Review Article

Metabolic syndrome and cardiovascular disease

Qing Qiao1,2, Weiguo Gao1,2, Lei Zhang1,2, Regzedmaa Nyamdorj1,2 and Jaakko Tuomilehto1,2,3

Abstract
Addresses The clustering of metabolic and pathophysiological cardiovascular risk factors has
1
Department of the Public Health, University long been recognized but it was Reaven who popularized the syndrome in the
of Helsinki, PL41, Mannerheimintie 172, Banting lecture of 1988. Since 1999, several major international or national
FIN-00014 Helsinki; organizations proposed their own definitions for the syndrome, named the metabolic
2
Diabetes and Genetic Epidemiology Unit,
National Public Health Institute, Helsinki; syndrome. The prevalence of the metabolic syndrome varies according
3
South Ostrobothnia Central Hospital, to definition, ethnicity and gender. The prevalence is under 20% among Chinese
Seinäjoki, Finland and Korean people but over 50% among Maori and Pacific Islanders in New
Zealand. People with the metabolic syndrome have 50–60% higher cardiovascular
Correspondence risk than those without. The absolute cardiovascular risk of the metabolic syndrome,
Dr Qing Qiao
however, is not necessarily higher than those of its individual components. The
Email: qing.qiao@ktl.fi
pathogenesis underlying the clustering of cardiovascular risk factors remains
This article was prepared at the invitation of unclear. Factors including genetic disposition, obesity, insulin resistance and
the Clinical Sciences Reviews Committee of inflammation have been suggested as being involved. Since the metabolic
the Association for Clinical Biochemistry syndrome is multifactorial in origin, strategies for reducing cardiovascular risk in
individuals with the metabolic syndrome involve the management of multiple risks.
Lifestyle changes are an effective first-line management; pharmacological
interventions for hypertension, diabetes and dyslipidaemia are in accordance with
established guidelines. Pharmacological and surgical therapies for obesity are
effective in selected patients. In this article we discuss the definitions, prevalence,
pathogenesis and management of the metabolic syndrome in relation to
cardiovascular risk.
Ann Clin Biochem 2007; 44: 232–263

Introduction diovascular disease (CVD). The cluster of risk factors

The clustering of metabolic and physiological
abnormalities was ¢rst described in 1923 by Kylin as
a syndrome consisting of the coexistence of hyper-
tension, hyperglycaemia and hyperuricaemia.1 In
1947 Vague noted the in£uence of body fat distribu-
tion on the development of metabolic abnormalities 2
but the real interest in the clustering of metabolic and
physiological abnormalities started in the 1980s.3--5
In 1988 Reaven described ‘syndrome X’as the cluster-
ing of the following abnormalities: resistance to insu-
lin-stimulated glucose uptake, hyperinsulinaemia,
hyperglycaemia, increased very low-density lipopro-
tein (VLDL) triglycerides, decreased high-density
lipoprotein cholesterol (HDL-C) and hypertension.6
Since then there has been a growing interest in this
co-occurrence of characteristics, which are individu-
ally known to be associated with increased risk of car-
of ‘syndrome X’ later become known as the ‘insulin
resistance syndrome’ 7 or ‘metabolic syndrome’.8 The
role of obesity and its central distribution in the meta-
bolic syndrome has continued to be a subject of some
debate. In Reaven’s original description obesity
was not considered a feature of ‘syndrome X’ but
could contribute to its development.6 Obesity -- parti-
cularly abdominal obesity -- is, however, generally
considered to be one of the components of the syn-
drome. More recently, several new components have
been proposed to belong to the syndrome,
including in£ammatory markers, microalbuminuria,
hyperuricaemia and abnormalities of ¢brinolysis and
coagulation.9
In this article we discuss the de¢nitions,
prevalence, pathogenesis and management of the
metabolic syndrome in relation to cardiovascular
risk.

232 r 2007 The Association for Clinical Biochemistry


Definitions of the metabolic syndrome
and their prevalence
Since 1998, ¢ve major de¢nitions for the metabolic syn-
drome have been approved by di¡erent expert groups:
by the World Health Organization (WHO) in 199810
and in a revised form in 1999;11 by the European Group
for Study of Insulin Resistance (EGIR) in 1999;12 by the
National Cholesterol Education Program Adult Treat-
ment Expert Panel III (NCEP) in 2001,13,14 further mod-
i¢ed in 2004;15 by the American Association of Clinical
Endocrinologists (AACE) in 2003;16,17 and by an Inter-
national Diabetes Federation (IDF) consensus group in
2005.18,19 The WHO and the EGIR de¢nitions have been
proposed primarily for research purposes and the
NCEP and AACE de¢nitions for clinical use. The AACE
de¢nition is less strict than others and was intended as
a guideline for physicians to de¢ne the metabolic syn-
drome. The IDF de¢nition was made in 2005 in an
attempt to unify existing de¢nitions. Major compo-
nents of the metabolic syndrome included in these de¢-
nitions are more or less similar but there are di¡erences
in the emphasis between the components and in their
individual diagnostic threshold values (Table 1). The
WHO de¢nition and the EGIR de¢nition emphasize the
primary importance of insulin resistance and glucose
intolerance, while the IDF de¢nition stresses the role
of central obesity. The NCEP criteria considered all ¢ve
factors included in the de¢nition equally. The di¡erence
in de¢nitions explains the di¡erence in the phenotypes
identi¢ed. The WHO de¢nition identi¢es more elderly
people who are glucose intolerant, while the NCEP de¢-
nition includes more subjects with dyslipidaemia.20
Individuals with the IDF de¢nition of the metabolic
syndrome are more obese than others (Diabetes Epide-
miology: Collaborative Analysis Of Diagnostic Criteria
in Europe (DECODE) study, unpublished data).
The prevalence of the metabolic syndrome varies
markedly depending on the de¢nitions used and popu-
lations studied (Tables 2--3, Figures 1--2). Among
2220--41 studies that used the original full de¢nition of
the NCEP, the prevalence of the metabolic syndrome
ranged from 5.6% in Chinese women in Hong Kong to
52.8% in Polynesian men in New Zealand (Table 2 and
Figure 1a). The prevalence was lowest among Chinese
and Korean people and highest among Maori and Paci-
¢c Islanders living in New Zealand in both men and
women. Of those 22 studies that used the original
NCEP de¢nition, ¢ve have estimated the prevalence
using the original IDF de¢nition in the same popula-
tion21,23,27,30,42 (Table 3, Figure 1b). The IDF de¢nition
yielded a higher prevalence of the metabolic syndrome
compared with the NCEP de¢nition in all these studies.
The prevalence of the metabolic syndrome is higher in
women than in men in Iranians, South Asians, Afri-
cans, Mexicans and Arabs, but lower in women than
Metabolic syndrome and cardiovascular disease 233
in men in Caucasians and Hispanics (Figure 2a--b)
using NCEP or IDF de¢nitions.
Anthropometric measurements for
obesity and cardiovascular disease risk
Obesity, as a major underlying risk factor for hypergly-
caemia, hypertension, dyslipidaemia and insulin resis-
tance, has been included in most de¢nitions of the
metabolic syndrome. The most commonly used anthro-
pometric measurements for obesity are body mass
index (BMI) indicating general obesity, waist circum-
ference (WC) and waist-to-hip ratio (WHR) as markers
for central obesity. Other indicators such as hip circum-
ference (HC),43--45 waist to height ratio (WHtR)46 and
waist to stature ratio (WSR)47 have also been suggested
to be useful markers of obesity.
The concept of central obesity was ¢rst introduced
by Vague in the 1940s2 and later in 1956 he pointed out
for the ¢rst time central obesity (android) was more
important than peripheral obesity (gynaecoid) in rela-
tion to diabetes, gout, atherosclerosis and urate calcu-
lus diseases.48 Since the 1990s interest on WC has
increased because it correlates more closely with the
abdominal visceral fat than either WHR or BMI.49--51
The association of these obesity indicators with CVD
risk factors such as hypertension, dyslipidaemia and
type 2 diabetes has been studied in di¡erent ethnic
groups in recent years. Results from most of the cross-
sectional studies have shown a closer association of
CVD risk pro¢les with central obesity (WC or WHR or
WHtR or all) than with general obesity (BMI) as indi-
cated by slightly larger areas under the receiver operat-
ing characteristic (ROC) curves or higher odds ratios for
central obesity,52--59 but in most of these studies the dif-
ferences observed were not statistically signi¢-
cant.53--55,57,58,60 Five population-based prospective
studies61--65 which have compared these anthropo-
metric indicators with regard to the prediction of inci-
dent diabetes did not ¢nd a di¡erence between general
and central obesity. There were, however, con£icting
¢ndings with regard to the prediction of coronary heart
disease (CHD) events. Some studies observed a higher
risk with central obesity,66,67 but others found a
lower68,69 or equal risk.62,69--71 The ‘di¡erences’ in many
of these studies were not supported by robust statistics,
and therefore more carefully designed studies are
required to re-examine the issue.
Cardiovascular events in relation to the
presence of the metabolic syndrome
Population-based studies using the original WHO de¢-
nition are extremely rare. Prospective studies that have
Ann Clin Biochem 2007; 44: 232–263
 234
Qiao et al.

Table 1 Metabolic components and their positive cut-off points in the definition of the metabolic syndrome by the WHO, EGIR, NCEP and IDF criteria
Components WHO 1999 EGIR 1999 NCEP 2001 NCEP 2004 IDF 2005
Insulin resistance Glucose uptake below lowest Top 25% distribution of fasting

Ann Clin Biochem 2007; 44: 232–263

quartile under insulin in non-diabetic
hyperinsulinaemic and subjects
euglycaemic condition
Hyperglycaemia
Fasting plasma glucose (mmol/L) X6.1 and or 6.1–6.9 X6.1 X5.6 X5.6
2-h plasma glucose (mmol/L) X7.8 Recommended
Previously diagnosed diabetes Included Excluded Included Included Included
Central obesity
Waist-to-hip ratio and/or 40.9 (40.85)
Body mass index (kg/m2) 430
Waist circumference (cm) X94 (X80) 4102 (488) 4102 (488) X94 (X80) for Europids,
ethnic specific
Elevated blood pressure
Blood pressure (mmHg) X140/90 X140/90 X130/85 X130/85 X130/85
Treatment for hypertension Not mentioned Included Included Included Included
Dyslipidaemia
Triglycerides (mmol/L) X1.7 and or 42.0 and/or X1.7 X1.7 X1.7
HDL-C (mmol/L) o0.9 (1.0) o1.0 o1.03 (o1.29) o1.03 (o1.29) o1.03 (o1.29)
Treatment for dyslipidaemia Not mentioned Included Not mentioned Not mentioned Included
Urinary albumin excretion or X20 mg/min
Albumin/creatinine ratio X30 mg/g
Cut-off points in parentheses are for women. WHO definition requires the presence of insulin resistance and/or hyperglycaemia plus any two of the four other factors. EGIR definition requires the presence
of insulin resistance plus any two of the four other factors. NCEP 2001 and NCEP 2004 (revised version) definition requires any three of the five other factors. IDF definition requires the presence of the
central obesity plus any two of the other four factors. Raised triglycerides and reduced HDL are counted as two individual factors in the NCEP and the IDF definitions but as one factor in the WHO and
EGIR definitions
 Metabolic syndrome and cardiovascular disease 235

Table 2 Ethnic and population differences in the prevalence (%) of the metabolic syndrome using the NCEP definition
Ethnicity Number of Country of residence Age group Prevalence Reference
subjects
Men Women
African-Caribbeans 781 United Kingdom 40–69 years 15.5 23.4 38
African-American 2412 United States of America X20 years 16.4 25.7 28
African-American 631 United States of America X20 years 24.5 36.4 27
Black Venezuelan 284 Venezuela X20 years 27.2 30.9 26
Arab 863 Tunisia X40 years 14.6* 30.8* 30
Arab 1419 Oman X20 years 19.5 23.0 22
Arab 542 United States of America 20–75 years 19.8 25.4 40
Arab 7162 Saudi Arabia 30–70 years 37.2 42.0 39
Asian Indian 1091 India 4 20 years 18.4 30.9 29
Asian Indian Unknown Singapore 18–69 years 21.7 19.3 37
Asian Indian 1180 Canada X18 years 29.3 45.0 33
Caucasianw 9140 Europe 30–77 years 21.4 20.9 20
Caucasian 2327 United Kingdom 40–69 years 18.4 14.4 38
Caucasian 4060 Australia X18 years 15.7 14.4 21
Caucasian 936 New Zealand (40–59) 24.6* 13.4* 36
Caucasian 2058 Canada X18 years 25.3 23.7 33
Caucasian 3599 United States of America X20 years 24.8 22.8 28
Caucasian 1834 United States of America X20 years 35.4 31.5 27
Caucasian 385 Venezuela X20 years 33.3 30.9 26
Caucasian 936 New Zealand (40–59) 24.6* 13.4* 36
Caucasian 2058 Canada X18 years 25.3 23.7 33
Chinese (workforce) 1513 Hong Kong, China 18–66 years 6.5* 5.6* 31
Chinese 2843 Hong Kong 25–74 years 15.3 18.8 306
Chinese Unknown Singapore, China 18–69 years 10.8 8.3 37
Chinese 48,406 Taiwan X35 years 10.7 12.1 35
French 4293 France 30–64 years 9.1 6.2 41
Greek 9669 Greece 18–70 years 24.5 for all 23
Inuit 328 Canada X18 years 8.2 22.0 33
Iranian 9846 Iran X20 years 24 42.0 24
Italian 888 Italy 40–79 years 17.8 for all 25
Korean 40,698 Korea 20–82 years 5.2 9.0 15
Malay Unknown Singapore, China 18–69 years 17.3 20.0 37
Maori 780 New Zealand (40–59) 52.8* 51.0* 36
Mexican American 2449 United States of America X20 years 28.3 35.6 28
Mexican-American 884 United States of America X20 years 40.3 44.0 27
Mixed-South Asiansz 1683 United Kingdom 40–69 years 28.8 31.8 38
Pacific Islander 1021 New Zealand 40–59 48.5* 45.5* 36
Thai 5099 Thailand X35 years 18.5 26.5 35
Turkish 2225 Turkey X28 years 31.5* 44.7* 34
Venezuelaan Amerindian 265 Venezuela X20 years 17.1 29.9 26
Venezuelan Mixed 2174 Venezuela X20 years 37.4 29.6 26
Prevalence was age standardized using different standard populations and age ranges in individual studies
*
Indicates crude prevalence
w
Excluding diabetic subjects
z
South Asians of Indian, Pakistan and Bangladesh origin

evaluated the association of the modi¢ed WHO for cardiovascular events using the modi¢ed WHO
de¢nition or the original NCEP de¢nition or both de¢nitions varied from 0.98 in Dutch women in the
with the risk of CVD are summarized in Table 4 and Hoorn Study to 4.3 in Finnish women in Kuopio
Figures 3a--b. Multivariate adjusted hazard ratios (Table 4, Figure 3a).72--81 Since de¢nitions varied

Ann Clin Biochem 2007; 44: 232–263

236 Qiao et al.
Table 3 Ethnic differences in the prevalence (%) of the metabolic syndrome using the IDF definition
Ethnicity Number of subjects Country of residence
African-American 631 United States of America
Arab 863 Tunisia
Caucasian 4060 Australia
Caucasian 1834 United States of America
Chinese 1513 Hong Kong, China
Greek 9669 Greece
Mexican-American 884 United States of America
Prevalence was age standardized using different standard populations and age ranges in individual studies
*Indicates crude prevalence
from study to study caution should be applied when
interpreting and comparing results from di¡erent stu-
dies.
The original and modi¢ed NCEP de¢nitions for the
metabolic syndrome have been widely applied. The
multivariate adjusted hazard ratios from 17 popula-
tion-based studies73,75--79,82--89 using the original NCEP
de¢nition are presented in Table 4 and Figure 3b. An
increased CVD risk in the presence of the metabolic
syndrome of the NCEP de¢nition was observed in most
studies, with an overall hazard ratio of 1.6 (95% con¢-
dence interval [CI] 1.5--1.8).
Accumulated evidence appears to leave little doubt
on the contribution of clustering of risk factors to
increased CVD risk. A hyperinsulinaemic-euglycaemic
clamp study, however, showed that about one-third of
the subjects who did not meet the NCEP criteria for
the metabolic syndrome were insulin resistant.90
Importantly, these subjects were not signi¢cantly dif-
ferent from those meeting the NCEP criteria in regard
to the prevalence of impaired fasting glycaemia (IFG),
impaired glucose tolerance (IGT), glucose disposal
rates and lipoprotein subclass composition (increased
VLDL size and large VLDL concentration and decreased
large HDL particles, and HDL size).90
Other studies have also shown that individual meta-
bolic syndrome components predicted the CVD risk by
a similar magnitude to that of the actual syn-
drome.72,75,78,91,92 Based on the large DECODE prospec-
tive database of 4715 European men and 5554
European women aged 30--89 years, we have recently
formally compared the risk sizes related to the meta-
bolic syndrome and its individual metabolic compo-
nents of di¡erent de¢nitions including the newly
issued IDF de¢nition.92 The multivariate adjusted
hazard ratios (95% CIs) for CVD mortality correspond-
ing to the WHO, NCEP, NCEP revised and the IDF de¢ni-
tions of the metabolic syndrome were respectively 2.09
(1.59--2.76) , 1.74 (1.31--2.30), 1.72 (1.31--2.26) and 1.51
(1.15--1.99) in men, and 1.60 (1.01--2.51), 1.39
Ann Clin Biochem 2007; 44: 232–263
Prevalence
Age group Men Women Reference
X20 years 27.1 38.8 27
X40 years 30.0* 55.8* 30
X18 years 26.4 19.4 21
X20 years 41.9 34.4 27
18–66 years 7.3 8.8 42
18–70 years 43.4 for all 23
X20 years 50.6 46.2 27
(0.89--2.18), 1.09 (0.70--1.69) and 1.53 (0.99--2.36) in
women. The paired homogeneity test showed that in
men the hazard ratio was higher with the WHO de¢ni-
tion than with the IDF de¢nition (P ¼ 0.03). In women
the hazard ratio was lower with the revised NCEP de¢-
nitions than with either the WHO (P ¼ 0.02) or the IDF
(P ¼ 0.01) de¢nition. With a few exceptions, hazard
ratios for full de¢nitions of the syndrome were not sig-
ni¢cantly di¡erent from those for their single compo-
nents.92
Three studies have compared the NCEP-de¢ned
metabolic syndrome and Framingham CVD risk score
in the prediction of CVD events. ROC analyses of data
from the San Antonio Study93 showed that the
Framingham risk score is a better screening tool for
CVD than the metabolic syndrome. In the Athersclero-
sis Risk in Communities (ARIC) cohort,86 the metabolic
syndrome was found to be predictive of cardiovascular
events in men and women, but as in the San Antonio
Study, it did not improve the coronary risk prediction
beyond that achieved by the Framingham risk score.
More recently, the British Regional Heart Study, based
on 5128 men aged 40--59 years without CHD or stroke,
showed that the area under the ROCs were 0.68 versus
0.59 for CHD and 0.66 versus 0.55 for stroke (Po0.001
for all) for Framingham risk score versus the number of
metabolic abnormalities de¢ned by the NCEP criteria.94
This is not surprising given that the Framingham score
has been speci¢cally developed to predict CVD events,
and unlike the metabolic syndrome includes age and
smoking in the equation. The question on whether the
metabolic syndrome identi¢es further individuals at
high risk of CVD mortality, beyond those identi¢ed by
the European Systematic Coronary Risk Evaluation
(SCORE) project equation, was estimated based on data
of 2790 non-diabetic men aged 50--69 years in the
DECODE Study.95 In men with 10-year risk of fatal CVD
under 5%, the age and centre adjusted hazard ratio for
fatal CVD mortality was 2.71 (95% CI 1.33--5.51) for men
with the NCEP-de¢ned metabolic syndrome compared
 Ch
Prevalence (%) Prevalence (%)

(b)
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Metabolic syndrome and cardiovascular disease

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Figure 1 Ethnic variation in the prevalence of metabolic syndrome by the NCEP definition (a) and by the IDF definition (b)
ea d
la
nd

factors remains unclear. Factors including genetic

237

The pathogenesis underlying the clustering of CVD risk

Ann Clin Biochem 2007; 44: 232–263

238 Qiao et al.

(a) 15

10
Difference in prevalence (%)

10

15

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Figure 2 Absolute difference in the prevalence of metabolic syndrome according to gender and ethnicity, using the NCEP
definition (a) and the IDF definition (b)

deposition, obesity, insulin resistance and in£amma- tance and pancreatic islet b-cell dysfunction are the
tion have been suggested to be involved. The possible hallmarks of impaired glucose metabolism.6 The
roles of insulin resistance, obesity and in£ammation subsequent hyperglycaemia and glucotoxicity wor-
in relation to the pathogenesis of the metabolic syn- sens insulin resistance and islet b-cell insulin dys-
drome are reviewed below. function.101 In adipose tissue, insulin resistance
increases lipolysis. The increased free fatty acid
(FFA) £ux disrupts lipid metabolism. Circulating
Insulin resistance HDL-C concentrations fall because of overconsump-
Insulin resistance is widely considered to be the uni- tion. The blood LDL pool becomes enriched with
fying mechanism underlying the constellation of the small dense LDL particles since the liver produces
metabolic abnormalities (Figure 4). Insulin resis- small VLDL.102 Hepatic overload with FFAs increases

Ann Clin Biochem 2007; 44: 232–263

 Table 4 Hazard ratios for metabolic syndrome defined by different criteria in relation to fatal and non-fatal cardiovascular event
Studies Sample Sex Age, year Follow-up CV events No. of events Definition Hazard ratio Adjustment for
size (range or mean) (year) (95% CI)
Isomaa et al.72 4483 Men; women 35–70 6.9 CVD mortality 209 Modified WHO* 1.81 Age, sex, LDL-C, and
(1.24–2.65) current smoking

Onat et al.82 2398 Men; women X28 3.0 Non-fatal MI or 126 NCEP 1.709 Age
fatal CHD (1.180–2.473)
Men 1.648
(0.981–2.768)
Women 1.944
(1.108–3.411)

Lakka et al.73 1209 Men 42–60 11.4 CVD death 46 NECP 2.27 (0.96–5.36) Age, examination year,
smoking, LDL-C,
family history of CHD,
fibrinogen, white blood
cell count, alcohol,
socioeconomic status
Modified WHOw 2.83 (1.43–5.59)
CHD death 27 NECP 4.26 (1.62–11.2)
Modified WHOw 3.32 (1.36–8.11)

Resnick et al.87 2283 Men; women 45–74 7.6 CVD death 181 NCEP 1.11 (0.79–1.56) Age, centre, sex, BMI,
fibrinogen, smoking,
LDL-C
Low CRP 2.3 (1.6–3.3) Age
High CRP 4.0 (3.0–5.4)

Bonora et al.74 888 Men; women 40–79 5 Fatal and non- 46 Modified WHO* 2.3 (1.2–4.3) Age, sex, smoking,
fatal CHD alcohol, physical
activity, social status,
LDL-C, baseline
carotid
Metabolic syndrome and cardiovascular disease

atherosclerosis,
baseline CHD
239

Ann Clin Biochem 2007; 44: 232–263

 Table 4 Continued 240
Studies Sample Sex Age, year Follow-up CV events No. of events Definition Hazard ratio Adjustment for
size (range or mean) (year) (95% CI)
Katzmarzyk 19,233 Men 20–83 10.2 CVD mortality 161 NCEP 1.89 (1.36–2.60) Age, smoking, alcohol,
Qiao et al.

et al.85 family history of CVD,

cardiorespiratory
fitness

Ann Clin Biochem 2007; 44: 232–263

Rutter et al.88 3037 Men; women 26–82 6.9 Fatal or non-fatal 189 NCEP 2.1 (1.5–2.8) Age, sex
CV events

Hunt et al.75 2815 Men; women 25–64 12.7 CVD mortality 117 NCEP 2.53 (1.74–3.67) Age, sex, race
Modified WHOz 1.63 (1.13–2.36)
Fatal or non-fatal 1.49 (0.99–2.25) Age
MI

McNeill et al.86 12,089 Men; women 45–64 11 Fatal or non-fatal 879 NCEP 1.46 (1.23–1.74) for Age, race, study centre,
CV events men and 2.05 LDL-C, smoking
(1.59–2.64) for
women
Incident 216 NCEP 1.42 (0.96–2.11) for
ischaemic men and 1.96
stroke (1.28–3.00) for
women

Dekker et al.76 1364 Men; women 50–75 10 Fatal CVD 39 (men); NCEP 2.25 Age
26 (women) (1.16–4.34)
for men and
0.76 (0.32–1.83)
for women
Modified WHOz 1.45 (0.77–2.74) for
men and 0.98
(0.43–2.21) for
women
Takeuchi 808 Men 60.3 6 Occurrence of 49 NCEP 2.23 (1.14–4.34) Age, smoking, total
et al.89 cardiac cholesterol
disease
 Table 4 Continued
Studies Sample Sex Age, year Follow-up CV events No. of events Definition Hazard ratio Adjustment for
size (range or mean) (year) (95% CI)
Scuteri et al.77 2175 Men; women 73 4.1 Incident CVD 464 NCEP 1.38 (1.07–1.79) Age, sex, family history of
MI, smoking, LDL-C,
individual components
of the metabolic
syndrome
Modified WHOw 1.15 (0.88–1.50) Age, sex, family history of
MI, smoking, LDL-C,
individual components
of the metabolic
syndrome

Lawlor et al.78 3589 Women 60–79 15,778 Fatal and non- 194 NCEP 1.27 (0.90–1.79) Smoking, inactive, life-
women- fatal CHD course socioeconomic
years position
Modified WHOy 1.31 (0.90–1.90) Smoking, inactive, life-
course socioeconomic
position
IDF 1.25 (0.96–1.61) Smoking, inactive, life-
course socioeconomic
position

Bulter et al.83 3035 Men; women 70–79 6 CVD mortality 130 NCEP 1.23 Age, race, gender,
smoking, marital
status, site, the
presence of diabetes
at baseline
Incident coronary 472 1.56 (1.28–1.91)
event
Metabolic syndrome and cardiovascular disease

Sundström 2322 Men 50 29.8 CVD mortality 502 Modified WHO** 1.35 (1.06–1.73) Smoking, diabetes,
et al.79 hypertension, total
241

Ann Clin Biochem 2007; 44: 232–263

cholesterol
 Table 4 Continued 242
Studies Sample Sex Age, year Follow-up CV events No. of events Definition Hazard ratio Adjustment for
size (range or mean) (year) (95% CI)
70 9.1 133 NCEP 1.43 (0.95–2.17)
Qiao et al.

WHO 1.53 (1.01–2.34)

Modified WHO** 1.70 (1.12–2.59)

Jeppesen 2493 Men; women 41–72 9.5 Fatal and non- 233 NCEP plus 3.21 (1.99–5.17) Age, sex, smoking

Ann Clin Biochem 2007; 44: 232–263

et al.84 fatal CV LDL-C 45.02
events mmol/L
NCEP plus 1.80 (1.26–2.57) Age, sex, smoking
LDL-C
p5.02
mmol/L

Kurl et al.80 1131 Men 42, 48, 54 or 60 14.3 Incident stroke 65 Modified WHOz 2.08 (1.12–3.87) for Age, examination year,
all strokes; 2.47 socioeconomic status,
(1.21–5.07) for smoking, alcohol,
ischaemic family history of heart
stroke disease, ischaemic
changes during
exercise test, LDL-C,
energy intake for
saturated fats, energy
expenditure of leisure
time physical activity,
blood leukocyte count
and plasma fibrinogen

Juutilainen 1281 Men; women 54.4 18 CVD mortality 98 Modified WHOww 1.7 (1.0–2.9) for Age, area of residence,
et al.81 men and 4.3 current smoking and
(1.8–10.2) for total cholesterol
women

Lahoz et al.307 1001 Men; women 60–79 10 Incident 38 NCEP No significant Age, tobacco
peripheral association consumption, LDL-C,
artery disease HDL-C, triglycerides,
and hypertension
 Table 4 Continued
Studies Sample Sex Age, year Follow-up CV events No. of events Definition Hazard ratio Adjustment for
size (range or mean) (year) (95% CI)
The DECODE 10269 Men; women 30–89 7–16 CVD mortality 299 Modified WHOz 2.09 (1.59–2.76) for Age, cohort, smoking and
Study men and 1.60 total cholesterol
Group92 (1.01–2.51) for
women
NCEP 1.74 (1.31–2.30) for
men and 1.39
(0.89–2.18) for
women
NCEP revised 1.72 (1.31–2.26) for
men and 1.09
(0.70–1.69) for
women
IDF 1.51 (1.15–1.99) for
men and 1.53
(0.99–2.36) for
women
*
Insulin resistance defined by the highest quartile of Homeostasis Model Assessment (HOMA)
w
Impaired glucose tolerance or microalbuminuria unavailable
z
Insulin resistance defined by the upper quartile of fasting insulin concentration of non-diabetic participants; microalbuminuria not available
y
Fasting plasma glucose X6.1 mmol/L is used in place of glucose intolerance assessed by oral glucose tolerance test (OGTT), HOMA used instead of euglycaemic clamp techniques, microalbuminuria
unavailable
**
Insulin resistance defined by the highest quartile of HOMA, BMI430 kg/m2 used in place of waist-to-hip ratio40.90 for men; microalbuminuria unavailable
ww
Insulin resistance defined by the upper quartile of fasting insulin concentration of non-diabetic participants
Metabolic syndrome and cardiovascular disease
243

Ann Clin Biochem 2007; 44: 232–263

244 Qiao et al.

(a)

1. Isomaa (2001), men and women, 35 − 70 years 1

2. Lakka (2002), men, aged 42 − 60 years 2
3. Bonora (2003), men and women aged 40 − 79 years 3
4. Hunt (2004), men and women aged 25 − 64 years 4
5. Dekker (2005), men aged 50 − 75 years 5
6. Dekker (2005), women aged 50 − 75 years 6
7. Scuteri (2005), men and women aged 73 years 7
8. Lawlor (2006), women aged 60 − 79 years 8
9. Sundström (2006), men aged 50 years 9
10. Sundström (2006), men aged 70 years 10
11. Kurl (2006), men aged 42 − 60 years 11
12. Juutilainen (2006), men aged 54 years 12
13. Juutilainen (2006), women aged 54 years 13
Overall (meta-analysis) 14
15
0 1 2 3 4 5 6
Relative risk (95%CI) using modified WHO definition
(b)
1. Onat (2002), men and women, = 28 years old 1
2. Lakka (2002), men, aged 42 − 60 years 2
3. Resnick (2003), men and women aged 45 − 74 years 3
4. Katzmarzyk (2004), men aged 20 − 83 years 4
5. Rutter (2004), men and women aged 26 − 82 years 5
6. Hunt (2004), men and women aged 25 − 64 years 6
7. McNeill (2005), men aged 45 − 64 years 7
8. McNeill (2005), women aged 45 − 64 years 8
9. Dekker (2005), men aged 50 − 75 years 9
10. Dekker (2005), women aged 50 − 75 years 10
11. Takeuchi (2005), men aged 60 years 11
12. Scuteri (2005), men and women aged 73 years 12
13. Lawlor (2006), women aged 60 − 79 years 13
14. Bulter (2006), men and women aged 70 − 79 years 14
15. Sundström (2006), aged 70 years 15
*16. Jeppesen (2006), men and women aged 41 − 72 years 16
**17. Jeppesen (2006), men and women aged 41 − 72 years 17
Overall (meta-analysis) 18
19
0 1 2 3 4 5 6
*LDL>5.02 mmol/l, **LDL = 5.02 mmol/l
Relative risk (95%CI) using original NCEP definition

Figure 3 Hazard ratios ( ) and their 95% CI ( ) for fatal and non-fatal cardiovascular events using modified WHO definitions (a)
and the original NCEP definition (b). Detailed information can be found from the Table 4. The meta-analysis was made according to
Fleiss JL (Stat Methods Med Res 1993; 2: 121–145)

triglyceride production and secretion as well as
hepatic triglyceride deposition, predisposing to fatty
liver. Increased circulating FFAs worsen insulin
resistance through inhibiting the glucose uptake
and utilization in the cells.103 In the islet b-cell, ele-
vated FFAs initially stimulate but subsequently
impair insulin secretion.
In endothelium cells, insulin stimulates the produc-
tion of nitric oxide (NO) and endothelin-1 (ET-1). How-
ever, insulin resistance disrupts the balance between

Ann Clin Biochem 2007; 44: 232–263

 Metabolic syndrome and cardiovascular disease 245

the production of NO and ET-1 leading to endothelial
dysfunction.104--108 The production of plasminogen
activator inhibitor 1 (PAI-1), tissue-type plasminogen
activator (tPA) and VonWillebrand factor (vWF) is unre-
gulated;9,109 and insulin-related vasodilator action is
blocked.110 NO-dependent anti-in£ammatory and
antithrombotic e¡ects are suppressed.111 Insulin
directly stimulates the expression of vascular cell adhe-
sion molecular 1 (VCAM-1) and E-selectin in endothe-
lium cells.112 The increased prothrombotic pro¢les
result in a hyperthrombotic state.
Insulin resistance and hyperinsulinaemia are
reported to be closely related with essential
hypertension113--115 via several possible mechanisms
(Figure 4). However, whether insulin resistance causes
hypertension has not been determined.116,117 The
antinatriuretic e¡ect of insulin and its activation
of the sympathetic system may be responsible for

Blood glucose uptake and oxidization by cells

Glucogen syntheses Glucose intolerance
Liver gluconeogensis Liver glucose exportation
Liver glucogennolysis
Islet β-cell insulin secretion
Adipose lipolysis Blood FFA flux Insulin sensitivity
FFA esterification Lipid deposit in tissue
FFA utilization Blood triglyceride HDL-c NAFLD
Dyslipidaemia
Small and dense LDL perticle
Insulin −induced endothelium NO production Endothelial dysfunction Insulin − related vasodilatation
Insulin −induced endothelium ET-1 production PAI expression
ICAM, E-selection Prothrombotic state
Na+− k+exchange in kidney Antinatriuresis
Sympathetic system activity
Adipose tissue angiotensinogen Hypertension
expression
Urinary albumin excretion Albuminuria

Figure 4 Role of insulin resistance in the development of metabolic abnormalities. FFA, free fatty acid; NO, nitric oxide; ET-1,
endothelin-1; NAFLD; non-alcoholic fatty liver disease; PAI, plasminogen activator inhibitor; ICAM, intercellular adhesion molecule

Insulin sensitivity
Islet β-cell insulin secretion Insulin resistance
Cellular glucose uptake and utilization Glucose intolerance
Liver gluconeogensis and glycogenolysis
Adipose lipolysis Blood FFA flux
Blood triglyceride Liver VLDL production
HDL-c Dyslipidaemia
Small and dense LDL particle NAFLD
Tissue lipid deposition

Adipose lipolysis
Adipose insulin sensitivity
TNF-α Adiponectin production
Adipose PAI-1 production Prothrombotic state
Other inflammation mediator factors production Low grade inflammation

Insulin sensitivity Insulin resistance

IL-6 Adipose lipolysis Dyslipidaemia
Liver triglyceride output
Liver CRP, PAI, fibrinogen production Low grade inflammation
CRP Liver inflammation mediators, fibrinogen production Prothrombotic state

PAI-1 secretion Prothrombotic state

Adiponectin secretion Antiinflammatory effect

Insulin sensitivity Insulin resistance
Resistin secretion Insulin sensitivity

Leptin secretion Sympathetic system activity

Angiotensinogen production
Angiotensinogen production Hypertension

Figure 5 Role of obesity, especially abdominal adiposity in the development of metabolic abnormalities. FFA, free fatty acid;
NAFLD; non-alcoholic fatty liver disease; PAI, plasminogen activator inhibitor; TNF-a, tumour necrosis factor-alpha; IL-6, interleukin-
6; CRP, C-reactive protein

Ann Clin Biochem 2007; 44: 232–263

246 Qiao et al.
sustaining high blood pressure rather than causing
hypertension.
Obesity and inflammation
Obesity, especially abdominal adiposity, and chronic,
low-grade in£ammation may be important in the
pathogenesis of metabolic syndrome (Figure 5).
Adipose tissue in obese individuals releases increased
FFAs and triglycerides. Elevated FFAs and triglycerides
in the circulation inhibit cellular glucose uptake,
decreasing cellular glucose utilization.103 Elevated
FFAs and associated lipotoxicity induce insulin resis-
tance, islet b-cell dysfunction, dyslipidaemia, fatty liver
and possibly higher blood pressure.118 Accumulated tri-
glycerides in the liver increases hepatic synthesis of
PAI-1, ¢brinogen and in£ammatory factors.119
Adipose tissue synthesizes and secretes more
tumour necrosis factor-alpha (TNF-a), interleukin (IL)-
6 and other cytokines in obese subjects than those
without obesity.120,121 These in£ammatory mediators
might contribute to insulin resistance, impaired lipid
metabolism and endothelial dysfunction.122--124 IL-6
also increases the hepatic synthesis of acute-phase
reactants, including C-reactive protein (CRP) and ¢bri-
nogen.125 CRP induces synthesis of cytokines, cellular
adhesion molecules and tissue factors in monocytes
and endothelial cells.
Adiponectin improves insulin resistance and has
anti-in£ammatory and antiatherogenic proper-
ties.126--128 Adiponectin concentrations correlate inver-
sely with markers of obesity and the low
concentrations of adiopectin in obese persons may
deprive them of its protective e¡ects against metabolic
syndrome. Resistin, another adipose tissue hormone
which appears to have anti-insulin activity, may also
have a pathological role in metabolic syndrome.129 In
addition, adipose tissue synthesizes and secretes PAI-1
into the circulation. Insulin resistance and subsequent
hyperinsulinaemia in obese subjects upregulates the
secretion of PAI-1 by adipose tissue.130 Adipose tissue
PAI-1 production correlates positively with BMI and
abdominal adipose tissue mass.130
Hypertension is consistently reported to be closely
associated with obesity, although the exact mechanism
is not clear. Increased angiotensin II and leptin concen-
trations that occur with obesity might be
involved.131--135 Weight loss accompanied by decreased
angiotensin II concentration has been reported to
decrease blood pressure.136,137
However, whether insulin resistance, obesity and
in£amation share the same underlying background,
or are causally related, or just coincidental, is far from
understood. Insulin is anti-in£ammatory and this
e¡ect is reduced in insulin resistance.124 Hyperglycae-
mia also causes in£ammation by glucose-induced oxi-
Ann Clin Biochem 2007; 44: 232–263
dative stress.138 Obesity, especially abdominal adiposity,
is closely related with insulin resistance.139,140 Some
studies have suggested that obesity is a low-grade
in£ammatory state.141 However, insulin resistance
occurs in individuals without obesity. Low-grade
in£ammation is not only related to the extent of obesity
but also to other factors such as age, diet, smoking and
drugs.109,142--146 The pathogenesis of obesity, therefore,
appears to mainly related to energy imbalance, rather
than insulin resistance or low-grade in£ammation.
Mechanism underlying the relationship
between metabolic syndrome and CVD
risk
It has been commonly accepted that the endothelial
injury and dysfunction, the deposition of LDL choles-
terol (LDL-C), and the recruitment, migration and pro-
liferation of monocytes in smooth muscle cells in the
artery wall are central to the initiation and progression
of atherosclerosis.147 As shown in Figure 6, compo-
nents of the metabolic syndrome may either directly or
indirectly be involved in atherogenesis through these
central links. However, whether they are involved in
the causal chain or interact with each other is still
unknown.
Metabolic syndrome and non-alcoholic
fatty liver disease
Primary non-alcoholic fatty liver disease (NAFLD) is a
metabolic liver disease characterized by a histological
fatty liver in the absence of toxic alcoholic intake.
NAFLD is closely related to metabolic syndrome and
its components such as obesity, glucose intolerance
and hypertriglyceridemia.148 Raised alaninine amino-
transferase (ALT) activity, a marker for the liver cell
damage, was reported to be independently associated
with the metabolic syndrome.149,150 The mechanisms
of NAFLD are poorly understood. Insulin resistance
and associated hyperinsulinaemia, increased FFA £ux
to liver and elevated in£ammatory mediators which are
involved in the development of the metabolic syndrome
are also suggested to be involved in the pathogenesis of
NAFLD.151
Metabolic syndrome and polycystic
ovarian syndrome
Insulin resistance, abdominal adiposity, hypertension,
hypertriglyceridemia, low HDL-C and impaired glu-
cose metabolism are common in women with polycys-
tic ovary syndrome (PCOS).145,152,153 Abdominal
 Metabolic syndrome and cardiovascular disease 247

Hexosamine biosnthetic pathway

Activation of some cell signal Endothelial dysfunction
Hyperglycaemia transport system Prothrombotic state Thrombosis (mural thrombi)
Oxidative stress Modified protein, especially LDL Deposit of cholesterol
Advanced glycation end product
modification

Endothelium dysfunction
Prothrmbotic state Thrombosis (mural thrombi)
Insulin resistance Proliferation of artery
and hyperinsulinaemia smooth muscle cells
Dyslipidaemia Deposit of cholesterol
Hypertension Endothelial injury

Insulin resistance
Elevated FFA
Low HDL-c
Obesity, especially
visceral obesity Small dense LDL particles
Low grade inflammation
Prothrombotic state
Deficiency of adiponectin
Elevated resisitin
Hypertension
Endothelial dysfunction
Deposit of cholesterol
Thrombosis (mural thrombi)
Differentiation of macrophages into foam cells
Proliferation of artery smooth muscle cells
Endothelial injury

Insulin resistance
Dyslipidaemia
Prothrombotic state
Inflammatory mediators Low grade inflammation
Hypertension
Deposit of cholesterol
Thrombosis (mural thrombi)
Endothelium dysfunction
Recruitment, migration and proliferation of monocyte,
and artery smooth muscle cells
Endothelial injury

Figure 6 Pathogenic mechanisms between metabolic abnormalities and cardiovascular disease

adiposity in women is usually associated with elevated Therapeutic lifestyle changes

circulating total and free testosterone.154 Moreover,
insulin resistance has been suggested to play an impor-
tant role in the pathogenesis of PCOS.155,156 Thus PCOS
seems to have many of the features of the metabolic
syndrome, suggesting a link between them. Although
most subjects with PCOS have polycystic ovaries on
ultrasongraphy,157 the hallmarks of the PCOS are
hyperandrogenism and chronic anovulation.158 Hyper-
androgenism and chronic anovulation, however, are
not as common in women with metabolic syndrome as
in those with PCOS, and there are as yet no de¢ned
changes in ovarian morphology in women with meta-
bolic syndrome. Furthermore, in men, metabolic syn-
drome is reported to be associated with a low
concentration of androgen.159--161 Although PCOS
shares many common features with the metabolic syn-
drome, there are several di¡erences and many putative
links between the metabolic syndrome and PCOS
remain to be unravelled.
Management of the metabolic syndrome
Since the metabolic syndrome is multifactorial in ori-
gin, strategies for reducing CV risk in individuals with
the metabolic syndrome involve the management of
multiple risks.
Lifestyle changes are the ¢rst-line management for the
metabolic syndrome. Evidence from controlled clinic
trials have demonstrated that intensive lifestyle modi¢-
cation, including increased physical activity and diet-
ary changes, reduced the risk of diabetes by
39--58%.162--164 Furthermore, secondary analysis of
data from the Diabetes Prevention Program (DPP),165
after 3.2 years of follow-up, showed a 41% reduction
in the incidence of the metabolic syndrome in the life-
style group (Po0.001) (including those without the
syndrome at baseline) compared with placebo group.
In the Third National Health and Nutrition Examina-
tion Survey (NHANES III),166 the prevalence of meta-
bolic syndrome was much lower in those individuals
who were non-obese, physically active, non-smokers,
eating a relatively low carbohydrate diet and consum-
ing moderate amounts of alcohol. Therefore, therapeu-
tic lifestyle changes (TLC) not only prevent diabetes but
also reduce the risk of developing the metabolic syn-
drome. The NCEP Adult Treatment Panel III (ATPIII)
report13 and current European guidelines167 recom-
mend multifactorial TLC (Table 5) to reduce CHD risk.
Physical activity
Epidemiological studies have indicated that regular
physical activity and ¢tness reduce the increased
risk of CVD associated with insulin-resistant

Ann Clin Biochem 2007; 44: 232–263

248 Qiao et al.

Table 5 Therapeutic lifestyle changes13

Component Recommendation
Total calories Adjust total energy intake to maintain desirable body weight/prevent weight gain
Carbohydrate* 50–60% of total calories
Proteinw Approximate 15% of total calories
Cholesterol o200 mg/day
Total fat* 25–35% of total calories
Saturated fatz o7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Dietary fibre 20–30 g/day
Increased viscous (soluble) fibrey 10–25 g/day
Plant stanols/sterolsy 2 g/day
Alcohol consumption** p2 drinks/day for men
p1 drink/day for women
Folate 400 mg/day largely from dietary resources
Antioxidant 75 and 90 mg/day for women and men, respectively, for vitamin C
and 15 mg/day for vitamin D
Sodium o 2400 mg/day
Potassium Approximate 90 mmoL/day
Physical activityww 30 min of moderate intensity physical activity on most, if not all, days of week
Smoking Cessation
*
ATP III allows an increase of total fat to 35% of total calories and a reduction in carbohydrate to 50% for patients with the metabolic syndrome;
carbohydrate should derive predominantly from food rich in complex carbohydrates including grain (especially whole grain), fruits and vegetables;
any increase in fat intake should be in the forms of either polyunsaturated or monounsaturated fat
w
Food sources containing soy protein are acceptable as replacement for animal food products containing animal fats
z
Trans fatty acids raise serum LDL-C concentrations and should be kept at a low intake
y
Therapeutic option for LDL-C lowering
**
A drink is defined as 5 ounces of wine, 12 ounces of beer or 1.5 ounces of 80 proof whiskey; persons who do not drink should not be encouraged
to initiate regular alcohol consumption
ww
Enough moderate exercise to expend at least 200 kcal/day

conditions.168--170 Low cardiorespiratory ¢tness is a
strong and independent predictor of incident metabolic
syndrome.171 In the Canadian Heart Health Survey,
physically active men were more than 50% less likely
to have the metabolic syndrome than physically inac-
tive men.172 In the Cross-Cultural Activity Participa-
tion Study,169,173 higher concentrations of physical
activity were inversely associated with the metabolic
syndrome among African American, Native American
and Caucasian women. Furthermore, physically active
individuals with the metabolic syndrome had improved
metabolic pro¢le174 (lipid, blood pressure, fasting blood
glucose and WC) and lower concentrations of in£am-
matory indicators175 (CRP, white blood cell counts, ser-
um amyloid-A, TNF-a and IL-6), compared with
sedentary individuals.
E¡ects of physical activity on CVD risk have also
been reported. Moderate or higher levels of physical
activity were associated with reduced risks of total
and cardiovascular mortality regardless of BMI, blood
pressure, total cholesterol and smoking in patients
with type 2 diabetes.176 The Aerobics Center Longitudi-
nal Study (ACLS),85 which enrolled 15,466 healthy men
and 3757 men with the metabolic syndrome, examined
the relationship between cardiorespiratory ¢tness and
mortality. A maximal treadmill exercise test was used
to evaluate cardiorespiratory ¢tness, and those in the
upper four quintiles of maximum oxygen uptake were
de¢ned as ¢t. The cardiovascular mortality in ¢t men
with the metabolic syndrome was signi¢cantly
reduced (by 19.1%) compared with un¢t men.
Promotion of a physically active lifestyle should,
therefore, be a public health priority. NCEP-ATPIII,
American Heart Association (AHA) and European
guidelines recommend at least 30 min of moderate-
intensity activities for most people on most days of the
week,13,167,177 and this has been formally endorsed by
both the Centers for Disease Control and Prevention
and the American College of Sports Medicine.178 Cur-
rent recommendations, however, may be insu⁄cient
to achieve maximum reduction of CVD risk in insulin-
resistant groups, such as those with the metabolic syn-
drome, and perhaps higher level of physical activity (for
example, 60 min of moderate physical activity per day)
should be speci¢cally recommended for these popula-
tions.179,180

Ann Clin Biochem 2007; 44: 232–263


Dietary modifications
Dietary Approaches to Stop Hypertension (DASH), a
randomized controlled trial, reported that a diet rich
in vegetables, fruits and low-fat dairy products signi¢-
cantly improved blood pressure, HDL-C, triglycerides,
fasting glucose and weight in patients with the meta-
bolic syndrome.181 A low-sodium DASH diet produced
a greater reduction in blood pressure than either the
DASH diet alone or a reduction in sodium alone.182
The Mediterranean-style diet, which is rich in whole
grain, vegetables, fruits, nuts and olive oil, is associated
with reduced risk of CVD mortality.183 In a recent
randomized trial,143 patients with the metabolic
syndrome following the Mediterranean-style diet
achieved a signi¢cant reduction in body weight, WC,
blood pressure, plasma glucose, total cholesterol, trigly-
cerides, CRP, IL-6 and IL-18, as well as improvement in
HDL-C concentration and endothelial function, com-
pared with the control group. A meta-analysis of
cohort studies has shown that increased vegetable
and fruit intake was associated with a reduced risk of
stroke184 and CHD.185
In addition, higher intakes of magnesium,186--188
potassium,189,190 calcium191--194 and dairy consump-
tion195 may also bene¢t components of the metabolic
syndrome. However, the evidence is inconsistent. The
British Women’s Heart and Health Study,196 for exam-
ple, showed a reverse relationship between milk con-
sumption and risk of the metabolic syndrome.
Randomized controlled studies are therefore needed to
increase the evidence base and clarify the con£icting
data.
The recent NCEP-ATPIII recommendation for
macronutrient intakes (see Table 5) is applicable to
patients with the metabolic syndrome. To maximize
dietary bene¢t, subjects should adhere to their recom-
mended diets since the Framingham O¡spring-Spouse
Study197 reported an independent relationship
between habitual dietary patterns and risk of meta-
bolic syndrome.
Smoking cessation
Smoking is a risk factor for atherosclerosis and CVD198
and seems to be important in the metabolic syn-
drome.199,200 Current recommendations consistently
encourage smoking cessation.13,167,177 NHANES III166
showed that in adjusted models, never smoking was
associated with lower risk for metabolic syndrome in
both genders compared with current smoking. There
was a dose-dependent relationship between current
smoking and the metabolic syndrome.201 Furthermore,
either active or passive smoking is associated with at
least four-fold increase in the risk of the metabolic syn-
drome among adolescents.202 Smokers are also insulin
resistant compared with non-smokers.203--205 In addi-
Metabolic syndrome and cardiovascular disease 249
tion, smoking is associated with increased concentra-
tions of plasma macrophage-colony-stimulating factor
(M-CSF), CRP and platelet activity in patients with cor-
onary artery disease.206 In the Multiple Risk Factor
Intervention Trial (MRFIT),207 smokers did not bene¢t
from intensive lifestyle intervention with regard to the
prevention of type 2 diabetes compared with non-smo-
kers, whereas other studies208--211 reported mixed
e¡ects of smoking on components of the metabolic syn-
drome. Weight gain and increase in WC after smoking
cessation also need to be considered.212
Pharmacological therapy
Lifestyle changes, although bene¢cial, are often di⁄-
cult to implement and maintain. Therefore, pharmaco-
logical intervention may also be appropriate to
individuals with the metabolic syndrome to further
modify cardiovascular risk factors. The Steno 2
study213 compared the e¡ect of a targeted, intensive,
multifactorial intervention with that of conventional
treatment on modi¢able risk factors for CVD in patients
with type 2 diabetes and microalbuminuria. After 7.8-
year follow-up, blood pressure, urinary albumin excre-
tion, concentrations of glycosylated haemoglobin, cho-
lesterol, triglyceride and risk for CVD (hazard ratio
0.47, 95% CI 0.24--0.73) signi¢cantly declined in the
intensive-therapy group compared with the conven-
tional-therapy group. Pharmacological therapies fol-
low current recommendations for treatment of the
metabolic syndrome.
Antihypertensive therapy
Currently used antihypertensive drugs, including
diuretics and b-blockers, although helpful in control-
ling blood pressure may potentially cause deterioration
in the metabolic syndrome or increase the risk of type 2
diabetes.214--216 As a result, angiotensin-converting
enzyme inhibitors (ACEIs) and angiotensin receptor
blockers (ARBs), which have vascular-protective and
renoprotective e¡ects, have attracted increased atten-
tion in the management of the metabolic syndrome.
The randomized, double-blind Heart Outcomes Pre-
vention Evaluation (HOPE) study demonstrated that
ramipril, an ACEI, signi¢cantly reduced the risk of car-
diovascular death by 26% in patients at high risk, com-
pared with placebo;217 ramipril also lowered the risk of
myocardial infarction (MI) by 22%, stroke by 33% and
cardiovascular death by 37% in patients with dia-
betes.218 In the Losartan Intervention For Endpoint
reduction in hypertension (LIFE) study, a double-
masked, randomized, parallel-group study, treatment
with losartan (an ARB) signi¢cantly reduced the risk
for cardiovascular and total mortality by 24% and
39%, respectively, compared with atenolol.219 Several
Ann Clin Biochem 2007; 44: 232–263
250 Qiao et al.

o 3.4 mmol/L (130 mg/dL)

o 4.1 mmol/L (160 mg/dL)
o 5.0 mmol/L (190 mg/dL)
large-scale clinical studies also reported a consistent
reduction in the incidence of type 2 diabetes in indivi-

Non-HDL-cholesterol
duals treated with eitherACEI orARB, compared with a
thiazide diuretic, b-blocker, calcium channel blocker or
placebo.217,220--223 However, other randomized placebo-
controlled trials including the Antihypertensive Treat-
ment and Lipid Pro¢le in a North of Sweden E⁄cacy
Evaluation (ALPINE)224 and Candesartan Role on Obe-

—
—
NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; CVD, cardiovascular disease; LDL, low-density lipoprotein; HDL, high-density lipoprotein
sity and on Sympathetic System (CROSS)225 studies
failed to ¢nd any bene¢cial e¡ect of candesartan
(another ARB) on serum concentrations of glucose,
insulin or triglycerides.

o4.5 mmol/L (175 mg/dL)

o5.0 mmol/L (190 mg/dL)
Recently, telmisartan and irbesartan were found to
be capable of activating peroxisome proliferator acti-
vated receptor (PPAR) g;226--228 this would be of

Total cholesterol
immense value in the treatment of the metabolic syn-
drome. Telmisartan improves isulin sensitivity and low-
ers blood glucose and triglyceride concentrations in
patients with the metabolic syndrome.229,230 In hyper-
tensive diabetic patients, glycosylated haemoglobin

—
—
—
(HbA1c) signi¢cantly decreased after three months of
treatment with telmisartan compared with candesar-
tan.231 In other studies,232,233 telmisartan lowered cho-

o 2.5 mmol/L (100 mg/dL)

o 3.4 mmol/L (130 mg/dL)
o 4.1 mmol/L (160 mg/dL)
lesterol and LDL-C, but failed to improve glucose

o2.5 mmol/L (100 mg/dL)

o3.0 mmol/L (115 mg/dL)
metabolism. As yet, there is no clinical evidence for
irbesartan having insulin-sensitizing e¡ects.
LDL-cholesterol

Lipid-modifying therapy
According to the NCEP-ATPIII guidelines, LDL-C con-
centration is the primary target of therapy. The latest
European guidelines167 also recommend cardiovascu-
lar risk-strati¢ed treatment goals for the management
of dyslipidaemia. Current recommended goals for
Include coronary heart disease (CHD) and CHD risk equivalent (e.g. diabetes)
Table 6 Recommended treatment cholesterol goals in CVD prevention

lipid-lowering treatment in CVD prevention are sum-

10-year risk p20% and X2 risk factors

marized in Table 6.
Statins, the ¢rst-line lipid-lowering therapy,234
10-year risk of CVD death X5%w

reduce CVD events in patients with features of the

10-year risk of CVD death o5%

metabolic syndrome.235 In the Heart Protection Study,

a randomized placebo-controlled study, diabetic
patients receiving 40 mg simvastatin daily had a signif-
icant reduction of 22% in their ¢rst vascular event.236
*
CVD risk categories
10-year risk 420%

The Collaborative Atorvastatin Diabetes Study

o 2 risk factor

(CARDS),237 a randomized controlled clinical trial,

was terminated two years early because patients with
type 2 diabetes receiving atorvastatin 10 mg daily
Include established CVD or diabetes

showed a signi¢cant reduction of 36%, 48% and 31%,

respectively, in acute coronary disease, stroke and
revascularization compared with the placebo group.
The Greek Atovastatin and Coronary-Heart-Disease
Evaluation (GREACE) study238 showed that treatment
13

with atorvastatin reduces cardiovascular events in

NCEP ATP III

European167

patients with components of the metabolic syndrome.

Guidelines

The majority of randomized controlled clinical

trials235,239,240 demonstrated bene¢cial e¡ects of statin
therapy on CVD morbidity and mortality in patients
w
*

Ann Clin Biochem 2007; 44: 232–263


with features of the metabolic syndrome . In the Anglo-
Scandinavian Cardiac Outcomes Trial-Lipid Lowering
Arm (ASCOT-LLA) trial241,242 andWest of Scotland Cor-
onary Prevention Study (WOSCOPS),243 however, no
signi¢cant reductions in non-fatal or fatal coronary
heart disease were observed in patients with the meta-
bolic syndrome or diabetes.
Statins vary in their e⁄cacy on reducing LDL-C con-
centrations. The recent Measuring E¡ective Reductions
in Cholesterol Using Rosuvastatin therapY I
(MERCURY I) trial,244 Statin Therapy for Elevated
Lipid Levels compared Across doses to Rosuvastatin
(STELLAR) trial245 and The COmparative study with
rosuvastatin in subjects with the METabolic Syndrome
(COMETS) study246 showed that rosuvastatin is more
e¡ective in decreasing LDL-C, triglycerides, non-HDL-
C, the total cholesterol/HDL-C ratio and apolipoprotein
B and increasing HDL-C in patients with the metabolic
syndrome compared with other statins.
Statins also exhibit pleiotropic actions beyond the
lipid-lowering e¡ect. Statins favorably modulate
in£ammatory, oxidative and thrombotic responses. In
a randomized crossover trial, three statins (pravasta-
tin, simvastatin and atorvastatin) were shown to pro-
duce similar reductions in CRP concentrations (20.3%,
22.8%, and 28.3%, respectively; Po0.025 versus base-
line) in patients with combined hyperlipidaemia.247
The Protease Activated Receptor-1 (PAR-1) Inhibition
by Statin (PARIS) study248 indicated that statins inhibit
the activity of the platelet PAR-1 thrombin receptor,
which has a major role in regulating platelet activity
and thrombin formation.
Fibrates, PPARa agonists, exert bene¢cial e¡ects on
the atherogenic lipid pro¢le associated with the meta-
bolic syndrome, especially in lowering triglyceride and
raising HDL-C concentrations. Data from Veterans
A¡airs Cooperative Studies Program HDL-C Interven-
tion Trial (VA-HIT) study suggested that patients with
diabetes or metabolic syndrome might bene¢t most
from ¢brates.249,250 Results from 18-year follow-up of
the Helsinki Heart Study indicated that gem¢brozil
reduced the risk of CHD mortality by 23% compared
with the placebo group, and the risk reduced by 71%
in those in the highest tertile of BMI and triglyceride
concentration at baseline.251 Beza¢brate is shown to
attenuate progression of insulin resistance in patients
with coronary arterial disease252 and to reduce the
incidence of MI by 29% in patients with the metabolic
syndrome.253 These results suggest ¢brates may be use-
ful in the management of the metabolic syndrome.
Some studies,253,254 however, failed to show a signi¢-
cant reduction in cardiac mortality associated with
¢brate in either patients with or without the metabolic
syndrome, possibly because of the signi¢cantly greater
use of statins in the placebo group. The main use of
¢brates is probably in combination with statins.255 In
Metabolic syndrome and cardiovascular disease 251
combination with statins, fenobrate seems preferable
to gem¢brozil because of a lower risk for severe myopa-
thy,256 but this remains unclear.257 The pressing ques-
tion is whether adding ¢brate to statin therapy is safe
and reduces cardiovascular events beyond what can
be achieved with statin alone. This should be answered
by the ongoing Action to Control CardiOvascular Risk
in Diabetes (ACCORD) trial, which is expected to report
in 2010.
Nicotinic acid decreases non-HDL-C concentrations
and reduces CVD risk in patients with the metabolic
syndrome and type 2 diabetes.258 In the ARterial
Biology for the Investigation of the Treatment E¡ects
of Reducing cholesterol (ARBITER)-2 trial,259 statin
therapy plus niacin slowed the progression of athero-
sclerosis among CHD patients with low HDL-C concen-
trations. Although nicotinic acid, particularly in large
doses, is reported to decrease insulin sensitivity and
increase plasma glucose concentrations,260,261 recent
data have indicated that it reduces cardiovascular
events despite the moderate increase in glucose con-
centrations.258 Treatment with an extended-release
nicotinic acid by altering FFAs has minimal e¡ects on
insulin sensitivity in patients with the metabolic syn-
drome.262 If nicotinic acid is used with a statin, higher
doses of the statin generally should be avoided to mini-
mize risks for myopathy or hepatic side-e¡ects.
Ezetimibe, a selective inhibitor of intestinal choles-
terol absorption, lowers LDL-C and could help patients
achieve treatment goals. Co-administration of ezeti-
mibe with statin263,264 or ¢brate265 is more e¡ective
than statin alone on lowering plasma concentrations
of LDL-C, non-HDL-C, total cholesterol, apolipoprotein
B and triglycerides. Combining ezetimibe with statin or
¢brate might be another treatment option for patients
with mixed dyslipidaemias.
Cholesteryl ester transfer protein (CETP) appears to
play an important role in cholesterol metabolism, being
responsible for the transfer of cholesteryl esters from
HDL to VLDL and LDL.266 Therefore, inhibitors of CETP,
which are currently being developed, may potentially
o¡er bene¢t to patients with the metabolic syn-
drome.267
Hypoglycaemic and insulin-sensitizing therapy
At present, two classes of drugs target insulin resis-
tance directly, the biguanides (metformin) and the
PPAR agonists thiazolidinediones (TZDs). In the Dia-
betes Prevention Program Trial, metformin reduced
the incidence of the metabolic syndrome by 17%
(P ¼ 0.03) during 3.2-year follow-up compared with
placebo in those without the metabolic syndrome at
baseline.165 Metformin also improves endothelial func-
tion268,269 in patients with metabolic syndrome.
TZDs improve insulin sensitivity and lower glucose
Ann Clin Biochem 2007; 44: 232–263
252 Qiao et al.
concentrations in patients with diabetes or the meta-
bolic syndrome.270,271 They may therefore have a role
in the management of the metabolic syndrome despite
the hepatotoxity of troglitazone (withdrawn from the
market) and undesirable e¡ects including weight gain
and oedema.272 Rosiglitazone lowers in£ammatory
markers and improves endothelial function in patients
with type 2 diabetes or proven coronary disease.273 In a
randomized, double-blind, placebo-controlled trial
involving patients with the metabolic syndrome,274 12-
month treatment with rosiglitazone signi¢cantly
improved serum concentrations of CRP, IL-6, IL-18,
adiponectin and £ow-mediated vasodilation compared
with placebo. A recent trial found that pioglitazone was
associated with signi¢cant improvements in triglycer-
ides, HDL-C, non-HDL-C and LDL particle size com-
pared with rosiglitazone.275 Furthermore, TZDs were
associated with signi¢cant reduction of blood pressure
in patients with components of the metabolic syn-
drome.276,277 Results from randomized Prospective Pio-
glitazone Clinical Trial in macrovascular events
(PROactive) trial278 in 5238 patients with type 2 dia-
betes at high risk of macrovasuclar events showed
treatment with pioglitazone was associated with a sig-
ni¢cant 16% reduction in the secondary composite
endpoint of death, myocardial infarction and stroke.
Data, however, regarding the e¡ect of these agents on
vascular endpoints in patients with metabolic syn-
drome are limited.
The multicentre double-blind, placebo-controlled,
randomized Study to Prevent Noninsulin-Dependent
Diabetes Mellitus (STOP-NIDDM) trial279,280 reported
that acarbose, an a-glucosidase inhibitor, signi¢cantly
reduced risk of CVD and hypertension as well as pro-
gression to diabetes in patients with IGT. Dual (a/g)
PPAR activators are in development as they have the
potential to reduce CVD risks. Animal experiments184
and clinical trials281--283 have shown beni¢cial e¡ects
of these agents on glycaemic control and dyslipidae-
mia, which may improve metabolic abnormalities asso-
ciated with insulin resistance.Weight gain and oedema
were, however, more common with dual PPAR activa-
tors compared with pioglitazone.283 Furthermore in a
meta-analysis, these agents were associated with an
increased incidence of MI, transient ischaemic attack
and stroke,284 raising doubts about their usefulness.
Other emerging therapies such as incretin mimetics285
and dipeptidyl peptidase IV inhibitors286 may o¡er
potential in managing the metabolic syndrome.
Anti-obesity therapy
Orlistat is a gastrointestinal lipase inhibitor that
reduces intestinal fat absorption. Orlistat treatment is
associated with weight loss and an improvement in
dyslipidaemia, glucose and HbA1c.287,288 In the XENical
Ann Clin Biochem 2007; 44: 232–263
in the prevention of Diabetes in Obese Subjects (XEN-
DOS) trial,289 a randomized double-blind study of 3305
obese non-diabetic individuals, orlistat (plus lifestyle
changes) signi¢cantly reduced the incidence of type 2
diabetes by 37.3% compared with placebo (plus lifestyle
changes). Furthermore, in the ORLIstat and CARdio-
vascular risk pro¢le in patients with metabolic syn-
drome and type 2 DIAbetes (ORLICARDIA) study,290 a
prospective, multicentre, open-label, randomized, con-
trolled study, the six-month co-administration of orli-
stat plus a hypocaloric diet reduced the proportion of
patients meeting the de¢nition of the metabolic syn-
drome by 35% compared with hypocaloric diet alone
(Po0.0001) in patients with both type 2 diabetes and
the metabolic syndrome. These ¢ndings suggest that
pharmacotherapy for obesity should be used as an
adjunct to, rather than as a replacement of lifestyle
changes.
Inhibition of the endocannabinoid system is believed
to play a key role in the central and peripheral regula-
tion of energy balance, fat accumulation, glucose and
lipid metabolism.291 Rimonabant, a selective blocker of
cannabinoid 1 (CB1) receptors with both central and
peripheral actions,291 improves CV risk factors in high-
risk populations. In the Rimonabant in Obesity (RIO)-
North America trial,292 20 mg of rimonabant plus a
standard dietary intervention produced sustained
weight loss and favourable changes in cardiovascular
risk factors compared with placebo. Two randomized,
double-blind, placebo-controlled trials, the RIO-Europe
study,293 along with the RIO-Lipids study,294 reported
that the prevalence of the metabolic syndrome was sig-
ni¢cantly reduced by 22--29% in the group receiving
20 mg of rimonabant compared with the placebo group
in dyslipaemic patients who are overweight. In the RIO-
Lipids study, rimonabant was associated with a signi¢-
cant increase in concentration of plasma adiponectin
(57.7%) and a signi¢cant decrease in plasma concentra-
tions of leptin and CRP. The adverse events reported,
including nausea, diarrhoea, dizziness and mood disor-
ders were transient, generally mild or moderate and
occurring early in the treatment period.293,294 Treat-
ment with CB1 receptors blocker o¡er a novel approach
in management of the metabolic syndrome.
Antiplatelet therapy
Aspirin is widely used in the prevention of cardiovascu-
lar events in high-risk populations. A meta-analysis295
showed that aspirin was associated with a signi¢cant
32% and 15% reduction in the risk of ¢rst MI and all
vascular events respectively among the 55,580 rando-
mized participants (11, 466 women), but it had no sig-
ni¢cant e¡ects on non-fatal stroke or vascular death.
A randomized primary-prevention trial in women
demonstrated that low-dose aspirin lowered the risk of

stroke without a¡ecting the risk of MI or death from
CVD.296 Another recent sex-speci¢c meta-analysis of
randomized controlled trials297 revealed that aspirin
therapy reduced the risk of cardiovascular events in
women largely due to a 24% risk reduction in ischae-
mic stroke and in men largely due to a 32% risk reduc-
tion in MI. There are several possible explanations for
these gender di¡erences. The pharmacological e¡ect of
aspirin might be reduced in women compared with
men; women have a great proportion of strokes
compared with MI, while men have great proportion
of MI compared with strokes; aspirin resistance is more
common in women than in men.298 Aspirin reduces
the concentrations of CRP and IL-6,299,300 but the dose
of aspirin required to achieve the maximal anti-in£am-
matory e¡ect remains unknown.
These data emphasize the importance of aspirin as
adjunctive therapy for patients with the metabolic syn-
drome. Guidelines from the AHA recommend the use of
low-dose aspirin (75--160 mg/day) for individuals at
high risk especially for those with a 10-year risk of a
coronary event of at least 10%.177
Surgical treatment
Surgery is an e¡ective option for grossly obese patients.
In the Swedish Obese Subject (SOS) study,301 weight loss
by gastric banding, vertical banded gastroplasty (VBG)
or gastric bypass resulted in signi¢cant reductions in
the two-year and eight-year incidence of diabetes and
other cardiovascular risk factors compared with
weight stability, while the eight-year incidence of
hypertension was equal in the two treatment groups.
Surgical weight loss by laparoscopic Roux-en-Y gas-
tric bypass is reported to reduce the prevalence of the
metabolic syndrome from 70% to 14% (Po0.001) in
severely obese patients with non-alcoholic fatty liver
disease.302 A 10-year follow-up study303 showed that
after gastric bypass and biliopancreatic diversion
(BPD), fasting glucose, triglyceride and total cholester-
ol concentrations steadily normalized in most of all 312
subjects with abnormally high preoperative values, and
that arterial hypertension disappeared in the majority
of the preoperatively hypertensive patients. BPD, there-
fore, favourably in£uences the major components of
the metabolic syndrome. In another study,304 Swedish
Adjustable Gastric Banding (SAGB) in 51 premenopau-
sal severely obese women signi¢cantly reduced BMI,
Homeostasis Model Assessment (HOMA) index and the
prevalence of the metabolic syndrome (58.8% versus
21.6%, Po0.001) within one year of surgery.
In severely obese patients, surgery has a role in redu-
cing cardiovascular risk and improving long-term
prognosis. Obese patients with a BMI of 40 kg/m2 or
greater may bene¢t from surgical treatment.305
Metabolic syndrome and cardiovascular disease 253
Weight-loss operations, however, are not without risk
and careful selection of patients involves a multidisci-
plinar approach.
Summary and conclusion
The de¢nition of the metabolic syndrome remains
imprecise with several di¡erent de¢nitions. The com-
ponents involved in the de¢nitions however are more
or less similar but with di¡erent cut-o¡ values and
emphasis. The prevalence of the metabolic syndrome
varies according to de¢nition, ethnicity and gender.
Subjects with the metabolic syndrome are at increased
cardiovascular risk but whether it is a useful cardiovas-
cular risk marker above and beyond the risk associated
with its individual components is uncertain. The
mechanism underlying the clustering of cardiovascu-
lar risk factors remains unclear. Factors including
genetic disposition, obesity, insulin resistance and
in£ammation have been suggested to be involved in its
pathogenesis. Since the metabolic syndrome is multi-
factorial in origin, strategies for reducing cardiovascu-
lar risk in individuals with the metabolic syndrome
involve the management of multiple risks and include
lifestyle changes and pharmacological interventions
for hypertension, diabetes and dyslipidaemia. In
grossly obese patients pharmacological and surgical
therapies may be useful options.
Debate continues on whether the metabolic syn-
drome is a separate disease entity, whether we can ¢nd
a globally uni¢ed de¢nition, whether the metabolic
syndrome is more useful than its single individual com-
ponents in prediction of CVD risk and whether there is
any clinical value in diagnosing the metabolic
syndrome since its management is no di¡erent
than the management of each of its individual compo-
nents.
Acknowledgements
The work has been carried out with a help of a grant
from the Finnish Academy (118492), and from Novo
Nordisk Foundation 2005.
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Accepted for publication 13 February 2007
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