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The metabolic syndrome and cardiovascular

disease

Enzo Bonora

To cite this article: Enzo Bonora (2006) The metabolic syndrome and cardiovascular disease,
Annals of Medicine, 38:1, 64-80, DOI: 10.1080/07853890500401234

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Annals of Medicine. 2006; 38: 64–80

The metabolic syndrome and cardiovascular disease

ENZO BONORA

Department of Endocrinology and Metabolic Diseases, University of Verona Medical School, Verona, Italy

Abstract
The metabolic syndrome, which is very common in the general population, is defined by the clustering of several classic
cardiovascular risk factors, such as type 2 diabetes, hypertension, high triglycerides and low high-density lipoprotein
cholesterol (HDL). Central obesity and insulin resistance, which are the two underlying disorders of the syndrome, are
further risk factors for cardiovascular disease. Moreover, a panel of novel (non-traditional) risk factors are ancillary features
of the metabolic syndrome. They include biomarkers of chronic mild inflammation (e.g. C-reactive protein, CRP),
increased oxidant stress (e.g. oxidized low density lipoprotein, LDL), thrombophilia (e.g. plasminogen activator inhibitor-1,
PAI-1) and endothelial dysfunction (e.g. E-selectin). Therefore, subjects with the metabolic syndrome are potentially at
high risk of developing atherosclerosis and clinical cardiovascular events.
In recent years several longitudinal studies have confirmed that subjects with the metabolic syndrome present with
atherosclerosis and suffer from myocardial infarction and stroke at rates higher than subjects without the syndrome. The risk
of cardiovascular disease (CVD) is particularly high in women with the syndrome and in subjects with pre-existing diabetes,
CVD and/or high CRP. However, an increased risk is already present in subjects with a cluster of multiple mild
abnormalities. The risk related to the metabolic syndrome is definitely higher when subjects affected are compared to
subjects free of any metabolic abnormality.

Key words: Cardiovascular disease, central obesity, dyslipidaemia, hypertension, insulin resistance, metabolic syndrome,
microalbuminuria, type 2 diabetes mellitus

Historical background occurred from a pathophysiologically oriented

It has been known for a long time that metabolic
disorders such as adult-onset diabetes (nowadays
type 2 diabetes, T2DM), dyslipidaemia, gout and
obesity often occur together and cluster with
hypertension and cardiovascular disease (CVD).
This notion is deeply rooted in the history of
pioneers of medicine. However, the first descriptions
in modern literature of what today is called meta-
bolic syndrome were made by Kylin in Sweden (1),
Vague in France (2), and Avogaro and co-workers in
Italy (3). A giant step in the development of the
concepts surrounding the metabolic syndrome and a
strong impulse to the research in the field came from
Reaven (4), who was the first to provide a nosologic
dignity to the syndrome and pointed out the
importance of insulin resistance in its pathogenesis.
Interestingly, Reaven excluded obesity from the
features of the syndrome, whereas central (visceral)
obesity became a common denominator of the
syndrome in more recent years (5). In fact, in the
diagnosis of the syndrome, a methodological switch
approach, requiring the intriguing and more or less
accurate assessment of insulin resistance (6), to a
clinically oriented approach, based upon the assess-
ment of parameters easily available for any physician
and easier to standardize (5,7).
Since the beginning of the story of the metabolic
syndrome it seemed that CVD could be a potential
complication in subjects affected. In fact, sparse
clinical observations and, later, many epidemiologi-
cal data clearly indicated that the metabolic dis-
orders featuring the syndrome (e.g. diabetes and
hypertension) were factors strongly predisposing to
CVD. Therefore, it was postulated that subjects with
the syndrome have a high cardiovascular risk. This
concept was clearly expressed by Vague (2) in the
1940s and by Crepaldi and colleagues (3) in the
1960s. However, the unquestionable evidence came
many years later, when largely accepted sets of
diagnostic criteria for the syndrome were estab-
lished, and when these criteria were used in large
scale longitudinal studies. In fact, only in the last few
years there was a clear demonstration of an increased

Correspondence: Prof. Enzo Bonora, Endocrinologia e Malattie del Metabolismo, Ospedale Maggiore, Piazzale Stefani, 1, 37126 Verona, Italy. Fax: +39 045
917374. E-mail: enzo.bonora@univr.it – enzobonora@virgilio.it
ISSN 0785-3890 print/ISSN 1365-2060 online # 2006 Taylor & Francis
DOI: 10.1080/07853890500401234
 The metabolic syndrome and cardiovascular disease 65

incidence of cardiovascular events in the clinical

condition that now is universally called metabolic
syndrome but in the past has been called syndrome
X (4), insulin resistance syndrome (8), deadly
quartet (9) or with a variety of other names (10–12).
Classic features of the metabolic syndrome and
cardiovascular disease
According to a document issued by a committee of
experts of the World Health Organization in 1999,
the diagnostic criteria of the metabolic syndrome
are: impaired glucose regulation (impaired fasting
glucose, IFG, or impaired glucose tolerance, IGT, or
T2DM), insulin resistance, dyslipidaemia (high
triglycerides and/or low HDL cholesterol), hyper-
tension, obesity or central fat distribution, and
microalbuminuria (6) (Table I). According to the
experts of the National Cholesterol Education
Program-Adult Treatment Program III (NCEP-
ATPIII) the diagnostic criteria are: fasting hypergly-
cemia (IFG or T2DM), high triglycerides, low HDL
cholesterol, hypertension and excess of central fat
(7) (Table II). The latter criteria were recently
considered valid, with few changes, by a group of
experts gathered by the International Diabetes
Federation (8) (Table III). In the next paragraphs,
the most relevant data supporting the conclusion
that each of these abnormalities predisposes to CVD
are briefly reviewed. As a corollary, any cluster of
these abnormalities is logically a clinical condition
strongly predisposing to CVD.
Key messages
N The metabolic syndrome, which is a very
common clinical condition, is strongly
associated with cardiovascular morbidity
and mortality.
N The cardiovascular risk related to the
syndrome is higher in women (about 4-
fold) than in men (about 2-fold), and in
subjects with pre-existing diabetes or
cardiovascular disease.
N The increased cardiovascular risk is well
evident also when abnormalities composing
the syndrome are mild, and is definitely
higher (several-fold) if it is calculated using
as the reference category subjects without
any of the disorders composing the
syndrome and not subjects without the
metabolic syndrome.
Impaired glucose regulation and cardiovascular disease
Diabetes mellitus is one of the main risk factors for
atherosclerosis, as indicated by several studies,
including ours (13,14). Accordingly, diabetes is
associated with an increased cardiovascular morbid-
ity and mortality. This was clearly documented by
the Framingham Study (15), the Multiple Risk
Factors Intervention Trial (MRFIT) (16), the
Nurses’ Health Study (17) and many other long-
itudinal surveys (18–20). Diabetes increases the risk
of myocardial infarction about 2-fold in men and

Table I. Diagnostic criteria of the metabolic syndrome according to WHO (6).

Impaired glucose regulation (impaired fasting glucose, IFG; impaired glucose tolerance, IGT; type 2 diabetes mellitus) and/or
insulin resistance (under hyperinsulinaemic euglycaemic conditions, glucose uptake below lowest quartile for background population
under investigation), with
two or more of the components listed below:
N impaired glucose regulation
N insulin resistance
N hypertension (systolic >140 mmHg and/or diastolic >90 mmHg and/or anti-hypertensive treatment)
N dyslipidaemia (triglycerides >1.7 mmol/L and/or HDL cholesterol v0.9 mmol/L in men and v1.0 mmol/L in women)
N central obesity (WHR w0.90 in men and w0.85 in women and/or BMI w30)
N microalbuminuria (urinary albumin excretion w20 mg/min or urinary albumin/creatinine ratio w30 mg/g)

Table II. Diagnostic criteria of the metabolic syndrome according to NCEP-ATP III (7).

Any combination of three or more of the following clinical/biochemical abnormalities:

N fasting plasma glucose >6.1 mmol/L or known diabetes
N systolic blood pressure >130 and/or diastolic blood pressure >85 mmHg and/or treatment
N plasma triglycerides >1.7 mmol/L
N plasma HDL-cholesterol v1.03 mmol/L in men and v1.29 mmol/L in women
N waist circumference w102 cm in men or w88 cm in women.
66 E. Bonora

Table III. Diagnostic criteria of the metabolic syndrome according to IDF (8).

Central obesity (waist >94 cm in Europid men and >80 cm in Europid women; cut-offs are different for other ethnic groups), plus
any two of the following four abnormalities:
N raised triglycerides (>1.7 mmol/L) or specific treatment for this abnormality
N reduced HDL cholesterol (v1.03 mmol/L in men; v1.29 mmol/L in women) or specific treatment for this abnormality
N raised blood pressure (systolic >130 and/or diastolic >85 mmHg) or treatment for previously diagnosed hypertension
N raised fasting plasma glucose (>5.6 mmol/L) or previously diagnosed type 2 diabetes

about 4-fold in women. It also increases 2- to 4-fold
the risk of stroke and 4- to 9-fold the risk of
peripheral vascular disease, especially in women.
Moreover, after any acute cardiovascular event, the
presence of diabetes makes the outcome poorer
(21,22). Not surprisingly, CVD is the leading cause
of death in diabetes, largely exceeding cancer or
other diseases (23,24).
Interestingly, the pre-diabetic states of IFG and
IGT are already featured by an increased cardiovas-
cular risk (25,26). This is the main explanation of why
the improvement of glucose control in T2DM did not
result in a remarkable reduction of cardiovascular
disease (27). In fact, to achieve a substantial reduction
of CVD in diabetic individuals their glycaemic control
should be brought down to the condition of normo-
glycaemia. Accordingly, the plasma glucose values
representing the cut-off points of the condition of IFG
were recently lowered to 100 mg/dL (28).
Obesity, central fat distribution and cardiovascular
disease
Obese subjects experience CVD at a higher rate than
non-obese individuals (29,30). Nevertheless, there
has been a great debate on the independent role of
obesity in CVD. The debate is more academic than
substantial because the true issue is whether obese
people have an increased risk rather than whether
obesity is a risk factor per se, independently of the
disturbances commonly accompanying the excess of
body fat. In fact, obesity (and also overweight) is
often associated with T2DM, dyslipidaemia and
hypertension (31,33) and, through these classic risk
factors, it obviously conveys a higher cardiovascular
risk. Anyway, there are studies claiming also a role of
obesity independently of these factors (34,35), and
this further strengthens the message that excess
weight is deleterious and, therefore, should be
prevented and corrected.
The pioneer studies on central fat distribution and
CVD were carried out in Sweden more that 20 years
ago. These studies showed that subjects with high
waist-to-hip ratio (WHR) had an increased inci-
dence of CVD (36,37) and T2DM (38,39), which is
regarded as a special type of CVD by some
authorities (40). In fact, subjects with a predomi-
nantly central fat distribution have a constellation
of metabolic, haemodynamic and pro-coagulant
abnormalities (41,42), and are featured by insulin
resistance (43,44). Recently, the focus was on waist
as a risk factor because a high waist measurement is a
good proxy of an excess of visceral adipose tissue
(42,45,46), the fat depot which seems to convey the
greater risk of developing metabolic disturbances
and cardiovascular events (47,48).
Hypertriglyceridaemia and cardiovascular disease
There has been a great debate on the independent
role of hypertriglyceridaemia in CVD, but in recent
years a consensus was reached on the risk conveyed
by this abnormality in the lipid profile (49,50). More
recently, it has been reported that even mild
hypertriglyceridemia can significantly increase the
risk of myocardial infarction and stroke (51,52). The
increased cardiovascular risk related to hypertrigly-
ceridaemia is more evident in subjects with a
concomitant hypercholesterolaemia (53), but the
role of hypertriglyceridaemia in the so-called athero-
genic dyslipidaemia is no longer debated (54). The
risk associated with hypertriglyceridaemia is lower
than that associated with hypercholesterolaemia, but
triglyceride-rich lipoproteins (very-low-density lipo-
proteins, VLDL) seem to play a direct role in the
vascular injury. Moreover, an excess of these
particles has a crucial role in the genesis of small
dense low-density lipoproteins (LDL) (55), which
are very susceptible to oxidation and are implicated
in early stages of the atherosclerotic process (56),
and also in the genesis of lower concentrations of
high-density lipoproteins (HDL) (57).
Low HDL cholesterol and cardiovascular risk
Nowadays, low HDL cholesterol stands out among
major risk factors for CVD with a status not inferior
to high LDL cholesterol. Strong evidence on the
contribution of this abnormality in the lipoprotein
profile to the risk of CVD came initially from
the Framingham Study (58), but other longitu-
dinal surveys confirmed this finding (59,60). Low
HDL cholesterol is another feature of atherogenic
 The metabolic syndrome and cardiovascular disease 67

dyslipidaemia (54), which is typical of subjects with assessment of insulin resistance (HOMA-IR), a
central obesity and/or T2DM (61,62). HDL parti- surrogate measure well correlated with the gold
cles not only drive cholesterol from peripheral tissues standard measure of insulin sensitivity (95), and
(including the vasculature) to the liver (63) but also found that for one standard deviation increase in
exert anti-inflammatory and anti-oxidant actions in (log)HOMA-IR, the risk of developing a cardiovas-
the vascular wall (64). cular event was about 50% higher (OR 1.54, 1.14–
2.12, Pv0.001) (96). In the general population,
subjects in the top quartile of distribution of
Hypertension and cardiovascular risk
(log)HOMA-IR had a ,80% increase in the risk
The Framingham Study (65) as well as the MRFIT for CVD (OR 1.77, CI 1.03–3.02, P50.038), after
(66) and many other studies (67–69) have docu- adjusting for classic and non-traditional risk factors
mented the continuous increase in the risk of (Bonora et al. unpublished data).
myocardial infarction and stroke with increase in
blood pressure. More recently, it has been pointed
out that even a small increase in blood pressure can Other features of the metabolic syndrome are
predispose to clinical events (70). This is one of the novel cardiovascular risk factors
reasons why the cut-off values for diagnosing
Over the last decade many investigators, including
hypertension were recently reduced (71).
ourselves (97), reported that subjects with the
Hypertension is one of the factors which more
metabolic syndrome have a wide spectrum of
strongly damage the vascular wall, thus yielding an
additional biochemical abnormalities (Table IV).
endothelial dysfunction (72). The latter is the first
The long list of ancillary features of the metabolic
step in the atherosclerotic process (73) and can
syndrome includes higher levels of PAI-1, fibrino-
predict subsequent clinical vascular events (74,75).
gen, coagulation factors VII and VIII, von
Willebrand factor (vWF), apoprotein B, oxidized
Microalbuminuria and cardiovascular disease LDL, free fatty acids (FFA), urate, leukocytes, CRP,
A moderate increase in the urinary albumin excre-
Table IV. Ancillary (not diagnostic) features of the metabolic
tion rate (30 to 300 mg/day) is considered a
syndrome. These features are often but not necessarily found in
biochemical sign of incipient diabetic nephropathy subjects with the metabolic syndrome. The list is incomplete.
and a risk factor for subsequent development of
proteinuria and end-stage renal disease in diabetes Raised levels Reduced levels
(76). However, it has been repeatedly reported that PAI-1
microalbuminuria can also be considered a marker Fibrinogen
of endothelial dysfunction (77). Accordingly, in both Factor VII, factor VIII
diabetic and non-diabetic subjects microalbuminuria vonWillebrand factor
Apoprotein B Apoprotein A-1
is a risk factor of CVD (78,79). Interestingly, an Small dense LDL
increased risk of atherosclerosis was observed also Oxidized LDL
when albuminuria was in the top part of the range of Free fatty acids
normality (80). Urate
Leukocytes
CRP
Insulin resistance and cardiovascular disease ESR
Ferritin
Insulin resistance is associated with T2DM, obesity, Sialic acid
dyslipidaemia, hypertension (43,81–84). It is a a-1 Acid Glycoprotein
Amyloid A
common finding in several other clinical conditions
TNF-a
and can be found also in healthy subjects (85,86). IL-6
Several cross-sectional studies reported an indepen- Homocystein
dent association between insulin resistance of E-selectin
glucose metabolism, as assessed by various techni- P-selectin
ICAM-1
ques, and coronary, carotid or peripheral vascular VCAM-1
disease (87–91). More recently, longitudinal studies Leptin Adiponectin
suggested that insulin resistance can also predict Resistin
CVD independently of classic risk factors in Asymmetric dimethylarginine
GOT (AST)- GPT (ALT)
both non-diabetic and diabetic subjects (92–94).
Gamma-GT
In diabetic subjects we used homeostasis model
68 E. Bonora
erythrocyte sedimentation rate (ESR), sialic acid, a-
1 acid glycoprotein, ferritin, endothelial adhesion
molecules, homocystein, leptin, and lower levels of
apoprotein A-1, and adiponectin (97–114). Overall,
these abnormalities document chronic mild inflam-
mation, increased oxidant stress, thrombophilia and
endothelial dysfunction. Interestingly, most of these
abnormalities are associated with insulin resistance
(97,115–120). Moreover, all of these abnormalities
represent further risk factors for CVD and many of
them are thought to contribute causally to the
development of atherosclerosis and the occurrence
of clinical CVD in subjects with the meta-
bolic syndrome. In the next paragraphs the main
evidence supporting these conclusions are briefly
summarized.
Thrombosis, fibrinolysis and cardiovascular disease
Thrombus formation upon atherosclerotic plaques is
often the precipitating factor in the occurrence of
clinical cardiovascular events (121). Therefore a pro-
coagulant state and/or impaired fibrinolysis often play
a key role in the development of myocardial infarction
or stroke, the leading causes of death in western
countries. Fibrinogen and PAI-1 are among the
several potential markers of a pro-coagulant state
and an impaired fibrinolysis. Many reports pointed
out that higher fibrinogen levels represent a condition
of increased cardiovascular risk (122–124). Also high
PAI-1 concentrations turned out to be a risk factor
for CVD (125–127). In addition, other factors of
coagulation, e.g. factor VII and factor VIII, are able to
predict future cardiovascular events (128,129).
Apoprotein B, oxidized LDL, FFA and cardiovascular
disease
Several studies clearly demonstrated that high
concentrations of apoprotein B can predict CVD
(14,58,60,69,130–132). In some studies high apo-
protein B represented a risk factor even stronger
than total or LDL cholesterol. Each LDL particle
contains one molecule of apoprotein B. Therefore,
the higher the number of circulating apoprotein B
molecules, the higher is the number of LDL
circulating particles. In the metabolic syndrome,
serum LDL cholesterol is not significantly increased
(97), whereas apoprotein B levels are higher (97).
This means that the number of LDL particles is
increased in subjects with the metabolic syndrome
and that these particles are smaller and denser.
Experimental data showed that small dense LDL is
more susceptible to oxidation (56), and that oxidized
LDL particles play a crucial role in the initiation
and the progression of the atherosclerotic lesion
(56,133). Accordingly, the circulating levels of small
dense LDL and oxidized LDL are predictors of
cardiovascular events (134,135).
Increased concentrations of FFA are typically
observed in conditions of insulin resistance and
excess visceral fat (136). The experimental elevation
of circulating FFA impairs the endothelial function
(137). As previously mentioned, endothelial dys-
function is a predictor of clinical cardiovascular
events (74,75). Interestingly, higher FFA were
associated with sudden death (138), which is a
dramatic manifestation of CVD.
Urate and cardiovascular disease
Hyperuricaemia is a common finding in many
clinical conditions, including obesity, dyslipidaemia,
hypertension and T2DM (139). High serum urate is
an independent risk factor for cardiovascular events
(140–142). However, uric acid seems to participate
in the anti-oxidant defence of the body (143). This
finding suggested that hyperuricaemia might be just
a marker of an increased risk but without any causal
role. On the other hand, a pathogenetic role of urate
in the atherosclerotic process has been more recently
postulated (144).
Inflammatory markers and cardiovascular disease
In the last decade a number of experimental studies
documented that atherosclerosis is an inflammatory
process (145,146). Accordingly, circulating markers
of inflammation were reported to predict athero-
sclerosis and cardiovascular events. In particular
many studies showed that CRP is a biomarker
of future myocardial infarction as well as CVD
morbidity and mortality (147–149), and that its
power of prediction might be even stronger than that
of LDL cholesterol (150). Other markers of inflam-
mation were associated with atherosclerosis and
CVD. They include leukocytes, ESR, ferritin, and
others (151–155). Moreover, inflammatory cyto-
kines like tumour necrosis factor-a (TNF-a) and
Interleukin-6 (IL-6) have been associated with
subsequent cardiovascular events (156,157).
Adhesion molecules and cardiovascular disease
It is well known that one of the first steps in the
development of atherosclerosis is the adhesion of
monocytes to endothelium and the subsequent
migration of these cells in the subendothelial layer
where they differentiate into macrophages (158).
This process requires the interaction of circulating

monocytes with endothelial adhesion molecules like
E-selectin, P-selectin, intercellular adhesion mole-
cule-1 (ICAM-1), vascular cell adhesion molecule-1
(VCAM-1) and others (159). These molecules are
released into the circulating blood where they can be
measured. Higher levels of these molecules are
thought to represent endothelial dysfunction and
progressing atherosclerosis. In recent years a number
of longitudinal studies documented that serum levels
of these molecules can predict atherosclerosis and
CVD (160–163).
Adipokines and cardiovascular disease
Adipose tissue is now regarded as the greatest
endocrine gland of the body. In fact, adipocytes
secrete several molecules which act with autocrine,
paracrine and endocrine mechanisms (164). Among
the products of adipose cells are adipokines such as
leptin and adiponectin, two molecules which also
seem to have a strong impact on the vasculature.
Adiponectin, in particular, possesses several anti-
inflammatory effects (165,166). On the contrary
leptin seems to exert effects with a pro-atherosclerotic
potential (167,168). Preliminary studies indicated
that adiponectin is a marker of cardiovascular disease
with a protective meaning (the higher is adiponectin,
the lower is the risk) (169), whereas higher leptin
levels are associated with an increased risk (170).
Metabolic syndrome and cardiovascular
disease
The metabolic syndrome is very common (97,171–
174) and its prevalence and incidence are thought
likely to increase in the future, paralleling the
increase in the prevalence and incidence of obesity
(175) and T2DM (176). At present, several hundred
Table V. Risk of CHD morbidity or mortality in subjects with the metabolic syndrome.
No. of
First author: (Study) Country subjects
Bonora: (Bruneck study) Italy 888
Isooma: (Botnia study) Finland 3606
Lakka: (Kuopio study) Finland 1209
Sattar: (WOSCOPS) Scotland 6447
Hu: (DECODE) Europe 11,512
McNeill: (ARIC) USA 12,089
Hunt: (SAHS) USA 2815
Malik: (NHANES) USA 6255
OR5odds ratio; HR5hazard ratio; RR5relative risk. 95% C.I. are given in parentheses. See text for more details about the studies.
The metabolic syndrome and cardiovascular disease 69
million people, and perhaps more than one billion,
do have the metabolic syndrome throughout the
world (177). A fraction of these people have a full-
blown syndrome, with most or all of the abnormal-
ities featuring the metabolic syndrome well
expressed (i.e. diabetes, hypertension, dyslipidaemia
and obesity), others have only a cluster of mild
abnormalities (e.g. IFG, abdominal adiposity and
low HDL cholesterol) with a variety of possible
clinical/biochemical phenotypes and with a pheno-
type in continuous evolution, depending on changes
in life-style and, as a consequence, in insulin
sensitivity and body weight, the two major determi-
nants of the metabolic syndrome (97,178).
The majority of subjects with the metabolic
syndrome are thought to be at risk for CVD because
most of classic and non-classic clinical and bio-
chemical features of the syndrome are cardiovascular
risk factors. However, until an accepted set of
diagnostic criteria for the syndrome has been
established, it has been quite difficult to assess the
true cardiovascular risk in these individuals. After
the WHO criteria (6) and the NCEP-ATP III
criteria (7) had been issued, a number of studies
examined the incidence of atherosclerosis and CVD
in subjects with and without the metabolic syndrome
according to these criteria. Quite disappointingly,
in most of these studies modified WHO and/or
modified NCEP-ATP III criteria were used.
Moreover, the endpoints were often different.
Therefore, the results of these studies are not exactly
comparable. In the next paragraphs the most
relevant findings of these studies are presented,
and in Table V data on coronary heart disease
(CHD) are briefly summarized. More emphasis is
given to the results of the Bruneck study because,
within its frame, we have addressed several aspects
related to the metabolic syndrome and we examined
both atherosclerosis and clinical CVD.
Years of WHO criteria NCEP criteria
follow-up OR/HR/RR OR/HR/RR
5 2.03 (1.2–4.3) 1.50 (NS)
7 1.81 (1.24–2.65)
11 Men 2.87 (1.22–6.78) Men 4.16 (1.60–10.8)
5 Men 1.30 (1.00–1.67)
9 Men 2.26 (1.61–3.17)
Women 2.78 (1.57–4.94)
11 Men 1.46 (1.23–1.74)
Women 2.05 (1.59–2.64)
13 Men 1.15 (NS) Men 1.82 (1.14–2.91)
Women 2.83 (1.55–5.17) Women 4.65 (2.35–9.21)
13 2.02 (1.42–2.89)
70 E. Bonora
The Botnia study
This study examined Finnish subjects participating
in a project focusing on metabolic defects in families
with T2DM. A sub-study on the metabolic syn-
drome analyzed data from 4483 subjects aged 30–70
years who had T2DM (n51697), IFG and/or IGT
(n5798) or normal glucose regulation (NGR) with
various degree of insulin sensitivity (n51697) (179).
Therefore this is not a population-based study. In
these subjects the metabolic syndrome was diag-
nosed with slightly modified WHO criteria: it was
coded as present when insulin resistance (as assessed
by HOMA-IR) or abnormal glucose regulation
(IFG, IGT or T2DM) was associated with two
further abnormalities among obesity, hypertension,
dyslipidaemia or microalbuminuria. During a med-
ian follow-up of 6.9 years, cardiovascular death was
assessed in 3,606 subjects. The relative risk (RR)
of cardiovascular mortality associated with the
metabolic syndrome was 1.81 (C.I. 1.24–2.65,
P50.002), after adjusting for sex, age, LDL choles-
terol and smoking.
The Kuopio ischaemic heart disease risk factor study
In this study 1209 Finnish men aged 42 to 60 years
were randomly recruited from the general popula-
tion and followed up for a median of 11.9 years
(180). NCEP-ATP III or modified WHO criteria
(no microalbuminuria assessment; hyperinsulinae-
mia as a proxy of insulin resistance) were used for
diagnosing the metabolic syndrome. Diabetic sub-
jects were excluded from analyses. After adjusting
for age, family history of CHD, smoking and LDL
cholesterol, the RR of CHD mortality was 4.16
(1.60–10.8) when the metabolic syndrome was
diagnosed by NCEP-ATP III criteria, and 2.87
(1.22–6.78) when it was diagnosed by modified
WHO criteria. The corresponding figures for CVD
mortality were 2.52 (1.10–5.78) and 2.63 (1.37–
5.05), respectively. All these RRs were highly
significant.
The Bruneck study
This is a prospective population-based survey
examining 888 subjects aged 40–79 years of whom
those fulfilling the WHO criteria or the NCEP-ATP
III criteria for the metabolic syndrome were identi-
fied (181). As compared with controls, subjects with
the metabolic syndrome by WHO criteria had an
increased 5-year incidence and progression of
carotid atherosclerosis, after adjusting for several
confounders. Subjects with the metabolic syndrome
by these criteria also had an increased incidence of
CHD during follow-up. The multiple-adjusted odds
ratio (OR) for incident carotid plaques and for
incident carotid stenosis in subjects with the meta-
bolic syndrome as compared to controls were 1.5
(95% confidence intervals 1.1–2.1, P50.02) and 2.4
(C.I. 1.3–4.1, P50.01), respectively. The multiple-
adjusted odds ratio for incident CHD in subjects
with the metabolic syndrome was 2.3 (C.I. 1.2–4.3,
P50.01). When NCEP-ATPIII criteria were used
the multiple-adjusted risk of incident new plaques
(OR 1.30, P5NS) and incident carotid stenosis (OR
3.1, Pv0.001), as well as the multiple-adjusted risk
of incident CHD (OR 1.5, P5NS) were not super-
imposable but were similar to those we yielded when
using WHO criteria. Interestingly, both subjects
positive for the metabolic syndrome only by WHO
criteria and those positive only by NCEP-ATPIII
criteria were at greater risk (182). Therefore, none of
these sets of criteria seems superior to the other in
the definition of the cardiovascular risk. However,
NCEP-ATP III criteria identified only 50% of
subjects identified with the WHO criteria. Thus, a
greater number of subjects at risk are identified when
WHO criteria are used.
In our opinion, a major breakthrough related
to the concept of the metabolic syndrome is the
recognition of the high cardiovascular risk in sub-
jects with a cluster of mild abnormalities or with a
cluster of abnormalities that are not regarded
as driving forces in CVD (e.g. overweight or
higher plasma triglycerides). Accordingly, when we
excluded from the analysis subjects with dia-
betes and/or definite hypertension (treatment
and/or systolic blood pressure w160 and/or diastolic
blood pressure w95 mmHg) and focused on sub-
jects with mild abnormalities (IFG/IGT, mild
hypertension, along with dyslipidaemia, central
obesity, microalbuminuria and insulin resistance),
we found that none of the individual components
of the metabolic syndrome was an independent
predictor of carotid atherosclerosis or CHD but
that the metabolic syndrome was associated with a
4-fold increased risk of atherosclerosis and CHD
(182). These findings support the conclusion that a
focus on the coexistence of multiple mild abnorm-
alities allows one to identify a large number
of subjects at risk of atherosclerosis progression
and cardiovascular events who would be missed
if the focus were limited to major risk factors (e.g.
definite hypertension, diabetes, hypercholestero-
laemia). As a consequence, it seems that there
is a clear improvement in vascular risk pre-
diction when using the ‘metabolic syndrome
approach’.
 The metabolic syndrome and cardiovascular disease
The West of Scotland coronary prevention study
(WOSCOPS)
Within this trial on primary prevention of CHD by
pravastatin carried out in 6447 Scottish men, the
cardiovascular risk related to the metabolic syn-
drome was calculated (182). Modified NCEP-ATP
III criteria were used (body mass index (BMI)
replaced waist circumference as a marker of obesity).
Diabetic subjects were excluded. During a 4.9 year
follow-up subjects with the metabolic syndrome had
an unadjusted hazard ratio (HR) for CHD of 1.76
(1.44–2.15). The risk was slightly lower but still
significant (1.30, 1.00–1.67, P50.045) when the
model included as covariates age, smoking, systolic
blood pressure, total cholesterol to HDL-cholesterol
ratio and pravastatin treatment. When subjects with
no abnormality were the reference category, those
with three abnormalities (i.e. with the metabolic
syndrome) had an HR for CVD of 3.19 (1.98–5.12)
and those with four abnormalities had an HR of 3.65
(2.11–6.33).
The women’s health study (WHS)
In this intervention trial on primary prevention of
CVD by aspirin and vitamin E, 14,719 apparently
healthy women aged 45 years and over were
followed-up for 8 years (183). The metabolic
syndrome was diagnosed with modified NCEP-
ATP III criteria (BMI replaced waist circumference)
and women were stratified also for CRP (normal,
high). As compared with women without the
metabolic syndrome and with normal CRP
(v3 mg/l), those with the metabolic syndrome had
a RR of CVD events of 2.3 (1.6–3.3) when CRP was
normal, and 4.0 (3.0–5.4) when CRP was high. The
corresponding figures for CHD events were 3.1
(2.0–4.9) and 5.5 (3.8–8.0), respectively. As com-
pared to subjects without any abnormality, the risk
in women with three disorders (i.e. the metabolic
syndrome) was 4-fold higher when CRP was normal
and 7-fold higher when CRP was high.
The Verona diabetes complications study
Subjects with the metabolic syndrome, as defined
according to WHO criteria, were identified among
946 non-insulin-treated type 2 diabetic patients
examined within the Verona diabetes complications
study (184). Mean age was 64 and mean duration of
diabetes 9 years. At baseline and after a mean of 4.5
years follow-up, CVD was assessed by medical
history, physical examination, electrocardiogram
(ECG) and echo-duplex of carotid and lower limb
arteries. Death certificates and medical records of
71
subjects who died during the follow-up were care-
fully scrutinized in order to identify CVD deaths. In
statistical analyses, CVD was considered as an
aggregate end-point, including fatal and non-fatal
coronary, cerebrovascular and peripheral vascular
disease as well as ischaemic ECG abnormalities and
vascular lesions at the echo-duplex. The proportion
of subjects with the metabolic syndrome was very
high (92.3%). Among subjects free of CVD at the
baseline (n5559), CVD events during the follow-up
were significantly increased in patients with the
metabolic syndrome as compared with those without
it (19.9 % versus 3.9%, Pv0.001). Multiple logistic
regression analysis showed that, along with sex, age,
smoking and glycated hemoglobin (HbA1c), the
presence of the metabolic syndrome independently
predicted incident CVD and increased the risk of
about 5-fold (OR 4.89, 1.16–20.67, P50.031).
The DECODE study
This combined analysis of data from 11 prospective
European cohort studies included 6156 men and
5356 women without diabetes and aged 30 to 89
years (185). The median follow-up was 8.8 years
and the metabolic syndrome was diagnosed with
modified WHO criteria (microalbuminuria was not
assessed, and hyperinsulinaemia was used as a
surrogate of insulin resistance). Diabetic subjects
were excluded. In subjects with the metabolic
syndrome the HR for cardiovascular mortality was
2.26 (1.61–3.17) in men, and 2.78 (1.57–4.94) in
women, after adjusting for age, smoking and total
cholesterol. When hyperinsulinaemia was not con-
sidered and the diagnosis was made with an
approach similar to NCEP-ATP III criteria, the
corresponding figures were 1.74 (1.19–2.55) in men,
and 2.17 (1.13–4.19), in women, respectively.
The San Antonio heart study (SAHS)
This study was based upon the follow-up (average
12.7 years) of 2815 Hispanic and non-Hispanic
white subjects from San Antonio, Texas, USA, aged
25 to 64 years (186). The metabolic syndrome was
diagnosed by NCEP-ATP III criteria. The HR for
cardiovascular mortality was 1.82 (1.14–2.91) in
men and 4.65 (2.35–9.21) in women, after adjusting
for ethnicity and age. When modified WHO criteria
were used (no microalbuminuria assessment; hyper-
insulinaemia as a surrogate for insulin resistance) the
corresponding figures were 1.15 (0.72–1.86) in men
and 2.83 (1.55–5.17) in women. When subjects with
CVD at baseline were excluded from analysis, a
significant association of the metabolic syndrome
72 E. Bonora
with CVD was still found: NCEP-ATP III criteria
HR 1.81 (0.72–4.57) in men, and 3.93 (1.87–8.28)
in women; WHO criteria HR 1.15 (0.65–2.06) in
men, and 2.70 (1.36–5.37) in women.
The second national health and nutrition examination
survey (NHANES)
Subjects of the Second NHANES (n56255; age 30–
75 years) representative of 64 million adults in the
United States were followed-up for a mean of about
13 years (187). The metabolic syndrome was
diagnosed by modified NCEP-ATP III criteria
(BMI was used instead of waist circumference;
two-hour OGTT along with fasting plasma glucose
was used to identify impaired glucose regulation).
After adjusting for gender, age, smoking, physical
activity and LDL-cholesterol, the HR for CHD
mortality was 2.02 (1.42–2.89) and that for CVD
mortality was 1.82 (1.40–2.37) in subjects with the
metabolic syndrome as compared to subjects with-
out the syndrome, diabetes or CVD at baseline. In
those with the metabolic syndrome but without
diabetes the corresponding figures were 1.65 (1.10–
2.47) and 1.56 (1.15–2.12). When subjects without
any risk factors were used as the reference category,
the risk for CHD mortality in those with the
metabolic syndrome was higher (HR 3.51, 1.81–
6.81). In this analysis also having one to two risk
factors increased the risk of CHD mortality (HR
2.10, 1.05–4.19). In subjects with pre-existing
diabetes, the risk associated with the metabolic
syndrome was 3- to 5-fold higher, depending on
the reference category. The risk was 4- to 12-fold
higher in those with the metabolic syndrome and
pre-existing CVD, especially when diabetes was also
present.
The 4S and AFCAPS/TexCAPS
Post-hoc analyses of placebo data from the
Scandinavian Simvastatin survival study (4S) and
the Air Force/Texas coronary atherosclerosis pre-
vention study (AFCAPS/TexCAPS) were used to
estimate the long-term relative risk of CHD asso-
ciated with the metabolic syndrome, as assessed by
modified NCEP-ATP III criteria (188). Subjects
with diabetes mellitus were excluded. Placebo-
treated patients with the metabolic syndrome had a
risk of CHD about 1.5-fold higher in both 4S (HR
1.5; 1.2–1.8) and AFCAPS/TexCAPS (HR 1.4;
1.04–1.9). Therefore, the metabolic syndrome was
associated with increased risk of CHD both in
patients with hypercholesterolaemia and pre-existing
CHD (4S) and in subjects with low HDL cholesterol
but without CHD (AFCAPS/TexCAPS). Quite
surprisingly, the risk was not different in the two
categories.
The atherosclerosis risk in communities study (ARIC)
In this multicentre U.S. study 12,089 black and
white individuals aged 45–64 years were followed-up
for an average of 11 years (189). The metabolic
syndrome was diagnosed with NCEP criteria but
subjects with diabetes or CVD at baseline were
excluded. The risk of incident CHD was 1.5-fold
higher in men (HR 1.46, 1.23–1.74) and 2-fold
higher in women (HR 2.05, 1.59–2.64) with the
metabolic syndrome, after adjustment for centre,
race, age, smoking and LDL-cholesterol. Similar
association was found with stroke: HR in men 1.42
(0.96–2.11), HR in women 1.96 (1.28–3.00). As
compared to subjects without any abnormality,
women and men with three disorders (i.e. the
metabolic syndrome) had a 4-fold and a 2-fold
increase in CHD, respectively. The corresponding
increase in the risk in subjects with four disorders
was 7-fold and 2.5-fold in women and in men,
respectively.
The Framingham offspring study
This survey included 3037 men and women aged 26
to 82 years who were followed up for 7 years (190)
The metabolic syndrome was diagnosed by NCEP-
ATP III criteria. Subjects with diabetes and/or pre-
existing CVD were excluded. The end-points were
cardiovascular events, including angina, myocardial
infarction, stroke, transitory ischaemic attack, heart
failure and intermittent claudication. As compared
to subjects without the syndrome, those with the
metabolic syndrome had a sex-, age- and CRP-
adjusted HR for CVD of 1.8 (1.4–2.5). The risk was
higher in women (2.4, 1.1–5.4) than in men (1.8,
1.2–2.6).
The cardiovascular health study (CHS)
A total of 2175 American subjects from the
cardiovascular health study who were free of CVD
at baseline and were not taking antihypertensive or
lipid-lowering medications were followed up for
about 4 years (191). The metabolic syndrome was
assessed with modified-WHO and with NCEP-ATP
III criteria. When the metabolic syndrome was
defined with the latter criteria, the HR for CVD
(coronary and cerebrovascular events) was 2.04
(1.69–2.46), and when it was diagnosed with
WHO criteria the HR was 1.63 (1.33–2.01), after
 The metabolic syndrome and cardiovascular disease
adjusting for sex, age, smoking, LDL cholesterol and
family history of myocardial infarction. Interestingly,
when individual components of the syndrome were
included in the model, the HR still was significant
(HR 1.38; 1.06–1.79, Pv0.01). This means that
classic components of the syndrome do not explain
all the risk it conveys and, therefore, that the
assessment of its individual components without
focusing the presence of the syndrome might under-
estimate global risk of a given individual.
The Hoorn study
In this population-based Dutch study a cohort of
615 men and 749 women aged 50 to 75 years were
followed up for 10 years to evaluate fatal and non-
fatal CVD (192). The metabolic syndrome was
diagnosed by NCEP-ATP III and modified WHO
criteria, and also with those proposed by European
Group for the Study of Insulin Resistance (EGIR)
(193), and American College of Endocrinology
(ACE) (194). Subjects with diabetes and CVD at
baseline were excluded. The NCEP-ATP III defini-
tion was associated with about a 2-fold increase in
age-adjusted risk of fatal CVD in men and non-fatal
CVD in women. For the WHO, EGIR, and ACE
definitions, the HR were slightly lower. The risk
increased with the number of risk factors.
Studies with factor analysis
A number of studies used factor analysis to evaluate
whether the cluster of abnormalities featuring the
metabolic syndrome can predict CVD. In these
studies plasma insulin was assessed and used as a
proxy of insulin resistance. An insulin resistance
factor was generated by treating variables with factor
analysis. This factors generally included insulin,
glucose, triglycerides, BMI, WHR and blood pres-
sure, which are among the variables used to diagnose
the metabolic syndrome. Such an insulin resistance
factor was an independent predictor of subsequent
CHD and/or stroke in both non-diabetic and
diabetic subjects. In elderly non-diabetic men HR
for CHD associated with insulin resistance factor
was 1.33 (1.08–1.65) (195). In middle-age non-
diabetic men HR for CHD associated to insulin
resistance factor was 1.28 (1.10–1.50) and HR for
stroke was 1.64 (1.29–2.08) (196). In diabetic men
HR for CHD associated with insulin resistance
factor was 1.71 (1.08–2.71) (197). The results of
these studies are important because the components
of the metabolic syndrome were modelled as
continuous variables and no cut-offs were arbitrarily
imposed. Moreover, these studies pointed out the
73
potential role played by insulin resistance as a central
underlying disorder.
Conclusions
The risk of CVD in subjects with the metabolic
syndrome is 2- to 4-fold higher than in subjects
without the syndrome. The risk associated with the
syndrome is higher in women (about 4-fold) that in
men (about 2-fold). The risk is particularly high
when affected subjects have pre-existing diabetes
and/or CVD and/or chronic mild inflammation (high
CRP). Of note is that the cluster increases the risk
even when major risk factors, such as diabetes and
hypertension, are not present. However, it should be
underlined that in most studies carried out so far the
reference category was subjects without the syn-
drome and not subjects without any risk factor. In
fact, many among subjects without the syndrome
have one to two disorders and this misleadingly
attenuates the increase in the risk in subjects with the
metabolic syndrome. Interestingly, when subjects
without any disorders and subjects with multiple
disorders (three or more, i.e. with the metabolic
syndrome) were compared, the latter had a risk of
CVD several-fold higher. Therefore, the metabolic
syndrome is certainly a high risk condition but the
true risk of subjects affected is underestimated when
a dichotomous categorization is made (metabolic
syndrome yes versus no). This concept should be
carefully considered when criticisms of the syndrome
are made (198). In fact, the use of an appropriate
reference category is crucial before stating that the
risk of CVD in subjects with the metabolic syndrome
is not greater than the sum of the risk related to its
individual components. In this regard, the evaluation
of the number of risk factors clustering in the given
subject, and the comparison of these subjects to
those free of any disorder, give a better assessment of
true individual risk. Nevertheless, the ‘metabolic
syndrome approach’ remains valid because it pro-
vides a nosologic dignity for a very common clinical
condition which is often neglected when it is
composed of multiple minor disorders (central
adiposity, impaired fasting glucose, etc.). The
clustering of these minor disorders, however, is still
a risky condition. Moreover, the metabolic syn-
drome approach points out the existence of under-
lying pathogenic disorders of the cluster, i.e. central
obesity and insulin resistance. These underlying
disorders can be targeted by specific interventions in
order to prevent the metabolic syndrome in those
not affected yet, and CVD in those already affected.
The notion that treating the underlying disorders,
i.e. obesity and/or insulin resistance, with lifestyle
74 E. Bonora
changes or medication resulting in an amelioration
of several classic and ancillary components of the
metabolic syndrome (199–211) and, therefore, in a
substantial reduction of the cardiovascular risk,
deserves great emphasis.
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