisons of published prevalence for different
populations are difficult despite attempts to reach
agreement on the definition of the metabolic syndrome.1
Many studies compare prevalences using different
criteria, and perhaps their main achievement is to
reinforce the need for a standardised international
definition. Cameron and others1have published a
detailed review about the prevalence of the syndrome
with different criteria (table 1).
Figure 1 presents studies from various countries. They
differ with respect to study design, sample selection,
year that they were undertaken, precise definition of the
metabolic syndrome used, and age and sex structure of
the population. Although the obesity criteria in
NCEP:ATP-III are not necessarily appropriate for Asian
groups,20figure 1 only shows prevalences established
with NCEP:ATP-III criteria rather than the WHO’s.
Despite differences in the design of these studies and
other variables, certain inferences can be made. For
example, even for studies involving participants in the
same age-groups, there is wide variation in prevalence in
both sexes. In those studies that include people
20–25 years and older, the prevalence varies in urban
populations from 8% (India) to 24% (USA) in men, and
from 7% (France) to 43% (Iran) in women.
www.thelancet.com Vol 365 April 16, 2005
WHO, 1999European Group for the Study of Insulin Resistance, 1999ATP III, 2001
Diabetes or impaired fasting glycaemia or impaired glucose
tolerance or insulin resistance (hyperinsulinaemic, euglycaemic values from non-diabetic population
clamp-glucose uptake in lowest 25%)
Plus 2 or more of the following
Obesity: BMI ?30 or waist-to-hip ratio ?0·9 (male) or
Dyslipidaemia: triglycerides ?1·7 mmol/L or HDL cholesterol
?0·9 (male) or ?1·0 (female) mmol/L
Hypertension: blood pressure ?140/90 mm Hg
Microalbuminuria: albumin excretion ?20 ?g/min
Insulin resistance—hyperinsulinaemia: top 25% of fasting insulin
Plus 2 or more of the following
Central obesity: waist circumference ?94 cm (male) or ?80 cm
Dyslipidaemia: triglycerides ?2·0 mmol/L or HDL cholesterol ?1·0
Hypertension: blood pressure ?140/90 mm Hg and/or medication Hypertension: blood pressure ?135/85 mm Hg or medication
Fasting plasma glucose ?6·?1 mmol/L
3 or more of the following
Central obesity: waist circumference ?102 cm (male), ?88 cm (female)
Hypertriglyceridaemia: triglycerides ?1·7 mmol/L
Low HDL cholesterol: ?1·0 mmol/L (male), ?1·3 mmol/L (female)
Fasting plasma glucose ?6·1 mmol/L
Table 1: Comparison of definitions of the metabolic syndrome
An interesting example of the effect of ethnic origin on
the metabolic syndrome is a comparison of the
prevalence of the syndrome in the USA with lower
prevalence in non-Hispanic white people compared with
Mexican Americans, and in African American men
compared with non-Hispanic white and Mexican
A very consistent finding is that the prevalence of the
metabolic syndrome is highly age-dependent. This
pattern is clear in Iran where the prevalence is less than
10% for both men and women in the 20–29 year age-
group, rising to 38% and 67%, respectively, in the
60–69 year age-group.22
population, the prevalence rises from ?5·6% in the
30–39 year age-group to 17·5% in the 60–64 year age-
group.22Additionally, the prevalence of the metabolic
syndrome in the USA (national health and nutrition
examination survey [NHANES III]) increased from 7%
in participants aged 20–29 years to 44% and 42% for
those aged 60–69 years and at least 70 years,
Until recently, type 2 diabetes and the metabolic
syndrome have been regarded as a disease of adults.4
However, with increasing rates of obesity in young
people, it is clear that the disease can begin at different
ages in all ethnic groups, and that type 2 diabetes and the
metabolic syndrome can be evident in childhood.23–26
However, estimates of prevalence are difficult because of
the problem of producing an appropriate definition of
the syndrome in children and adolescents. In the USA,
Weiss and colleagues26reported that the prevalence of
the metabolic syndrome increased with severity of
obesity, and reached 50% in severely obese youngsters.
Each half-unit increase in BMI was associated with an
increase in the risk of the metabolic syndrome in
overweight and obese people (odds ratio 1·55), as was
each unit of increase in insulin resistance as assessed
with the HOMA model (odds ratio 1·12 for each
additional unit of insulin resistance).The prevalence of
the metabolic syndrome increased significantly with
increasing insulin resistanceafter adjustment for ethnic
group and degree of obesity. C-reactive protein
concentrations decreased with increasing obesity. The
researchers concluded that the prevalence of the
metabolic syndrome is high in obese children and
adolescents, and it increases with worsening obesity.
Biomarkers of an increased
cardiovascular outcomes are already present in these
In Taiwan, a screening study of 3 million students
(aged 6–18 years)24showed that people with type 2
diabetes had higher mean BMI, cholesterol, and blood
pressure than did those with a normal fasting glucose,
and, even at this young age, the metabolic syndrome was
present. Similar results have also been reported in Hong
Kong Chinese children.25
Similarly, in a French
risk of adverse
Finally, data from the
12–19 years age-group in the NHANES III study, with
NCEP:ATP-III criteria modified for adolescents,
reported that the prevalence of the metabolic syndrome
in adolescents was 4·2%.27
Relation to predictability of diabetes and
The metabolic syndrome is associated with an increased
risk of both diabetes5and cardiovascular disease.9,10,28,29
Several studies have indicated that the metabolic
syndrome predicts future diabetes.30,31However, since
impaired fasting glucose and impaired glucose tolerance
are components of the NCEP:ATP-III and the WHO
definitions respectively, this finding might not be a
In the DECODE study involving European men and
non-diabetic people with the metabolic
syndrome had an increased risk of death fromall causes
as well as from cardiovascular disease.32The overall
hazard ratios for all-cause and cardiovascular disease
mortality in people with the metabolic syndrome
compared with those without it were 1·44 and 2·26 in
men and 1·38 and 2·78 in women afteradjustment for
age, blood cholesterol concentrations, and smoking.
In two other prospective European studies,9,10the
presence of the syndrome
cardiovascular disease and coronary heart disease
mortality. Again, this finding is not unexpected since the
metabolic syndrome comprises established risk factors
for cardiovascular disease. In these two studies, as well as
the Verona Diabetes Complications Study,33the relative
hazard ratios for cardiovascular disease outcomes ranged
from 2 to 5. In addition, applying the ATP III criteria to
www.thelancet.com Vol 365 April 16, 2005 1417
USA (Native Americans) 45–49
USA (Filipina-Americans) 50–69
USA (non-Hispanic white) 30–79
USA (Mexican American) 30–79
Figure 1:Prevalence of the metabolic syndrome from ATPIII definition
Adapted from Cameron et al.1
10 537 NHANES III participants resulted in a significant
association between the metabolic syndrome with
prevalent myocardial infarction and stroke.34With a new
metabolic syndrome definition(s) imminent, it will be
important to establish whether there are differences
between ethnic groups in prediction using this new
definition(s). From this point of view, the findings of the
INTERHEART study35could be of great importance. This
study looked at putative cardiovascular risk factors in
nearly 30 000 people in 52 countries and from all
inhabited continents of the world. Abnormal lipids,
smoking, hypertension, diabetes, abdominal obesity,
psychosocial factors, consumption of fruits, vegetables,
and alcohol, and regular physical activity accounted for
most of the risk of myocardial infarction worldwide in
both sexes and at all ages in all regions. This result
suggests that approaches to cardiovascular disease
prevention can be based on similar principles worldwide.
In another study, the Diabetes Predicting Model and
the Framingham Risk Score were used to examine the
relative value of the metabolic syndrome in predicting
type 2 diabetes and cardiovascular disease, respectively.36
Initially 1709 non-diabetic participants in the San
Antonio Heart Study were followed up for 7·5 years, and
195 developed type 2 diabetes. Over the same interval,
156 of 2570 participants experienced a cardiovascular
disease event. The sensitivity for predicting diabetes
using the ATP III definition of the metabolic syndrome
was 66% and the false positive rate was 28%. The
sensitivity and false positive rate for the prediction of
cardiovascular disease were 67% and 34%, respectively.
At corresponding false positive rates, the two predicting
models had significantly higher sensitivities, and, at
corresponding sensitivities, significantly lower false
positive rates than the metabolic syndrome for both
outcomes. Thus, in the San Antonio Heart Study, the
metabolic syndrome proved inferior to established
predicting models for either type 2 diabetes or cardio-
Mechanisms underlying the metabolic
The most accepted and unifying hypothesis to describe
the pathophysiology of the metabolic syndrome is
insulin resistance. Insulin resistance has traditionally
been defined with a glucocentric view—ie, when a defect
in insulin action results in fasting hyperinsulinaemia to
maintain euglycaemia. Yet, even before fasting hyper-
insulinaemia develops, postprandial hyperinsulinaemia
A major contributor to the development of insulin
resistance is an overabundance of circulating fatty acids.
Plasma albumin-bound free fatty acids are derived
mainly from adipose tissue triglyceride stores released
through the action of the cyclic AMP-dependent enzyme
hormone sensitive lipase. Fatty acids are also derived
through the lipolysis of triglyceride-rich lipoproteins in
tissues by the action of lipoprotein lipase.37Insulin is
important to both antilipolysis and the stimulation of
lipoprotein lipase. Of note, the most sensitive pathway of
insulin action is the inhibition of lipolysis in adipose
tissue.38Thus, when insulin resistance develops, the
increased amount of lipolysis of stored triacylglycerol
molecules in adipose tissue produces more fatty acids,
which could further inhibit the antilipolytic effect of
insulin, creating additional lipolysis.
Upon reaching insulin sensitive tissues, excessive fatty
acids create insulin resistance by the added substrate
availability and by modifying downstream signalling
(figure 2). In muscle, fatty acids can impair activation of
protein kinase C-? and protein kinase C-?.39Moreover,
the generation of excess acyl CoAs or acyl-CoA
derivatives such as ceramide can diminish Akt1
activation.40In the liver of rats fed a high-fat diet, insulin
resistance can be attributed to a defect in insulin-
stimulated insulin receptor substrate-1 and insulin
receptor substrate-2 tyrosine phosphorylation. These
changes were associated with activation of protein
kinase C-? and c-Jun N-terminal kinase-1.41However, in
the liver there seems to be some discrepancy in the
metabolic effects of free fatty acids on insulin-mediated
glucose and lipid metabolism. While circulating free
fatty acids increase hepatic glucose production and
diminish inhibition of glucose production by insulin,42
lipogenesis, a pathway related to both the stimulatory
effects of such acids and insulin on sterol response
element binding protein-1c,43continues.
Studies of (1) insulin resistant people with obesity
and/or type 2 diabetes,44(2) offspring of patients with
type 2 diabetes,45and (3) the elderly46have identified a
defect in mitochondrial oxidative phosphorylation that
relates to the accumulation of triglycerides and related
lipid molecules in muscle. Moreover, in murine models
of obesity, another subcellular organelle could be
involved, the endoplasmic reticulum. In mice made
deficient in the endoplasmic reticulum X-box binding
protein-1, hyperactivation of c-Jun N-terminal kinase-1
increases serine phosphorylation of insulin receptor
substrate-1 and insulin resistance.47Thus, more basic
mechanisms of insulin resistance are being discovered
over time. Presumably, these biochemical changes in
insulin-mediated signalling pathways result in decreases
in insulin-mediated glucose transport and metabolism
in the metabolic syndrome as well.
Obesity and increased waist circumference
Although the first description of the metabolic
syndrome was in the early 20th century,2the worldwide
obesity epidemic has been the most important driving
force in the much more recent recognition of the
syndrome. Despite the importance of obesity in the
model, we should remember that patients of normal
weight can also be insulin resistant.48
www.thelancet.com Vol 365 April 16, 2005
For several definitions of the metabolic syndrome,
waist circumference is included.13–15Mechanistically, a
distinction between a large waist due to increases in
subcutaneous adipose tissue versus visceral fat is
debated. This distinction can be made with computed
tomography or magnetic resonance imaging.49With
increases in intra-abdominal or visceral adipose tissue, a
higher rate of flux of adipose tissue-derived free fatty
acids to the liver through the splanchnic circulation
would be expected, whereas increases in abdominal
subcutaneous fat would release lipolysis products into
the systemic circulation and avoid more direct effects on
hepatic metabolism (ie, glucose production, lipid
synthesis, and secretion of prothrombotic proteins such
as fibrinogen and plasminogen activator inhibitor 1).50
Despite these potential differences in mechanisms
related to excessive abdominal
distribution, the clinical diagnosis of the metabolic
syndrome does not distinguish between increases in
subcutaneous and visceral fat. Yet, perhaps by a
mechanism related to free fatty acid flux and
metabolism, the relative predominance of visceral rather
than subcutaneous adipose tissue with increasing waist
circumference in Asians and Asian Indians51renders the
relative prevalence of the syndrome higher than in
African-American men in whom subcutaneous fat
predominates.52However, there is evidence that the
elevated postprandial free fatty acid release in upper
body obese women originates from the non-splanchnic
upper body fat, and not from the visceral depot.53These
results suggest that visceral fat might be a marker for,
but not the source of, excess postprandial free fatty acids
In the setting of partial or complete lipoatrophy,
insulin resistance and the metabolic syndrome typically
coexist.54Evidence from these less common disorders
does support a genetic basis of the syndrome including
single gene defects in peroxisome-proliferator activated
receptor-?, lamin A/C, 1-acylglycerol-3-phosphate,
O-acyltransferase, seipin,55the ?-2 adrenergic receptor,56
In general, with increases in free fatty acid flux to the
liver, increased production of apo B-containing
triglyceride-rich very low-density lipoproteins (VLDL)
occurs.58The effect of insulin on this process is
somewhat complex. In the setting of insulin resistance,
increased flux of free fatty acids to the liver increases
hepatic triglyceride synthesis;
physiological conditions, insulin inhibits rather than
increases the secretion of VLDL into the systemic
circulation.59This response in part is an effect of insulin
on the degradation of apo B.60Yet, insulin is also
lipogenic, increasing the transcription and enzyme
activity of many genes that relate to triglyceride
biosynthesis.61Whether or not this pathway remains
operational in the setting of systemic insulin resistance
has not been completely addressed. Additionally, insulin
resistance could also reduce the concentrations of
lipoprotein lipase in peripheral tissues (ie, in adipose
tissue more than muscle).62This alteration in lipoprotein
lipase, however, seems to contribute less to the
hypertriglyceridaemia than does the overproduction of
VLDL. Nevertheless, hypertriglyceridaemia is an
excellent reflection of the insulin resistant condition and
is one of the important criteria for diagnosis of the
The other major lipoprotein disturbance in the
metabolic syndrome is a reduction in HDL cholesterol.
This reduction is a consequence of changes in HDL
composition and metabolism. In the presence of
hypertriglyceridaemia, a decrease in the cholesterol
content of HDL results from decreases in the cholesteryl
ester content of the lipoprotein core with variable
increases in triglyceride making the particle small and
dense, a function in part of cholesteryl ester transfer
protein.63This change in lipoprotein composition also
results in an increased clearance of HDL from the
circulation.64The relation of these changes in HDL to
insulin resistance are probably indirect, arising in
concert with the changes in triglyceride-rich lipoprotein
In addition to HDL, the composition of LDL is also
modified in a similar way. In fact, with fasting serum
triglycerides ?2·0 mmol/L, almost all patients have a
predominance of small dense LDL.65,66This change in
LDL composition is attributable to relative depletion of
unesterified cholesterol, esterified cholesterol, and
phospholipid with either no change or an increase in
LDL triglyceride.67,68Small dense LDL might be more
atherogenic than buoyant LDL because (1) it is more
toxic to the endothelium; (2) it is more able to transit
through the endothelial basement membrane; (3) it
adheres well to glycosaminoglycans; (4) it has increased
susceptibility to oxidation; and/or (5) it is more
selectively bound to scavenger receptors on monocyte-
derived macrophages;69,70however, this contention is not
entirely accepted.71In some studies, this alteration in
LDL composition is an independent risk factor for
cardiovascular disease.72However, more often this
association is not independent, but related to the
concomitant changes in other lipoproteins and other
The defects in insulin action in glucose metabolism
include deficiencies in the ability of the hormone to
suppress glucose production by the liver and kidney, and
to mediate glucose uptake and metabolism in insulin
sensitive tissues (ie, muscle and adipose tissue). The
relation between impaired fasting glucose or impaired
glucose tolerance and insulin resistance is well
supported by human, non-human primate, and rodent
www.thelancet.com Vol 365 April 16, 2005 1419
studies. To compensate for defects in insulin action,
insulin secretion and/or clearance must be modified to
sustain euglycaemia. If this compensation fails, defects
in insulin secretion predominate.
Insulin resistance in pancreatic islet ? cells implies
that signals that generate glucose-dependent insulin
secretion have been adversely modified, and fatty acids
are prime candidates. Although free fatty acids can
stimulate insulin secretion, increasing and prolonged
exposure to excessive concentrations results in falls in
insulin secretion.74The mechanism for this alteration
has been attributed to lipotoxicity through several
potential different mechanisms.75–77
Insulin also can feedback on its own secretion. The
importance of this system comes from experiments in
rodents in which the insulin receptor is tissue-
specifically deleted. When the insulin receptor is deleted
in skeletal muscle, hyperglycaemia does not result;78
however, the ?-cell specific knockout of the insulin
receptor produces progressive glucose intolerance and
diabetes.79In people with genetic predispositions to
development of diabetes, the presumed stress of the
insulin resistant environment on ?-cell function causes
glucose intolerance and ultimately higher risk of
hypertension is well established,80and relates to several
different mechanisms. First, it is important to note that
insulin is a vasodilator when given intravenously to
people of normal weight,81with secondary effects on
sodium reabsorption in the kidney.82Evidence indicates
that sodium reabsorption is increased in white people
but not Africans or Asians with the metabolic
syndrome.83In the setting of insulin resistance, the
vasodilatory effect of insulin can be lost,84but the renal
effect on sodium reabsorption preserved.85Fatty acids
themselves can mediate relative vasoconstriction.86
Insulin also increases the activity of the sympathetic
nervous system,87, an effect that might also be preserved
in the setting of the insulin resistance.88However, when
assessed by concentrations of fasting insulin, HOMA or
the HOMA insulin resistance index (HOMA-IR),16
insulin resistance contributes only modestly to the
increased prevalence of hypertension in the metabolic
between insulin resistance and
Insulin resistance is accompanied by many other
alterations that are not included in the diagnostic criteria
for the metabolic syndrome (panel). Increases in apo B
and C-III, uric acid, prothrombotic factors (fibrinogen,
plasminogen activator inhibitor 1), serum viscosity,
asymmetric dimethylarginine, homocysteine, white
blood cell count, pro-inflammatory cytokines, the
presence of microalbuminuria, non-alcoholic fatty liver
disease and/or non-alcoholic steatohepatitis, obstructive
sleep apnoea, and polycystic ovarian disease are all
associated with insulin resistance.
Non-alcoholic fatty liver disease (fatty liver) is
common; however, in non-alcoholic steatohepatitis both
triglyceride accumulation and inflammation coexist.90
Non-alcoholic steatohepatitis in particular is becoming
an important health problem that is present in 2–3% of
individuals in the USA and other western countries.91As
the incidence of overweight/obesity and the metabolic
syndrome increases, this disease could become one of
the more frequent causes of end stage liver disease and
Cigarette smoking92and sedentary lifestyle93can also
produce many of the major criteria of the syndrome and
beyond. Increases in apo B and C-III,94and non-
alcoholic steatohepatitis95are tied to the effects of fatty
acids on VLDL production by the liver, and in the case
of apo B and C-III provide evidence of an increased
of proatherogenic particles
Hyperuricaemia results from defects in insulin action
in the circulation.
www.thelancet.com Vol 365 April 16, 2005
Panel:Changes associated with insulin resistance
Increased apo B
Decreased apo A-1
Small dense LDL and HDL
Increased apo C-III
Increased plasminogen activator inhibitor 1
Increased white blood cell count
Increased interleukin 6
Increased tumour necrosis factor ?
Increased C-reactive protein
Increased asymmetric dimethylarginine
Increased uric acid
Polycystic ovaries syndrome
Obstructive sleep apnoea
on the renal tubular reabsorption of uric acid,96whereas
the increase in asymmetric dimethylarginine, an
endogenous inhibitor of nitric oxide synthase, relates to
endothelial pathophysiology in insulin resistant states
could be microalbuminuria.97
An extended form of
The association of the metabolic syndrome with
inflammation is well documented.98The increases in
proinflammatory cytokines including interleukin 6,
resistin, tumour necrosis factor ?
reflect overproduction by the
expanded adipose tissue mass (figure 2).100Evidence
suggests that monocyte-derived macrophages reside in
adipose tissue and might be at least in part the source of
the generation of proinflammatory cytokines locally and
in the systemic circulation.101,102There is increasing
evidence that insulin resistance in the liver, muscle, and
adipose tissue is not only associated with the abundance
of proinflammatory cytokines (and relative deficiency of
the anti-inflammatory cytokine adiponectin), but is a
direct result of this burden.91It remains unclear,
however, how much of the insulin resistance related to
the adipose tissue content of macrophages is paracrine
As a general index of inflammation, C-reactive protein
concentrations vary by ethnic origin and within ethnic
groups by fitness.103,104For instance, concentrations of
C-reactive protein were higher in healthy Indian Asians
than in European white people and were related to
greater central obesity and insulin resistance in Indian
Asians.104At present it remains unclear whether these
differences when adjusted for other covariates will relate
to different rates of development of diabetes and/or
Adiponectin is an anti-inflammatory cytokine that is
produced exclusively by adipocytes. Adiponectin both
enhances insulin sensitivity and inhibits many steps in
the inflammatory process.105In the liver, it inhibits both
the expression of hepatic gluconeogenic enzymes and
the rate of endogenous glucose production.106In muscle,
it increases glucose transport and enhances fatty acid
oxidation, effects that are partly due to the activation of
concentrations of adiponectin could be important in
producing changes in metabolism consistent with the
metabolic syndrome,107,95with reductions in adiponectin
also apparent in people with the syndrome.108,96The
relative contribution of the deficiency in this cytokine
versus the overabundance of the proinflammatory
cytokines remains unclear. Some reports link low
concentrations of adiponectin to myocardial infarction109
and to the progression of subclinical coronary heart
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Small dense LDL
Small dense LDL
Figure 2: Pathophysiology of the metabolic syndrome (insulin resistance)
A: Free fatty acids (FFA) are released in abundance from an expanded adipose tissue mass. In the liver, FFA produce
an increased production of glucose, triglycerides and secretion of very low density lipoproteins (VLDL). Associated
lipid/lipoprotein abnormalities include reductions in high density lipoprotein (HDL) cholesterol and an increased
density of low density lipoproteins (LDL). FFA also reduce insulin sensitivity in muscle by inhibiting insulin-
mediated glucose uptake. Associated defects include a reduction in glucose partitioning to glycogen and increased
lipid accumulation in triglyceride (TG). Increases in circulating glucose and to some extent FFA increase pancreatic
insulin secretion resulting in hyperinsulinemia. Hyperinsulinaemia may result in enhanced sodium reabsorption
and increased sympathetic nervous system (SNS) activity and contribute to the hypertension as might increased
levels of circulating FFA.
B: Superimposed and contributory to the insulin resistance produced by excessive FFA is the paracrine and
endocrine effect of the proinflammatory state. Produced by a variety of cells in adipose tissue including adipocytes
and monocyte-derived macrophages, the enhanced secretion of interleukin-6 (IL-6) and tumor necrosis factor
alpha (TNF-?) among others results in more insulin resistance and lipolysis of adipose tissue triglyceride stores to
circulating FFA. IL-6 and other cytokines also are increased in the circulation and may enhance hepatic glucose
production, the production of VLDL by the liver and insulin resistance in muscle. Cytokines and FFA also increase
the production of fibrinogen and plasminogen activator inhibitor-1 (PAI-1) by the liver that complements the
overproduction of PAI-1 by adipose tissue. This results in a pro-thrombotic state. Reductions in the production of
the anti-inflammatory and insulin sensitizing cytokine adiponectin are also associated with the metabolic
syndrome and may contribute to the pathophysiology of the syndrome. PAI1=plasminogen activator inhibitor 1.
FFA=free fatty acids.
www.thelancet.com Vol 365 April 16, 2005
Beyond insulin resistance
Despite the substantial amount of evidence in support of
the notion that the metabolic syndrome is an insulin
resistance syndrome, quantification of insulin action in
vivo is not always strongly related to the presence of the
syndrome.111Several key questions are raised. First, if the
metabolic syndrome is a consequence of only insulin
resistance, is the definition appropriately constructed?
Second, is it possible that the current components and
their relation to the metabolic syndrome exist as three-
factor or four-factor aggregates—eg, insulin or glucose,
lipids or lipoproteins, blood pressure, and obesity
assessments (BMI, waist circumference)?112Third, do
other mechanisms remain to be discovered? And fourth,
if other mechanisms exist, do some components of the
syndrome need to be grouped with insulin resistance
and the others separately?
An alternative concept suggested by Unger113to explain
the metabolic syndrome is leptin resistance.113In
general, conditions in which leptin deficiency or
resistance are present are associated with triglyceride
accumulation in non-adipose organs (eg, liver, muscle,
and the islets).113This pathophysiology could relate to the
absence of down regulation of sterol response element
binding protein 1c by leptin114and/or the inability of
leptin to activate AMP-kinase in muscle.115Leptin also
seems to lower insulin secretion,116but leptin resistance
could relate to the hyperinsulinaemia that develops in
the setting of the metabolic syndrome before defects in
insulin secretion lead to the development of diabetes.117
Management of metabolic syndrome
The presence of the metabolic syndrome carries
increased risk for cardiovascular disease10,118and type 2
Some affected people are at high or
moderately high risk for major cardiovascular disease
events in the short term (?10 years); others are at less
risk in the short term, but carry a fairly high long-term
In the latter group, therapeutic lifestyle
modification is first-line therapy, but if 10-year risk is
high, drug therapy to modify cardiovascular disease risk
factors might be required as well.120For this reason, a
10-year risk assessment is needed in all those who have a
diagnosis of the metabolic syndrome.
Several approaches are available to estimate 10-year
risk for cardiovascular disease (or coronary heart
disease).120,121These risk engines incorporate the major
risk factors for cardiovascular disease: cigarette
smoking, blood pressure, total cholesterol, HDL
cholesterol, age, sex, and sometimes other risk factors
such as diabetes. In some guidelines,120diabetes counts
as a high-risk condition independent of other risk
factors. According to the Framingham Heart Study,
adding abdominal obesity, triglycerides, and fasting
glucose to the Framingham risk algorithm yields little or
no increase in power of prediction; 119,122however, in the
Quebec Cardiovascular Study concentrations of fasting
insulin, triglycerides, apo B, small dense LDL, and waist
circumference all proved important determinants.11,123
The PROCAM risk algorithm124
triglycerides and a family history of premature coronary
heart disease.124Whether adding further factors—
abdominal obesity, apo B, small LDL, C-reactive protein,
and insulin and glucose concentrations—to the current
definition of the metabolic syndrome will enhance risk
prediction for cardiovascular disease has not been
rigorously tested, but elevated C-reactive protein seems
to carry increased risk for coronary heart disease beyond
The finding of IFG or IGT nonetheless signifies a
higher risk for type 2 diabetes.127It is noteworthy that
when the NCEP:ATP-III and WHO criteria for the
metabolic syndrome were compared in subjects with or
without a history of cardiovascular disease, the age-
adjusted prevalence was 23·9% according to the ATP III
definition and 25·1% according to the WHO
definition.128Estimates differed substantially for some
subgroups—in African-American men, the WHO
estimate was 24·9%, compared with the ATP III
estimate of 16·5%. Yet, NCEP:ATP-III and WHO
criteria were similar at identifying the relative risk for
cardiovascular disease in the presence and absence of
the metabolic syndrome.
The incidence of cardiovascular disease in Asian
people is much less than in white people,129and the
Framingham risk algorithm reportedly overestimates
the risk of coronary heart disease in Asians.130This
finding suggests that evaluation of cardiovascular
disease risk based on a database of mainly white people
could be inappropriate for Asians. This possibility
certainly needs to be considered seriously in the
diagnosis and approach to prevention and treatment of
cardiovascular disease in these populations with the
Management of underlying risk factors
Although the metabolic syndrome appears to be more
common in people who are genetically susceptible,
acquired underlying risk factors—being overweight or
obese, physical inactivity, and an atherogenic diet—
commonly elicit clinical manifestations. Clinical
management should first focus on management of these
underlying risk factor independent of an individual’s
risk status (table 2).
Abdominal obesity is the body fat parameter most
closely associated with the metabolic syndrome.120,131As
noted previously, definitions of abdominal obesity vary
according to population. Clinical management of obesity
should adhere to several well-established principles.5
Effective weight reduction improves all risk factors
associated with the metabolic syndrome,132and it will
further reduce the risk for type 2 diabetes.133,134
Weight reduction is best achieved by behavioural
change to reduce energy intake and by physical activity
to enhance energy expenditure.132Caloric intake should
be reduced by 500–1000 calories per day to produce a
weight loss of 0·5–1·0 kg per week. The goal is to reduce
bodyweight by about 7–10% over 6–12 months, followed
by long-term behaviour modification and maintenance
of increased physical activity. To date, weight reduction
drugs have not been particularly effective for treatment
of obesity; on the other hand, in the USA, bariatric
surgery has been used increasingly to treat patients with
morbid obesity.135The effectiveness and safety of
bariatric surgery in patients with the metabolic
syndrome has been quite encouraging with 95% of
patients free of the syndrome 1 year after the
operation.136Longer periods of observation after weight
stabilisation are, however, needed.
Current guidelines137recommend practical, regular, and
moderate regimens of physical activity (eg, 30 min
sustained physical activity will improve all risk factors of
the metabolic syndrome.27,93Sedentary activities in
leisure time should be replaced by more active behaviour
such as brisk walking, jogging, swimming, biking,
golfing, and team sports. Combination of weight loss
and exercise to reduce the incidence of type 2 diabetes in
patients with glucose intolerance should not be
daily). Regular and
Atherogenic and diabetogenic diets
There is general agreement that persons with the
metabolic syndrome should adhere to a set of dietary
principles: low intakes of saturated fats, trans fats, and
cholesterol, reduced consumption of simple sugars, and
increased intakes of fruits, vegetables, and whole
grains.120More controversial is the relative amounts of
carbohydrate and unsaturated fats. Some investigators
favour lower fat intakes, whereas others recommend
higher fat diets.139Low-fat diets have been advocated to
promote weight reduction,140
monounsaturated fat intakes diminish postprandial
glycaemia, reduce serum triglycerides, and raise
concentrations of HDL-cholesterol.139
Management of metabolic risk factors
The metabolic risk factors that are part of the definition
of the syndrome include atherogenic dyslipidaemia,
elevated blood pressure, and elevated plasma glucose;
however, we will also consider the prothrombotic state
and a proinflammatory state. Effective treatment of the
underlying risk factors will reduce the severity of all of
the metabolic risk factors. However, if people are found
to be at particularly high risk or if a given risk factor is
severely abnormal, drug therapy may be necessary.
Approaches to each risk factor can be considered briefly.
This condition consists of elevations of triglycerides and
apo B, small LDL particles, and low HDL cholesterol.
inhibitors (statins) reduce risk for major cardiovascular
disease events in high risk patients with the metabolic
syndrome by reducing all apo B containing lipo-
Fibrates mitigate atherogenic dyslipi-
daemia and appear to reduce the risk for cardiovascular
disease in patients with the metabolic syndrome.143Their
use in combination with statins is particularly attractive,
but carries some increased risk for myopathy. This
increase in risk with a statin plus fibrate has been
particularly noted for the fibrate gemfibrozil.144A higher
risk from the combination could result from pharmaco-
logical interaction of gemfibrozil with the statin to
produce higher concentrations of the statin in the
www.thelancet.com Vol 365 April 16, 2005 1423
Therapeutic goals and recommendations
Abdominal obesityGoal: 10% weight loss first year, thereafter continued weight loss or maintain weight
Recommendation: caloric restriction; regular exercise; behaviour modification
Goal: regular moderate-intensity physical activity
Recommendation: 30–60 min moderate-intensity exercise daily
Goals: reduced intakes of saturated fats, trans fats and cholesterol
Recommendations: saturated fat ,7% of total calories; reduce trans fat; dietary cholesterol
?200mg daily; total fat 25–35% of total calories
Goal and recommendation: complete smoking cessation
Goals: High-risk patients*—LDL cholesterol ?1 g/L (2·6 mmol/L)
Therapeutic option—LDL cholesterol ?0·7 g/l (1·8 mmol/L)
Moderately high-risk patients†—LDL cholesterol ?1·3 g/L (3·4 mmol/L)
Therapeutic option—LDL cholesterol ?1 g/L (2·6 mmol/L)
Moderate-risk patients‡—LDL cholesterol ?1·3 g/L (3·4 mmol/L)
Recommendations: high-risk patients—lifestyle therapies§ and LDL-cholesterol lowering
drug to achieve recommended goal
Moderately high-risk patients—lifestyle therapies; add LDL-cholesterol lowering drug if
necessary to achieve recommended goal when baseline LDL cholesterol ?1·3 g/L
Moderate risk patients—lifestyle therapies; add LDL-cholesterol lowering drug if necessary
to achieve recommended goal when baseline LDL cholesterol ?1·6 g/L (4·1 mmol/L)
Goal: insufficient data to establish goal
Recommendation: High-risk patients—consider adding fibrate (preferably fenofibrate) or
nicotinic acid to LDL-lowering drug therapy
Elevated blood pressure Goals: blood pressure ?135/?85 mm Hg. For diabetes or chronic
kidney disease: blood pressure ?130/80 mm Hg
Recommendation: lifestyle therapies; add antihypertensive drug(s) when necessary to
achieve goals of therapy
Elevated glucoseGoal: maintenance or reduction in fasting glucose if ?1 g/L (5·5 mmol/L). Haemoglobin
A1C ?7·0% for diabetes
Recommendation: lifestyle therapies; add hypoglycaemic agents as necessary to achieve
goal fasting glucose or haemoglobin A1C
Prothrombotic stateGoal: reduction of prothrombotic state
Recommendation: High-risk patients—initiate low-dose aspirin therapy; consider
clopidogrel if aspirin is contraindicated
Moderately high-risk patients—consider low-dose aspirin therapy
Proinflammatory state Recommendations: no specific therapies
High triglyceride or
*High-risk patients: those with established atherosclerotic cardiovascular disease, diabetes, or 10-year risk for coronary heart
disease ?20%. ‡Moderately high-risk patients: those with 10-year risk for coronary heart disease 10–20%. ‡Moderate risk
patients: those with metabolic syndrome but 10-year risk for coronary heart disease ?10%. §Lifestyle therapies include weight
reduction, regular exercise, and antiatherogenic diet.
Table 2: Targets, goals, and recommendations for clinical management of metabolic syndrome
combined with a statin is less likely to cause myopathy
than is gemfibrozil.146The combination of a statin with a
low dose of nicotinic acid is an alternative to a statin plus
fibrate.147Although low doses of nicotinic acid can be
tolerated by most patients with the metabolic syndrome,
some patients might find it difficult to take on a long-
term basis. For patients with diabetes, nicotinic acid can
raise glucose concentrations, but as long as the dose is
kept relatively low, it does not produce substantial
deterioration of glycaemic control in most patients.148
Recent studies suggest that fenofibrate
Mild elevations of blood pressure can often be controlled
with lifestyle changes, but if hypertension persists
despite such therapies, antihypertensive drugs are
usually required.149The benefits of blood pressure
reduction for reducing major cardiovascular disease has
been well established through many clinical trials,149
including those in patients with type 2 diabetes.150Some
investigators believe that
enzyme (ACE) inhibitors or angiotension receptor
blockers are better first-line therapy for metabolic
syndrome patients, especially when type 2 diabetes is
present,151but the issue of the most effective drug has
not been entirely resolved.152
Insulin resistance and hyperglycaemia
Lifestyle intervention can reduce the risk for conversion
of IFG/IGT to type 2 diabetes.133,134,138Preliminary reports
indicate that metformin or thiazolidinediones also
reduce risk for type 2 diabetes in people with IFG or
IGT.133,153On the other hand, no clinical trial evidence
indicates that these drugs will reduce risk for
cardiovascular disease events in patients with the
metabolic syndrome. Currently,
thiazolidinediones are not recommended solely for the
prevention of diabetes. The cost-effectiveness of this
approach has not been established.
When patients with type 2 diabetes concomitantly
exhibit other features of the metabolic syndrome they
are at particularly high risk for cardiovascular disease.
Clinical trials show that high priority should be given to
treatment of dyslipidaemia154
Glycaemic control to a haemoglobin A1c of less than 7%
will reduce microvascular complications and could
decrease risk for macrovascular disease as well.155
The use of lipid-altering, antihypertensive and
hypoglycaemic drugs can modify insulin sensitivity and
bodyweight. Metformin and thiazolidinediones improve
insulin sensitivity but have discrepant effects on
bodyweight: metformin reduces weight whereas
thiazolidinediones increase it.156,157The increase in
weight in patients treated with insulin secretagogues
(sulfonylureas and repaglinide or nateglinide) and
insulin results mostly from improved glycaemic control
and increases in caloric intake as a result of
hypoglycaemia. With the exception of nicotinic acid,
lipid-altering drugs do not affect insulin sensitivity or
weight, whereas the effect of antihypertensive drugs is
more complex. ?-adrenergic blockers and thiazide
diuretics might decrease insulin sensitivity but less so at
low doses, whereas ACE inhibitors and angiotensin II
receptor antagonists have variable effects.151By uncertain
mechanisms, ACE inhibitors and angiotensin II
receptor antagonists seem to decrease the incidence of
type 2 diabetes.158
This risk factor is characterised by elevations of
fibrinogen, plasminogen activator inhibitor 1, and
possibly other coagulation factors. The only available
clinical approach to an increased risk for arterial
thrombosis in patients with diabetes is low-dose aspirin
or other antiplatelet drugs.159These drugs are universally
recommended unless contraindicated in patients with
established cardiovascular disease. Their efficacy in
patients with type 2 diabetes in the absence of
cardiovascular disease has not been established through
clinical trials, although they are widely recommended.
In other people with the metabolic syndrome, aspirin
prophylaxis is a therapeutic option when the risk for
cardiovascular disease events is judged to be relatively
This condition can be identified by elevated cytokines
(eg, TNF? and interleukin 6) as well as by elevations in
acute phase reactants
fibrinogen). An elevated concentration of C-reactive
protein is widely thought to be an indicator of a
proinflammatory state and to be associated with higher
risk for both cardiovascular disease and diabetes.161
Lifestyle therapies, especially weight reduction, will
reduce concentrations of this cytokine and thus can
mitigate an underlying inflammatory state.162No specific
anti-inflammatory drugs are available to treat the
proinflammatory state. However, several drugs used to
treat other metabolic risk factors—statins, fibrates, and
thiazolidinediones—have been reported to reduce
concentrations of C-reactive proteins.163,164The drugs,
however, cannot be recommended specifically to reduce
a proinflammatory state independent of other risk
(C-reactive protein and
Conflict of interest statement
R H Eckel has a Merck grant, “The Impact of HMG Co-A Reductase
Inhibitors on C-reactive Protein in Patients with Type 2 Diabetes”.
P Z Zimmet is a consultant for Novartis, GlaxoSmithKline, Bristol-
Myers Squibb, Abbott, and Merck, and has received payment for
speaking for E Merck, Bayer, Sanofi, AstraZeneca, and Kissei. In the
past 5 years, S M Grundy has been an investigator on research grants
awarded to the University of Texas Southwestern Medical Center (UT
Southwestern), Dallas, Texas, for the study of statins (Merck),
fenofibrate (Abbott), and nicotinic acid (Kos). Additionally, during this
period, he has given lectures approved by UT Southwestern to health
professionals on cholesterol management, in which cholesterol-
www.thelancet.com Vol 365 April 16, 2005
lowering drugs were discussed and for which he received honoraria that
were funded either directly or indirectly (through continuing medical
education programmes) from the following companies: Merck (statins),
Pfizer (statins), Sankyo (colesevelam), Schering Plough (ezetimibe), Kos
(nicotinic acid), Abbott (fenofibrate), Fournier (fenofibrate), Bristol-
Myers Squibb (statins), and AstraZeneca (statins).
We thank Dalan Jensen and Julie Morris for their assistance in
producing this Seminar. No funding was received except for a small
payment from The Lancet.
1 Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome:
prevalence in worldwide populations. Endocrinol Metab Clin
North Am 2004; 33: 351–75.
2 Kylin E. Studien. Hypertonie-Hyperglykamie-
Hyperurikamiesyndrome. Zentralblatt fur innere Medizin (44).
3Vague J. La differenciation sexuelle, facteur determinant des
formes de l’obesite. Presse Med. 1947; 30: 339–40.
4Zimmet P, Alberti KG, Shaw J. Global and societal implications of
the diabetes epidemic. Nature 2001; 414: 782–87.
5 Grundy SM, Hansen B, Smith SC Jr, Cleeman JI, Kahn RA.
Clinical management of metabolic syndrome: report of the
American Heart Association/National Heart, Lung, and
Blood Institute/American Diabetes Association conference
on scientific issues related to management. Circulation 2004;
6 Reaven GM. Banting lecture 1988. Role of insulin resistance in
human disease. Diabetes 1988; 37: 1595–607.
7 DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted
syndrome responsible for NIDDM, obesity, hypertension,
dyslipidemia, and atherosclerotic cardiovascular disease.
Diabetes Care 1991; 14: 173–94.
8 Kaplan NM. The deadly quartet. Upper-body obesity, glucose
intolerance, hypertriglyceridemia, and hypertension.
Arch Intern Med 1989; 149: 1514–20.
9 Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity
and mortality associated with the metabolic syndrome.
Diabetes Care 2001; 24: 683–89.
10 Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic
syndrome and total and cardiovascular disease mortality in middle-
aged men. JAMA 2002; 288: 2709–16.
11 Lemieux I, Pascot A, Couillard C, et al. Hypertriglyceridemic waist:
a marker of the atherogenic metabolic triad (hyperinsulinemia;
hyperapolipoprotein B; small, dense LDL) in men? Circulation
2000; 102: 179–84.
12 Reaven GM. Insulin resistance, cardiovascular disease, and the
metabolic syndrome: how well do the emperor’s clothes fit?
Diabetes Care 2004; 27: 1011–12.
13 Alberti KG, 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.
14 Executive Summary of The Third Report of The National
Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, And Treatment of High Blood Cholesterol In Adults
(Adult Treatment Panel III). JAMA 2001; 285: 2486–97.
15 Balkau B, Charles MA. Comment on the provisional report from
the WHO consultation. European Group for the Study of Insulin
Resistance (EGIR). Diabet Med 1999; 16: 442–43.
16 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF,
Turner RC. Homeostasis model assessment: insulin resistance and
beta-cell function from fasting plasma glucose and insulin
concentrations in man. Diabetologia 1985; 28: 412–19.
17 Einhorn D, Reaven GM, Cobin RH. American College of
Endocrinology position statement on the insulin resistance
syndrome. Endocr Pract 2002; 9: 236–52.
18 Eckel RH. Obesity: mechanisms and clinical management.
Philadelphia (PA): Lippincott Williams & Wilkins, 2003.
19 World Health Organisation, Western Pacific Region. The Asia-
Pacific Perspective. Redefining Obesity and its Treatment.
20 Appropriate body-mass index for Asian populations and its
implications for policy and intervention strategies. Lancet 2004;
21 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic
syndrome among US adults: findings from the third National
Health and Nutrition Examination Survey. JAMA 2002; 287:
22 Azizi F, Salehi P, Etemadi A, Zahedi-Asl S. Prevalence of metabolic
syndrome in an urban population: Tehran Lipid and Glucose
Study. Diabetes Res Clin Pract 2003; 61: 29–37.
23 Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose
tolerance among children and adolescents with marked obesity.
N Engl J Med 2002; 346: 802–10.
24 Wei JN, Sung FC, Lin CC, Lin RS, Chiang CC, Chuang LM.
National surveillance for type 2 diabetes mellitus in Taiwanese
children. JAMA 2003; 290: 1345–50.
25 Sung RY, Tong PC, Yu CW, et al. High prevalence of insulin
resistance and metabolic syndrome in overweight/obese
preadolescent Hong Kong Chinese children aged 9–12 years.
Diabetes Care 2003; 26: 250–51.
26 Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic
syndrome in children and adolescents. N Engl J Med 2004; 350:
27 Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH.
Prevalence of a metabolic syndrome phenotype in adolescents:
findings from the third National Health and Nutrition Examination
Survey, 1988–1994. Arch Pediatr Adolesc Med 2003; 157: 821–27.
28 Girman CJ, Rhodes T, Mercuri M, et al. The metabolic syndrome
and risk of major coronary events in the Scandinavian Simvastatin
Survival Study (4S) and the Air Force/Texas Coronary
Atherosclerosis Prevention Study (AFCAPS/TexCAPS).
Am J Cardiol 2004; 93: 136–41.
29 Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic
syndrome on mortality from coronary heart disease, cardiovascular
disease, and all causes in United States adults. Circulation 2004;
30 Hanson RL, Imperatore G, Bennett PH, Knowler WC.
Components of the “metabolic syndrome” and incidence of type 2
diabetes. Diabetes 2002; 51: 3120–27.
31 Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT,
Lakka TA. Metabolic syndrome and development of diabetes
mellitus: application and validation of recently suggested
definitions of the metabolic syndrome in a prospective cohort
study. Am J Epidemiol 2002; 156: 1070–77.
32 Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K,
Pyorala K. Prevalence of the metabolic syndrome and its relation to
all-cause and cardiovascular mortality in nondiabetic European
men and women. Arch Intern Med 2004; 164: 1066–76.
33 Bonora E, Targher G, Formentini G, et al. The Metabolic
Syndrome is an independent predictor of cardiovascular disease
in Type 2 diabetic subjects. Prospective data from the Verona
Diabetes Complications Study. Diabet Med 2004; 21: 52–58.
34 Ninomiya JK, L’Italien G, Criqui MH, Whyte JL, Gamst A,
Chen RS. Association of the metabolic syndrome with history
of myocardial infarction and stroke in the third national health
and nutrition examination survey. Circulation 2004; 109: 42–46.
35 Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially
modifiable risk factors associated with myocardial infarction in
52 countries (the INTERHEART study): case-control study.
Lancet 2004; 364: 937–52.
36 Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ,
Haffner SM. Does the metabolic syndrome improve identification
of individuals at risk of type 2 diabetes and/or cardiovascular
disease? Diabetes Care 2004; 27: 2676–81.
37 Eckel RH. Lipoprotein lipase. A multifunctional enzyme
relevant to common metabolic diseases. N Engl J Med 1989; 320:
38 Jensen MD, Caruso M, Heiling V, Miles JM. Insulin regulation of
lipolysis in nondiabetic and IDDM subjects. Diabetes 1989; 38:
39 Kim YB, Shulman GI, Kahn BB. Fatty acid infusion selectively
impairs insulin action on Akt1 and protein kinase C lambda/zeta
but not on glycogen synthase kinase-3. J Biol Chem 2002; 277:
www.thelancet.com Vol 365 April 16, 2005 1425
40 Chavez JA, Knotts TA, Wang LP, et al. A role for ceramide, but not
diacylglycerol, in the antagonism of insulin signal transduction by
saturated fatty acids. J Biol Chem 2003; 278: 10297–303.
41 Samuel VT, Liu ZX, Qu X, et al. Mechanism of hepatic insulin
resistance in non-alcoholic fatty liver disease. J Biol Chem 2004;
42 Boden G, Shulman GI. Free fatty acids in obesity and type 2
diabetes: defining their role in the development of insulin
resistance and beta-cell dysfunction. Eur J Clin Invest 2002;
32 (suppl 3): 14–23.
43 Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS,
Goldstein JL. Insulin selectively increases SREBP-1c mRNA
in the livers of rats with streptozotocin-induced diabetes.
Proc Natl Acad Sci USA 1999; 96: 13656–61.
44 Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of
mitochondria in human skeletal muscle in type 2 diabetes.
Diabetes 2002; 51: 2944–50.
45 Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI.
Impaired mitochondrial activity in the insulin-resistant offspring
of patients with type 2 diabetes. N Engl J Med 2004; 350: 664–71.
46 Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction
in the elderly: possible role in insulin resistance. Science 2003; 300:
47 Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress
links obesity, insulin action, and type 2 diabetes. Science 2004; 306:
48 Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S. The
metabolically obese, normal-weight individual revisited. Diabetes
1998; 47: 699–713.
49 Lee S, Janssen I, Ross R. Interindividual variation in abdominal
subcutaneous and visceral adipose tissue: influence of
measurement site. J Appl Physiol 2004; 97: 948–54.
50 Aubert H, Frere C, Aillaud MF, Morange PE, Juhan-Vague I,
Alessi MC. Weak and non-independent association between
plasma TAFI antigen levels and the insulin resistance syndrome.
J Thromb Haemost 2003; 1: 791–97.
51 Bajaj M, Banerji MA. Type 2 diabetes in South Asians: a
pathophysiologic focus on the Asian-Indian epidemic.
Curr Diab Rep 2004; 4: 213–18.
52 Tanaka S, Horimai C, Katsukawa F. Ethnic differences in
abdominal visceral fat accumulation between Japanese, African-
Americans, and Caucasians: a meta-analysis. Acta Diabetol 2003;
40 (suppl 1): S302–S304.
53 Guo Z, Hensrud DD, Johnson CM, Jensen MD. Regional
postprandial fatty acid metabolism in different obesity phenotypes.
Diabetes 1999; 48: 1586–92.
54 Garg A, Misra A. Lipodystrophies: rare disorders causing
metabolic syndrome. Endocrinol Metab Clin North Am 2004; 33:
55 Hegele RA. Monogenic forms of insulin resistance: apertures that
expose the common metabolic syndrome. Trends Endocrinol Metab
2003; 14: 371–77.
56 Dallongeville J, Helbecque N, Cottel D, Amouyel P, Meirhaeghe A.
The Gly16—?Arg16 and Gln27—?Glu27 polymorphisms of
beta2-adrenergic receptor are associated with metabolic syndrome
in men. J Clin Endocrinol Metab 2003; 88: 4862–66.
57 Fumeron F, Aubert R, Siddiq A, et al. Adiponectin gene
polymorphisms and adiponectin levels are independently
associated with the development of hyperglycemia during a 3-year
period: the epidemiologic data on the insulin resistance syndrome
prospective study. Diabetes 2004; 53: 1150–57.
58 Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G.
Interaction between free fatty acids and insulin in the acute
control of very low density lipoprotein production in humans.
J Clin Invest 1995; 95: 158–66.
59 Lewis GF, Steiner G. Acute effects of insulin in the control of
VLDL production in humans. Implications for the insulin-
resistant state. Diabetes Care 1996; 19: 390–93.
60 Taghibiglou C, Rashid-Kolvear F, Van Iderstine SC, et al.
Hepatic very low density lipoprotein-ApoB overproduction is
associated with attenuated hepatic insulin signaling and
overexpression of protein-tyrosine phosphatase 1B in a fructose-
fed hamster model of insulin resistance. J Biol Chem 2002; 277:
61 Foufelle F, Ferre P. New perspectives in the regulation of hepatic
glycolytic and lipogenic genes by insulin and glucose: a role for
the transcription factor sterol regulatory element binding protein-
1c. Biochem J 2002; 366: 377–91.
62 Eckel RH, Yost TJ, Jensen DR. Alterations in lipoprotein lipase in
insulin resistance. Int J Obes Relat Metab Disord 1995; 19 (suppl 1):
63 Murakami T, Michelagnoli S, Longhi R, et al. Triglycerides are
major determinants of cholesterol esterification/transfer and HDL
remodeling in human plasma. Arterioscler Thromb Vasc Biol 1995;
64 Brinton EA, Eisenberg S, Breslow JL. Increased apo A-I and apo A-
II fractional catabolic rate in patients with low high density
lipoprotein-cholesterol levels with or without hypertriglyceridemia.
J Clin Invest 1991; 87: 536–44.
65 de Graaf J, Hendriks JC, Demacker PN, Stalenhoef AF.
Identification of multiple dense LDL subfractions with enhanced
susceptibility to in vitro oxidation among hypertriglyceridemic
subjects. Normalization after clofibrate treatment.
Arterioscler Thromb 1993; 13: 712–19.
66 Manzato E, Zambon S, Zambon A, Cortella A, Sartore G,
Crepaldi G. Levels and physicochemical properties of lipoprotein
subclasses in moderate hypertriglyceridemia. Clin Chim Acta 1993;
67 Halle M, Berg A, Baumstark MW, Konig D, Huonker M, Keul J.
Influence of mild to moderately elevated triglycerides on low
density lipoprotein subfraction concentration and composition in
healthy men with low high density lipoprotein cholesterol levels.
Atherosclerosis 1999; 143: 185–92.
68 Kwiterovich PO Jr. Clinical relevance of the biochemical,
metabolic, and genetic factors that influence low-density
lipoprotein heterogeneity. Am J Cardiol 2002; 90: 30i–47i.
69 Packard CJ. LDL subfractions and atherogenicity: an hypothesis
from the University of Glasgow. Curr Med Res Opin 1996; 13:
70 Krauss RM. Dense low density lipoproteins and coronary artery
disease. Am J Cardiol 1995; 75: 53B–57B.
71 Lada AT, Rudel LL. Associations of low density lipoprotein
particle composition with atherogenicity. Curr Opin Lipidol 2004;
72 Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a
new pathophysiological mechanism for coronary artery disease
regression: hepatic lipase-mediated changes in LDL density.
Circulation 1999; 99: 1959–64.
73 Sacks FM, Campos H. Clinical review 163: Cardiovascular
endocrinology: Low-density lipoprotein size and cardiovascular
disease: a reappraisal. J Clin Endocrinol Metab 2003; 88: 4525–32.
74 Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH.
Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent
diabetes mellitus of obese rats: impairment in adipocyte-beta-cell
relationships. Proc Natl Acad Sci USA 1994; 91: 10878–82.
75 Yaney GC, Corkey BE. Fatty acid metabolism and insulin secretion
in pancreatic beta cells. Diabetologia 2003; 46: 1297–312.
76 Boucher A, Lu D, Burgess SC, et al. Biochemical mechanism of
lipid-induced impairment of glucose-stimulated insulin secretion
and reversal with a malate analogue. J Biol Chem 2004; 279:
77 Joseph JW, Koshkin V, Saleh MC, et al. Free fatty acid induced
beta-cell defects are dependent on uncoupling protein 2 expression.
J Biol Chem 2004; 279: 15049–56.
78 Bruning JC, Michael MD, Winnay JN, et al. A muscle-specific
insulin receptor knockout exhibits features of the metabolic
syndrome of NIDDM without altering glucose tolerance. Mol Cell
1998; 2: 559–69.
79 Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA,
Kahn CR. Tissue-specific knockout of the insulin receptor in
pancreatic beta cells creates an insulin secretory defect similar to
that in type 2 diabetes. Cell 1999; 96: 329–39.
80 Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance
in essential hypertension. N Engl J Med 1987; 17: 350–57.
81 Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD.
Insulin-mediated skeletal muscle vasodilation is nitric oxide
dependent. A novel action of insulin to increase nitric oxide
release. J Clin Invest 1994; 94: 1172–79.
www.thelancet.com Vol 365 April 16, 2005
82 DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ. The
effect of insulin on renal handling of sodium, potassium, calcium,
and phosphate in man. J Clin Invest 1975; 55: 845–55.
83 Barbato A, Cappuccio FP, Folkerd EJ, et al. Metabolic syndrome
and renal sodium handling in three ethnic groups living in
England. Diabetologia 2004; 47: 40–46.
84 Tooke JE, Hannemann MM. Adverse endothelial function and the
insulin resistance syndrome. J Intern Med 2000; 247: 425–31.
85 Kuroda S, Uzu T, Fujii T, et al. Role of insulin resistance in the
genesis of sodium sensitivity in essential hypertension.
J Hum Hypertens 1999; 13: 257–62.
86 Tripathy D, Mohanty P, Dhindsa S, et al. Elevation of free fatty
acids induces inflammation and impairs vascular reactivity in
healthy subjects. Diabetes 2003; 52: 2882–87.
87 Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL.
Hyperinsulinemia produces both sympathetic neural activation and
vasodilation in normal humans. J Clin Invest 1991; 87: 2246–52.
88 Egan BM. Insulin resistance and the sympathetic nervous system.
Curr Hypertens Rep 2003; 5: 247–54.
89 Hanley AJ, Karter AJ, Festa A, et al. Factor analysis of metabolic
syndrome using directly measured insulin sensitivity: The Insulin
Resistance Atherosclerosis Study. Diabetes 2002; 51: 2642–47.
90 Choudhury J, Sanyal AJ. Insulin resistance and the pathogenesis of
nonalcoholic fatty liver disease. Clin Liver Dis 2004; 8: 575–94, ix.
91 Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic
steatohepatitis: summary of an AASLD Single Topic Conference.
Hepatology 2003; 37: 1202–19.
92 Eliasson B, Attvall S, Taskinen MR, Smith U. The insulin
resistance syndrome in smokers is related to smoking habits.
Arterioscler Thromb 1994; 14: 1946–50.
93 Lakka TA, Laaksonen DE, Lakka HM, et al. Sedentary lifestyle, poor
cardiorespiratory fitness, and the metabolic syndrome.
Med Sci Sports Exerc 2003; 35: 1279–86.
94 Onat A, Hergenc G, Sansoy V, et al. Apolipoprotein C-III, a strong
discriminant of coronary risk in men and a determinant of the
metabolic syndrome in both genders. Atherosclerosis 2003; 168:
95 Medina J, Fernandez-Salazar LI, Garcia-Buey L, Moreno-Otero R.
Approach to the pathogenesis and treatment of nonalcoholic
steatohepatitis. Diabetes Care 2004; 27: 2057–66.
96 Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Relationship
between resistance to insulin-mediated glucose uptake, urinary
uric acid clearance, and plasma uric acid concentration. JAMA
1991; 266: 3008–11.
97 Rowley K, O’Dea K, Best JD. Association of albuminuria and the
metabolic syndrome. Curr Diab Rep 2003; 3: 80–86.
98 Sutherland J, McKinnley B, Eckel RH. The Metabolic Syndrome
and Inflammation. Metabolic Syndr Rel Disord 2004; 2: 82–104.
99 Fernandez-Real JM, Ricart W. Insulin resistance and chronic
cardiovascular inflammatory syndrome. Endocr Rev 2003; 24:
100 Trayhurn P, Wood IS. Adipokines: inflammation and the
pleiotropic role of white adipose tissue. Br J Nutr 2004; 92:
101 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL,
Ferrante AW Jr. Obesity is associated with macrophage
accumulation in adipose tissue. J Clin Invest 2003; 112: 1796–808.
102 Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays
a crucial role in the development of obesity-related insulin
resistance. J Clin Invest 2003; 112: 1821–30.
103 LaMonte MJ, Durstine JL, Yanowitz FG, et al. Cardiorespiratory
fitness and C-reactive protein among a tri-ethnic sample of women.
Circulation 2002; 106: 403–06.
104 Chambers JC, Eda S, Bassett P, et al. C-reactive protein, insulin
resistance, central obesity, and coronary heart disease risk in
Indian Asians from the United Kingdom compared with European
whites. Circulation 2001; 104: 145–50.
105 Nawrocki AR, Scherer PE. The delicate balance between fat and
muscle: adipokines in metabolic disease and musculoskeletal
inflammation. Curr Opin Pharmacol 2004; 4: 281–89.
106 Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous
glucose production is inhibited by the adipose-derived protein
Acrp30. J Clin Invest 2001; 108: 1875–81.
107 Yamauchi T, Hara K, Kubota N, et al. Dual roles of
adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic
adipokine. Curr Drug Targets Immune Endocr Metabol Disord 2003; 3:
108 Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin
and metabolic syndrome. Arterioscler Thromb Vasc Biol 2004; 24:
109 Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB,
Rimm EB. Plasma adiponectin levels and risk of myocardial
infarction in men. JAMA 2004; 291: 1730–37.
110 Maahs DM, Ogden LG, Kinney GL, et al. Low plasma adiponectin
levels predict progression of coronary artery calcification. Circulation
2005; 111: 747–53.
111 Hanley AJ, Wagenknecht LE, D’Agostino RB Jr, Zinman B, Haffner
SM. Identification of subjects with insulin resistance and beta-cell
dysfunction using alternative definitions of the metabolic syndrome.
Diabetes 2003; 52: 2740–47.
112 Shen BJ, Todaro JF, Niaura R, et al. Are metabolic risk factors one
unified syndrome? Modeling the structure of the metabolic
syndrome X. Am J Epidemiol 2003; 157: 701–11.
113 Unger RH. Lipid overload and overflow: metabolic trauma and the
metabolic syndrome. Trends Endocrinol Metab 2003; 14: 398–403.
114 Kakuma T, Lee Y, Higa M, et al. Leptin, troglitazone, and
the expression of sterol regulatory element binding proteins in
liver and pancreatic islets. Proc Natl Acad Sci USA 2000; 97: 8536–41.
115 Minokoshi Y, Kahn BB. Role of AMP-activated protein kinase in
leptin-induced fatty acid oxidation in muscle. Biochem Soc Trans
2003; 31: 196–201.
116 Cases JA, Gabriely I, Ma XH, et al. Physiological increase in plasma
leptin markedly inhibits insulin secretion in vivo. Diabetes 2001; 50:
117 Seufert J. Leptin effects on pancreatic beta-cell gene expression and
function. Diabetes 2004; 53 (suppl 1): S152–S158.
118 Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP.
National Cholesterol Education Program versus World Health
Organization metabolic syndrome in relation to all-cause and
cardiovascular mortality in the San Antonio Heart Study. Circulation
2004; 110: 1251–57.
119 Wilson PW. Estimating cardiovascular disease risk and the
metabolic syndrome: a Framingham view. Endocrinol Metab Clin
North Am 2004; 33: 467–81.
120 Third Report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III) final report.
Circulation 2002; 106: 3143–21.
121 Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year
risk of fatal cardiovascular disease in Europe: the SCORE project.
Eur Heart J 2003; 24: 987–1003.
122 Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C.
Definition of metabolic syndrome: Report of the National Heart,
Lung, and Blood Institute/American Heart Association conference
on scientific issues related to definition. Circulation 2004; 109:
123 Lamarche B, Tchernof A, Mauriege P, et al. Fasting insulin and
apolipoprotein B levels and low-density lipoprotein particle size as
risk factors for ischemic heart disease. JAMA 1998; 279: 1955–61.
124 Assmann G, Cullen P, Schulte H. Simple scoring scheme for
calculating the risk of acute coronary events based on the 10-year
follow-up of the prospective cardiovascular Munster (PROCAM)
study. Circulation 2002; 105: 310–15.
125 Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the
metabolic syndrome, and risk of incident cardiovascular events:
an 8-year follow-up of 14 719 initially healthy American women.
Circulation 2003; 107: 391–97.
126 Rutter MK, Meigs JB, Sullivan LM, D’Agostino RB Sr, Wilson PW.
C-reactive protein, the metabolic syndrome, and prediction of
cardiovascular events in the Framingham Offspring Study.
Circulation 2004; 110: 380–85.
127 Meigs JB, Williams K, Sullivan LM, et al. Using metabolic syndrome
traits for efficient detection of impaired glucose tolerance. Diabetes
Care 2004; 27: 1417–26.
128 Ford ES, Giles WH. A comparison of the prevalence of the metabolic
syndrome using two proposed definitions. Diabetes Care 2003; 26:
www.thelancet.com Vol 365 April 16, 2005 1427
Seminar Download full-text
129 van den Hoogen PC, Feskens EJ, Nagelkerke NJ, Menotti A,
Nissinen A, Kromhout D. The relation between blood pressure and
mortality due to coronary heart disease among men in different
parts of the world. Seven Countries Study Research Group.
N Engl J Med 2000; 342: 1–8.
130 Liu J, Hong Y, D’Agostino RB Sr, et al. Predictive value for the
Chinese population of the Framingham CHD risk assessment tool
compared with the Chinese Multi-Provincial Cohort Study. JAMA
2004; 291: 2591–99.
131 Carr DB, Utzschneider KM, Hull RL, et al. Intra-abdominal fat is a
major determinant of the National Cholesterol Education Program
Adult Treatment Panel III criteria for the metabolic syndrome.
Diabetes 2004; 53: 2087–94.
132 Clinical Guidelines on the Identification, Evaluation, and
Treatment of Overweight and Obesity in Adults—The Evidence
Report. National Institutes of Health. Obes Res 1998; 6 (suppl 2):
133 Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the
incidence of type 2 diabetes with lifestyle intervention or
metformin. N Engl J Med 2002; 346: 393–403.
134 Zimmet P, Shaw J, Alberti KG. Preventing Type 2 diabetes and
the dysmetabolic syndrome in the real world: a realistic view.
Diabet Med 2003; 20: 693–702.
135 Brolin RE. Bariatric surgery and long-term control of morbid
obesity. JAMA 2002; 288: 2793–96.
136 Lee WJ, Huang MT, Wang W, Lin CM, Chen TC, Lai IR. Effects of
obesity surgery on the metabolic syndrome. Arch Surg 2004; 139:
137 Thompson PD, Buchner D, Pina IL, et al. Exercise and physical
activity in the prevention and treatment of atherosclerotic
cardiovascular disease: a statement from the Council on Clinical
Cardiology (Subcommittee on Exercise, Rehabilitation, and
Prevention) and the Council on Nutrition, Physical Activity, and
Metabolism (Subcommittee on Physical Activity). Circulation 2003;
138 Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2
diabetes mellitus by changes in lifestyle among subjects with
impaired glucose tolerance. N Engl J Med 2001; 344: 1343–50.
139 Grundy SM, Abate N, Chandalia M. Diet composition and the
metabolic syndrome: what is the optimal fat intake? Am J Med
2002; 113 (suppl 9B): 25S–29S.
140 Klein S, Sheard NF, Pi-Sunyer X, et al. Weight management
through lifestyle modification for the prevention and management
of type 2 diabetes: rationale and strategies. A statement of the
American Diabetes Association, the North American Association
for the Study of Obesity, and the American Society for Clinical
Nutrition. Am J Clin Nutr 2004; 80: 257–63.
141 Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR,
Kjekshus J. Influence of low high-density lipoprotein cholesterol
and elevated triglyceride on coronary heart disease events and
response to simvastatin therapy in 4S. Circulation 2001; 104:
142 Pyorala K, Ballantyne CM, Gumbiner B, et al. Reduction of
cardiovascular events by simvastatin in nondiabetic coronary heart
disease patients with and without the metabolic syndrome:
subgroup analyses of the Scandinavian Simvastatin Survival Study
(4S). Diabetes Care 2004; 27: 1735–40.
143 Rubins HB. Triglycerides and coronary heart disease: implications
of recent clinical trials. J Cardiovasc Risk 2000; 7: 339–45.
144 Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with
HMG-CoA reductase inhibitors and gemfibrozil combination
therapy. Pharmacoepidemiol Drug Saf 2004; 13: 417–26.
145 van Puijenbroek EP, Du Buf-Vereijken PW, Spooren PF,
van Doormaal JJ. Possible increased risk of rhabdomyolysis during
concomitant use of simvastatin and gemfibrozil. J Intern Med 1996;
146 Bergman AJ, Murphy G, Burke J, et al. Simvastatin does not have a
clinically significant pharmacokinetic interaction with fenofibrate
in humans. J Clin Pharmacol 2004; 44: 1054–62.
147 Bays HE, McGovern ME. Once-daily niacin extended
release/lovastatin combination tablet has more favorable effects on
lipoprotein particle size and subclass distribution than atorvastatin
and simvastatin. Prev Cardiol 2003; 6: 179–88.
148 Grundy SM, Vega GL, McGovern ME, et al. Efficacy, safety, and
tolerability of once-daily niacin for the treatment of dyslipidemia
associated with type 2 diabetes: results of the assessment of
diabetes control and evaluation of the efficacy of niaspan trial.
Arch Intern Med 2002; 162: 1568–76.
149 Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the
Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure. Hypertension 2003; 42:
150 Tight blood pressure control and risk of macrovascular and
microvascular complications in type 2 diabetes: UKPDS 38. UK
Prospective Diabetes Study Group. BMJ 1998; 317: 703–13.
151 Julius S, Majahalme S, Palatini P. Antihypertensive treatment of
patients with diabetes and hypertension. Am J Hypertens 2001; 14:
152 Mogensen CE, Cooper ME. Diabetic renal disease: from recent
studies to improved clinical practice. Diabet Med 2004; 21: 4–17.
153 Buchanan TA, Xiang AH, Peters RK, et al. Preservation of
pancreatic beta-cell function and prevention of type 2 diabetes by
pharmacological treatment of insulin resistance in high-risk
hispanic women. Diabetes 2002; 51: 2796–803.
154 Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent
clinical trials for the National Cholesterol Education Program Adult
Treatment Panel III guidelines. Circulation 2004; 110: 227–39.
155 Standards of medical care in diabetes. Diabetes Care 2004;
27 (suppl 1): S15–S35.
156 Fonseca V. Effect of thiazolidinediones on body weight in patients
with diabetes mellitus. Am J Med 2003; 115 (suppl 8A): 42S–48S.
157 Setter SM, Iltz JL, Thams J, Campbell RK. Metformin
hydrochloride in the treatment of type 2 diabetes mellitus: a clinical
review with a focus on dual therapy. Clin Ther 2003; 25: 2991–3026.
158 Scheen AJ. Prevention of type 2 diabetes mellitus through
inhibition of the Renin-Angiotensin system. Drugs 2004; 64:
159 Colwell JA. Antiplatelet agents for the prevention of cardiovascular
disease in diabetes mellitus. Am J Cardiovasc Drugs 2004; 4:
160 Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for
Primary Prevention of Cardiovascular Disease and Stroke: 2002
Update: Consensus Panel Guide to Comprehensive Risk Reduction
for Adult Patients Without Coronary or Other Atherosclerotic
Vascular Diseases. American Heart Association Science Advisory
and Coordinating Committee. Circulation 2002; 106: 388–91.
161 Pearson TA, Mensah GA, Alexander RW, et al. Markers of
inflammation and cardiovascular disease: application to clinical
and public health practice: a statement for healthcare professionals
from the Centers for Disease Control and Prevention and the
American Heart Association. Circulation 2003; 107: 499–511.
162 van Dielen FM, Buurman WA, Hadfoune M, Nijhuis J, Greve JW.
Macrophage inhibitory factor, plasminogen activator inhibitor-1,
other acute phase proteins, and inflammatory mediators normalize
as a result of weight loss in morbidly obese subjects treated with
gastric restrictive surgery. J Clin Endocrinol Metab 2004; 89:
163 Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S.
Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor
therapy on high sensitive C-reactive protein levels. Circulation 2001;
164 Nesto R. C-reactive protein, its role in inflammation, Type 2
diabetes and cardiovascular disease, and the effects of insulin-
sensitizing treatment with thiazolidinediones. Diabet Med 2004; 21:
www.thelancet.com Vol 365 April 16, 2005