the metabolic syndromeb prevalence, chd risk, and treatment

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The metabolic syndromeB

Prevalence, CHD risk, and treatment

Cinzia Sartia,T, John Gallagher b

a National Public Health Institute, Helsinki, Finland

b AstraZeneca SA, Zaventem, Belgium

Received 4 February 2004; received in revised form 1 June 2005; accepted 7 June 2005

Abstract

An increased risk of coronary heart disease (CHD) morbidity and mortality is associated with the metabolic syndrome, a condition

characterized by the concomitant presence of several abnormalities, including abdominal obesity, dyslipidemia, hypertension, insulin

resistance (with or without glucose intolerance or diabetes), microalbuminuria, prothrombotic, and proinflammatory states. Estimates of the

prevalence of the metabolic syndrome indicate that this condition is now common and likely to increase dramatically over the coming decades,

in parallel with greater rates of obesity and Type 2 diabetes. Risk factors for the metabolic syndrome are already present in obese children and

adolescents. Thus, identifying and treating all affected individuals promptly and optimally are critical to ensure that this potentially challenging

healthcare burden is minimized. Here, we review the prevalence of the metabolic syndrome, dyslipidemias, and CHD risk. Although changes

in lifestyle are fundamental to reducing many of the CHD risk factors associated with the metabolic syndrome, pharmacologic interventions

also play an important role. Retrospective subanalyses of the effects of statins on coronary event rates and lipid levels in patients with the

metabolic syndrome included in clinical trials indicate that these agents are beneficial in correcting the extensive lipid abnormalities that are

frequently present in these individuals. However, the optimal management of metabolic syndrome dyslipidemia will depend on the outcomes

of future prospective clinical trials. This review examines the underlying causes and prevalence of the metabolic syndrome and its impact on

CHD morbidity and mortality and discusses the role of statins in optimizing its management.D 2006 Elsevier Inc. All rights reserved.

Keywords: Coronary heart disease; metabolic syndrome; statins; dyslipidemia

1. Introduction

Despite the introduction of guidelines for its prevention

and treatment, coronary heart disease (CHD) continues to be

a leading cause of death worldwide, and in 2001, mor e than

seven million deaths were attributable to this disease (World

Health Organization [WHO], 2002). In Europe, CHDaccounts for most deaths each year (almost two million,

representing 21% of all mortality; Rayner & Petersen, 2000).

The multifactorial nature of CHD is well established,

with both modifiable and nonmodifiable risk factors

contributing to its incidence (National Cholesterol Educa-

tion Program Adult Treatment Panel [NCEP ATP] III;

Expert Panel on Detection and Evaluation, and Treatment of

High Blood Cholesterol in Adults, 2001; De Backer et al.,

2003). However, the concomitant presence of several CHDrisk factors is now recognized as a disease entity that

impacts disproportionately and unfavorably on CHD mor-

bidity and mortality: the metabolic syndrome (Grundy,

1999; Kaplan, 1989; Reaven, 1988, 1995).

The optimal identification and treatment of patients with

the metabolic syndrome (also termed syndrome X, insulin

resistance syndrome, the deadly quartet, or dysmetabolic

syndrome X) is increasingly being recognized as critical in

preventing the condition becoming a major healthcare

1056-8727/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.jdiacomp.2005.06.014

B Funding for the article was supported by AstraZeneca.

T Corresponding author. Department of Epidemiology and Health

Promotion, National Public Health Institute, Mannerheimintie 166, Helsinki

FIN-00300, Finland. Tel.: +358 505 831305; fax: +358 947 448338.

E-mail address: [email protected] (C. Sarti).

Journal of Diabetes and Its Complications 20 (2006) 121 – 132



burden. This review is not intended to exhaustively cover all

the risk factors contributing to the metabolic syndrome but

concentrates on dyslipidemias and the role of statins in

optimizing its management. In particular, it examines the

prevalence of the metabolic syndrome, its impact on CHD

morbidity and mortality, and discusses the role of the risk

factors directly or indirectly relevant to dyslipidemias andthe conferred CHD risk.

2. Diagnostic features of the metabolic syndrome

The key components of the metabolic syndrome include

abdominal obesity, dyslipidemia, hypertension, insulin

resistance (with or without glucose intolerance or diabetes),

prothrombotic, and proinflammatory states (Grundy, 1999;

Reaven, 1988; Sakkinen, Wahl, Cushman, Lewis, & Tracy,

2000). The complex interactions and cause-and-effect

relationships between these factors make it difficult to

determine the relative importance or precise contribution of each (all the components can occur in isolation). However,

insulin resistance and obesity are frequently identified as

root causes of the syndrome.

The definition of the metabolic syndrome is not univer-

sally agreed, and at least three sets of criteria for identifying

patients have been developed (NCEP ATP III; Expert Panel

on Detection and Evaluation, and Treatment of High Blood

Cholesterol in Adults, 2001; Balkau et al., 2002; WHO, 1999;

Table 1). The WHO defines the metabolic syndrome as

requiring the presence of impaired glucose regulation or

insulin resistance and at least two risk factors among

hypertension, dyslipidemia, obesity, and microalbuminuria

and includes individuals with and without diabetes.In contrast, the European Group for the Study of Insulin

Resistance (EGIR) only defines the syndrome for those

without diabetes but with hyperinsulinemia (a sur rogate

marker of insulin resistance; Balkau et al., 2002). The

NCEP ATP III definition of the metabolic syndrome is

based on the WHO criteria and requires the presence of at

least three risk factors (hypertension, dyslipidemia, central

obesity, raised fasting glucose) but does not include any

measure of insulin resistance (NCEP ATP III; Expert Panel


Cholesterol in Adults, 2001). All the definitions recognizethe importance of visceral adiposity, but the threshold for

waist circumferences is least stringent for the NCEP ATP III

definition, while the WHO definition advocates the use of

waist-to-hip ratio rather than waist circumference.

Obesity is a major underlying cause of the metabolic

syndrome. It is most commonly assessed by measuring body

mass index (BMI), with definitions of normal, overweight,

and obesity provided by the WHO (James, Leach, Kalamara,

& Shayeghi, 2001). However, abdominal obesity (assessed

by waist circumference or waist-to-hip ratio) may be a better

indicator of increased CHD risk than overall excess body-

weight (Lakka, Lakka, Tuomilehto, & Salonen, 2002;Lapidus et al., 1984; Prineas, Folsom, & Kaye, 1993; Rimm

et al., 1995). Thus, in a population-based study of men from

Finland (the Kuopio Ischaemic Heart Disease Risk Factor

Study), the risk of coronary events in men with a waist-to-hip

ratio z0.91 was nearly threefold greater than in men with a

waist-to-hip ratio b0.91, and this increased risk was not

influenced significantly by BMI (Lakka, Lakka, et al., 2002).

The metabolic consequences of abdominal obesity include

increased risk of Type 2 diabetes, atherogenic dyslipidemia,

and hypertension, all well-established risk f actors for CHD

(Despres, Lemieux, & Prud’homme, 2001). Greater body

weight is also associated with more advanced coronary

atherosclerosis. Postmortem examination of cases of suddenunexpected death in women aged 15–50 years revealed that

the most severe coronary lesions were associated with mild-

to-moderate overweight and visceral adiposity (thickness of

abdominal subcutaneous fat; Kortelainen & Sarkioja, 1999).

Table 1

Criteria to define the metabolic syndrome

Criterion WHO (1999)

NCEP ATP (Expert Panel on

Detection and Evaluation, and

Treatment of High Blood

Cholesterol in Adults, 2001) EGIR (Balkau et al., 2002)

Requirement Impaired glucose regulation or diabetes and/or insulin resistance

plus z2 of the following

z3 of the following Hyperinsulinemia (fasting insulin concentrationabove the upper quartile for the nondiabetic subjects)

plus z2 of the following

Blood pressure z140/90 mm Hg z130/85 mm Hg z140/90 mm Hg and/or treatment for hypertension

Triglycerides

HDL-C

z1.7 mmol/l (150 mg/dl)

Men: b0.9 mmol/l (35 mg/dl)

Women: b1.0 mmol/l (39 mg/dl)

z1.7 mmol/l (150 mg/dl)

Men: b1.0 mmol/l (40 mg/dl)

Women: b1.3 mmol/l (50 mg/dl)

Triglycerides N2.0 mmol/l (180 mg/dl) and/or

HDL-C b1.0 mmol/l (40 mg/dl)

and/or treatment for dyslipidemia

Central obesity BMI N30 kg/m2 and/or

Men: waist-to-hip ratio N0.90 Men: waist circumference N102 cm Men: waist circumference z94 cm

Women: waist-to-hip ratio N0.85 Women: waist circumference N88 cm Women: waist circumference z80 cm

Microalbuminuria Urinary albumin excretion rate

z20 Ag/min or albumin: creatinine

ratio z30 mg/g

Fasting glucose z6.1 mmol/l (110 mg/dl) z6.1 mmol/l [110 mg/dl; z5.6 mmol/l

(101 mg/dl) for venous or capillary whole blood]

C. Sarti, J. Gallagher / Journal of Diabetes and Its Complications 20 (2006) 121–132122



Insulin resistance predisposes to features of the meta-

bolic syndrome, including dyslipidemia and hypertension,

as well as being the central metabolic defect that leads to

the development of Type 2 diabetes (Reaven, 1995). The

greatly increased CHD morbidity and mortality in pa-

tients with diabetes is well established (Haffner, Lehto,

Ronnemaa, Pyorala, & Laakso, 1998; Stamler, Vaccaro, Neaton, & Wentworth, 1993). For example, in a population-

based study from Finland, the risk of myocardial infarction

(MI) over 7 years in patients with diabetes without previous

MI at baseline was similar (20.2%) to that for patients

without diabetes but with previous MI (18.8%); however,

for patients with both diabetes and previous MI, the risk

was more than doubled (45%; Haffner et al., 1998). Among

men participating in the Multiple Risk Factor Intervention

Trial (MRFIT), the relative risk of death from CHD

(adjusted for age, race, income, systolic blood pressure,

and smoking) was 3.2-fold higher in the subpopulation of

diabetes patients compared with subjects without diabetes(Stamler et al., 1993).

Insulin resistance has been proposed as the underlying

pathophysiological mechanism of the metabolic syndrome

(Reaven, 1988), but this simplified theory does not take into

account the intercorrelation between the factors involved in

the syndrome. Factor analysis on Chinese patients, however,

showed that different components of the metabolic syn-

drome are clustered differently among diabetic and non-

diabetic subjects (Wang et al., 2003). While obesity and

insulin resistance factors were the strongest predictors of

Type 2 diabetes, blood pressure and lipids were more

important in the subjects without overt diabetes.

Specific triglyceride (TG) and high-density lipoproteincholesterol (HDL-C) levels are also included in all defi-

nitions, although the cutoff values vary across the different

sets of criteria. Patients with the metabolic syndrome are

characterized by a complex array of lipid abnormalities.

Atherogenic dyslipidemia [raised TG levels, low HDL-C

levels, and a greater preponderance of small, low-density

lipoprotein (LDL) particles] is frequently observed (Grundy,

1999); however, many patients also have raised LDL-C

levels. For example, in a pooled analysis of patients with

LDL-C levels z160 mg/dl, 33% met t he NCEP ATP III

definition of the metabolic syndrome (Ballantyne, Stein,

Paoletti, Southworth, & Blasetto, 2003). Furthermore, therisk of CHD in patients with the metabolic syndrome is

increased at all LDL-C levels (NCEP ATP III; Expert Panel


Cholesterol in Adults, 2001).

The lipid disturbances characteristic of atherogenic

dyslipidaemia are related to insulin resistance, and a number

of mediators are thought to be involved, including hepatic

lipase, lipoprotein li pase, and cholesterol ester transfer

protein (reviewed in Ayyobi & Brunzell, 2003; Rosenson,

2005). Other risk factors associated with the metabolic

syndrome, including hypertension and a procoagulant

state, are interrelated with TGs, and hypertriglyceridemia

is an important marker for the syndrome (Grundy, 1998).

Furthermore, raised TG levels are an independent risk

factor for C HD (Assmann, Schulte, Funke, & von

Eckardstein, 1998; Austin, Hokanson, & Edwards, 1998).

Low HDL-C levels are also associated with increased CHD

morbidity and mortality, and epidemiologic studies consis-

tently show that low HDL-C is an independent risk factor for CHD (NCEP ATP III; Expert Panel on Detection and

Evaluation, and Treatment of High Blood Cholesterol in

Adults, 2001). In addition, evidence from interventional

studies suggests that raising HDL-C is associated with

improved cardiovascular outcomes (Brown et al., 2001;

Rubins et al., 1999).

Results from several studies suggest that the beneficial

effect of statins is not due only to the control of lipid

parameters, but intervene in the atherosclerotic process at the

endothelial level. Endothelial dysfunction has been impli-

cated in the pathogenesis of atherosclerosis (Libby, Ridker,

& Maseri, 2002) and results in the promotion of lesionformation because of a disruption of anti-inflammatory

processes, greater endothelial permeability, and reduced

availability of vasodilators such as nitric oxide (NO). Several

studies suggest that insulin resistance may promote endo-

thelial dysfunction by a number of mechanisms, including

disturbance of cell signalling pathways shared by insulin

action and NO production and links with endothelin, the

r enin–angiotensin system, and adipose tissue meta bolism

(Wheatcroft, Williams, Shah, & Kearney, 2003). The

association of insulin resistance with increased plasma

concentrations of asymmetric dimethlyarginine (ADMA),

which inhibits endothelial NO synthase (eNOS) activity and

increases endothelial activity and monocyte adhesiveness,may also contribute to endothelial dysfunction (Stuhlinger

et al., 2002). There may also be a role of a genetic variation

in the eNOS gene in triggering some of the abnormalities

characteristic of the metabolic syndrome (Monti et al., 2003).

Activation of the sympathetic nervous system in metabolic

syndrome patients may also contribute to the pathogenesis

and complications of the metabolic syndrome through a

variety of actions (Egan, 2003).

Systemic oxidative stress has a contributory role in

atherosclerosis, with oxidatively modified LDL promoting

inflammatory responses and endothelial dysfunction. The

deleterious effects of oxidative stress are likely to beexacerbated in patients with the metabolic syndrome;

accelerated atherosclerosis is a feature of the metabolic

syndrome, insulin resistance, prediabetes, and overt Type 2

diabetes (Hayden & Tyagi, 2002). In individuals from the

Framingham Heart Study, smoking, diabetes, and obesity

were all found to be st rong independent predictors of

systemic oxidative stress (Keaney et al., 2003). Small dense

LDL particles, such as those associated with the metabolic

syndrome, are particularly atherogenic: as well as a greater

ability to penetrate the vessel walls, they are also more

susceptible to oxidation (De Graaf et al., 1991; Tribble, Holl,

Wood, & Krauss, 1992). This is further compounded by the

C. Sarti, J. Gallagher / Journal of Diabetes and Its Complications 20 (2006) 121–132 123



low levels of HDL-C in these patients, reducing the

beneficial effects of HDL-C in inhibiting LDL oxidation

(Mackness, Arrol, Abbott, & Durrington, 1993; Navab,

Hama, Anantharamaiah et al., 2000; Navab, Hama, Cooke

et al., 2000). Consistent with these factors is the observation

of elevated levels of oxidized LDL in patients with the

metabolic syndrome (Holvoet et al., 2002; Sigurdardottir,

Fagerberg, & Hulthe, 2002).

Increased levels of C-reactive protein (CRP) are alsocharacteristic of the metabolic syndrome. CRP is a marker

of inflammation that is a strong independent indicator of

incident cardiovascular disease (CVD), and its measurement

in patients with the metabolic syndrome adds important

prognostic information for assessing the risk of cardiovas-

cular events (Frohlich et al., 2000; Mora et al., 2003; Ridker,

Buring, Cook, & Rifai, 2003). An evaluation of more than

14,000 apparently healthy women followed prospectively

for 8 years showed a strong linear increase in CRP levels as

the number of components of the metabolic syndrome

increased. Moreover, the impact of raised CRP levels on the

risk of future cardiovascular events was particularly markedf or those women with three, four, or five components

(Ridker et al., 2003). In a population-based study conducted

in Germany, CRP levels correlated with features of the

metabolic syndrome; this correlation was significant for

BMI ( P =.0001), diabetes ( P =.005), and uric acid ( P =.01).

In addition, CR P values increased with the number of

features present (Frohlich et al., 2000).

An unfavorable balance between prothrombotic and

fibrinolytic factors is a feature of the metabolic syndrome.

For example, levels of plasminogen activator inhibitor Type

1 (PAI-1), a marker of decreased fibrinolytic capacity, were

strongly correlated with insulin levels in patients who were

included in the European Concerted Action on Thrombosis

and Disabilities (ECAT) angina pectoris study (Juhan-Vague,

Thompson, Jesperson, & on behalf of the ECAT Angina

Pectors Study Group, 1993). An analysis of participants in

the Cardiovascular Health Study and the Honolulu Heart

Program suggested that depressed plasmin generation may

enhance the progression of atherosclerosis in individualswith hyperinsulinemia or glucose intolerance (Sakkinen

et al., 1999). Furthermore, the overrepresentation of partic-

ular alleles of identified PAI-1 polymorphisms may also

contribute to a more severe insulin-resistant metabolic

profile in overweight participants (Lopes, Dina, Durand, &

Froguel, 2003). In contrast, the increased risk of subsequent

cardiovascular events associated with the von Willibrand

factor is largely independent of metabolic variables ( Nilsson,

Boman, Bjerle, Hallamns, & Hellsten, 1994).

In sum, the metabolic syndrome is a cluster of intercorre-

lated disorders, and none of the definitions put forward so far

seems to be optimal. While a consensus definition of themetabolic syndrome would be welcome (since different

definitions identify a different segment of the population at

risk of CHD), dyslipidemias is a central parameter of the

metabolic syndrome, regardless of the definition. The

clarification of the exact role of dyslipidemias, nowadays

effectively treated with statins and other drugs, in the

metabolic syndrome will promote the prevention of CHD.

3. Impact of the metabolic syndrome on CHD morbidity

and mortality

The greater incidence of CHD morbidity and mortality in patients with the metabolic syndrome is well established. In

the Botnia study (a family study conducted in Finland and

Sweden), the prevalence of CHD was significant ly greater

in patients with the metabolic syndrome (Fig. 1), with the

Fig. 1. Prevalence of CHD in individuals with and without metabolic

syndrome (Isomaa et al., 2001). * P b.05, *** P b.001 vs. nonmetabolic

syndrome patients. NGT, normal glucose tolerance; IFG, impaired fastingglucose; IGT, impaired glucose tolerance. Copyright 2001 American

Diabetes Association. From Diabetes Care, 24:2001;683–689. Reprinted

with permission from the American Diabetes Association.

Fig. 2. Total and cardiovascular mortality in individuals with and without

the metabolic syndrome (Isomaa et al., 2001). *** P b.001 vs. nonmetabolic

syndrome patients.




risk of CHD increased threefold ( P b.001) and car diovas-

cular mortality mor e than fivefold higher ( P b.001; Fig. 2;

Isomaa et al., 2001). Mortality (CHD, cardiovascular, and

total) was increased in middle-aged men with the metabolic

syndrome in the prospective population-based Kuopio Heart

Study (Lakka, Laaksonen, et al., 2002). Based on the WHO

definition of the metabolic syndrome and after adjustment for conventional cardiovascular risk factors, these individ-

uals were 2.9–3.3 times more likely to die of CHD (NCEP

ATP III: 2.9 – 4.2 times), with 2.6– 3.0 times higher CVD

mortality and 1.9–2.1 times higher all-cause mortality, even

in the absence of baseline CVD and diabetes. Cardiovas-

cular and overall mortality was slightly lower using the

NCEP criteria for the metabolic syndrome. In the MRFIT

study, men with the metabolic syndrome had a significantly

increased risk of total and CVD mortality ( P b.0001) relative

t o those with neither the metabolic syndrome nor diabetes

(Cohen, Eberly, Prineas, & Vasquez, 2003). In the West Of

Scotland COronary Prevention Study (WOSCOPS), menwith the metabolic syndrome had a significantly higher

cardiac event rate than did those without the syndrome

(12.6% vs. 7.3%, P b.0001; L’Italien, Ford, & Shepherd,

2003). There was also a strong and consistent relationship

between the metabolic syndrome and a history of MI and

stroke in the National Health and Nutrition Examination

Survey III (NHANES III; Ninomiya et al., 2003).

Although the Prospective Cardiovascular Mqnster (PRO-

CAM) study did not stratify participants according to recent

definitions of the metabolic syndrome, men with concom-

itant hyperlipidemia, hypertension, and/or diabetes had a

19-fold increase in the incidence of MI compared with

individuals without these risk factors (Assmann & Schulte,1988). In a cross-sectional study of normoglycemic men

with a waist circumference z90 cm and fasting triglycer-

idemia z2.0 mmol/l (177 mg/dl), the risk of coronary artery

disease was 5.4-fold higher compared with controls,

increasing to 8.5-fold in the presence of impaired fasting

glucose, whereas the latter alone only increased the risk 1.6-

fold (St-Pierre et al., 2002).

4. How prevalent is the metabolic syndrome?

In the absence of a universally accepted definition of the metabolic syndrome, estimates of its prevalence vary.

Data from studies performed in seven European countries

between 1981 and 1997 revealed prevalences ranging from

1% to 36% in men and 1% to 22% in women, depending

on the timing of the study, type of patient s included, and

differences in lifestyles (Balkau et al., 2002). In the Botnia

study, the metabolic syndrome (based on the WHO

definition) was evident in approximately 10% of normal

subjects, approximately 50% of those with impaired fasting

glucose or impaired glucose tolerance, and approximately

80% of Type 2 diabetes patients (Isomaa et al., 2001). The

metabolic syndrome (EGIR definition) was present in

19.4% of men and 15.0% of women in a cross-sectional

case-control study of subjects aged 45–68 years in

Sweden that excluded those with a history of MI, stroke,

diabetes, or a fasting glucose z6.1 mmol/l ( Nilsson &

Hedblad, 2002). The metabolic syndrome, defined as a

clustering of dyslipidemia (hypertriglyceridemia, low

HDL-C, or both) and insulin resistance (abnormal glucosetolerance, hyperinsulinemia, or both), was found in 17% of

men and in 8% of women from Finland (Vanhala,

Kumpusalo, Pitkajarvi, & Takala, 1997). In the Kuopio

Heart Study, the prevalence of the metabolic syndrome

was detected in 8.8–14.3% of men from Finland, depend-

ing on the criteria used (NCEP ATP III, WHO, and dif-

ferent definitions of abdominal obesity; Lakka, Laaksonen

et al., 2002).1

In the United States, the prevalence of the metabolic

syndrome has been assessed among adults aged z20 years

included in NHANES III (1988–1994; Ford & Giles, 2003;

Ford et al., 2002). The age-adjusted prevalences were 23.9%for the NCEP ATP III definition and 25.1% for the WHO

definition; overall, 86.2% of individuals were classified

concordantly for the two definitions of the metabolic

syndrome, although estimates differed among some sub-

groups (e.g., African-American men). Prevalence was

highly correlated with age, increasing from 6.7% among

20- to 29-year-olds to over 40% for those aged z60 years

(NCEP ATP III definition; Ford et al., 2002).

The prevalence of the met abolic syndrome increases

dramatically with higher BMI (Park et al., 2003). For men

participating in the NHANES III survey, the prevalence of

the metabolic syndrome was 4.9- and 13-fold higher for

those classified as overweight or obese compared with thoseof normal weight. A similar trend was evident in women,

with increased prevalences of 4.5- and 8.1-fold, respec-

tively. Weight gain in early-to-middle adulthood is also a

concern. In a population-based study, the risk of developing

the metabolic syndrome was increased by nearly 20% for

each 5% increase in weight from age 20 to an average age of

53 years (Everson et al., 1998).

The worldwide epidemic of obesity is evident in Europe,

with a prevalence of 10–20% in men and 10–25% in

women (WHO, 2000). The WHO MONICA (multinational

MONitoring of trends and determinants in CArdiovascular

disease) project observed a trend f or increasing BMI over a10-year period (Evans et al., 2001). Among men, BMI was

increased in approximately three-quarters of the study

populations [significantly ( P b.05) for half the populations].

For women, the trend was less marked, although upward

trends were evident in half the po pulations studied, half of

which were significant ( P b.05; Evans et al., 2001). The

proportion of CHD patients classed as overweight or obese

1 The provisional WHO definition of metabolic syndrome, differing

of BP (160/90; Alberti & Zimmet, 1998) was used by Ford, Giles, and

Dietz, 2002.




was consistently higher in all countries participating in

the second of the two European Action on Secondary Pre-

vention by Intervention to Reduce Events (EUROASPIRE)

surveys, with the proportion of obese patients (BMI z

30 kg/m2) increasing from 25.3% in 1995 –1996 t o 32.8% in

1999–2000 (EUROASPIRE I & II Group, 2001).

The prevalence of Type 2 diabetes is also increasing; by2025, the number of adults with diabet es has been

predicted to rise to 300 million worldwide (King, Aubert,

& Herman, 1998). Consistent with this, the prevalence of

reported diabetes mellitus in the second EUROASPIRE

survey (1999–2000) was 21.9% compared with 18.0% in

1995–1996. Clearly, the epidemiologic trends in obesity

and diabetes, as well as increasing longevity, will impact

significantly on the prevalence of the metabolic syndrome.

Indeed, with the increasing prevalence of obesity in the

United States since NHANES III was completed, and with

the use of different diagnostic criteria for the metabolic

syndrome, it is likely that the estimate of 47 millionindividuals having this condition (NCEP ATP III) has now

been exceeded (Ford et al., 2002).

4.1. The metabolic syndrome in children and young adults

Most studies have concentrated on the prevalence of the

metabolic syndrome in middle-aged and older individuals;

however, it is becoming clear that the risk factor s for its

development are evident much earlier in life (Sinaiko,

Donahue, Jacobs, & Prineas, 1999). In the Bogalusa Heart

Study, fatty streaks and fibrous plaques were observed in

the aorta and coronary arteries of children and adolescents,

and the severity of asymptomatic atherosclerosis increasedwith the number of cardiovascular risk factors present

(Berenson et al., 1998). The case of a 12-year-old girl with

the metabolic syndrome was recently described. The

authors of this report suggested that the presence of one

cardiovascular risk factor in an overweight child should

prompt the physician t o investigate for other features of the

metabolic syndrome (Falkner, Hassink, Ross, & Gidding,

2002). Hyperinsulinemia is already associated with a

cluster of CVD risk factors in young adulthood (Bonora

et al., 1997; Manolio et al., 1990; Ronnemaa et al., 1991).

The antecedents of adult disease occur in obese children and

adolescents (Kang et al., 2002; Sinha et al., 2002; Youssef,Valdez, Elkasabany, Srinivasan, & Berenson, 2002). In the

United States, impaired glucose tolerance has been

reported in 25% of obese children (aged 4–10 years) and

21% of obese adolescents (aged 11–18 years), and silent

Type 2 diabetes was diagnosed in 4% of the latter group

(Sinha et al., 2002). Among obese adolescents, the

atherogenic phenotype of small, dense LDL particles was

found to be common and significantly associated with other

markers of the metabolic syndrome, including greater

weight ( P =.033), high waist circumference ( P =.02),

raised TG ( P =.002), and very LDL cholesterol ( P =.003;

Kang et al., 2002).

Obesity in children is increasing at an alarming rate

(Rossner, 2002). Moreover, many obese children become

obese adults, and this correlates with an increased incidence

of the metabolic syndrome in adulthood, even when adult

obesity is taken into consideration (Vanhala, Vanhala,

Kumpusalo, Halonen, & Takala, 1998). The prevalence of

Type 2 diabet es in children has also increased dramatically inrecent years (Drake, Smith, Betts, Crowne, & Shield, 2002;

Ehtisham, Barrett, & Shaw, 2000; Fagot-Campagna et al.,

2000; Kaufman, 2002). The first cases of Type 2 diabetes in

children in the UK were reported in 2000; initially, patients

were mainly of Asian origin, but there are also now re ports of

Type 2 diabetes in white children (Drake et al., 2002). In the

United States, the problem is more acute, particularly among

North American Indian children (Fagot-Campagna et al.,

2000). In the early 1990s, the proportion of Type 2 diabetes

cases identified in U.S. pediatric diabetes clinics was less

than 5%, but this had r isen to 8–45% by the end of the

decade (Kaufman, 2002).The increasing awareness that being overweight or obese

during childhood and adolescence is strongly associated with

coronary risk factors–including the metabolic syndrome–in

later life has prompted three recent statements from the

American Heart Association on cardiovascular risk in

children (Kavey et al., 2003; Steinberger & Daniels, 2003;

Williams et al., 2002), including the first comprehensive set

of prevention guidelines for children (Kavey et al., 2003).

The best approach to prevent future CVD should focus on

the prevention of obesity in childhood, with early recog-

nition of the development of insulin resistance, glucose

intolerance, and Type 2 diabetes accompanied by aggressive

therapy as appropriate (Steinberger & Daniels, 2003).

5. Reducing the risk of CHD in patients with the

metabolic syndrome: the role of statins

The assessment by physicians of the multiple risk

factors for the metabolic syndrome in individuals (includ-

ing children) who present initially with just one aspect of

the condition is important in identifying all at-risk patients.

Initial strategies should address the improvement in life-

styles that are beneficial in reducing risk, for example,

increasing physical activity and losing weight (NCEP ATPIII; Expert Panel on Detection and Evaluation, and

Treatment of High Blood Cholesterol in Adults, 2001).

However, many patients will also require pharmacologic

intervention for the management of hypertension, diabetes,

and lipid abnormalities.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reduc-

tase inhibitors) are recommended as first-line agents for

lowering LDL-C levels and reducing the risk of CHD

(NCEP ATP III; Expert Panel on Detection and Evaluation,

and Treatment of High Blood Cholesterol in Adults, 2001;

De Backer et al., 2003). Statins available to treat

dyslipidemia vary both in their LDL-C lowering abilities




as well as in their effects on other lipid parameters (Jones

et al., 2003; Maron, Fazio, & Linton, 2000). Use of the

most efficacious statins is an important consideration in

achieving maximal LDL-C reductions, and agents such as

atorvastatin and rosuvastatin allow a greater proportion of

patients to achieve their lipid targets at initial doses, thus

minimizing the potential for undertreatment of patients for whom the necessary dose titration is not implemented

(Andrews, Ballantyne, Hsia, & Kramer, 2001; Shepherd,

Hunninghake, Barter, McKenney, & Hutchinson, 2003). In

addition, the multiple lipid abnormalities associated with

the metabolic syndrome make it important to use statins

that provide improvements across the lipid profile, with

maximal correction of both HDL-C and TG levels as well

as LDL-C lowering.

To date, no results from clinical trials specifically

designed to determine the efficacy of statin monotherapy in

patients with the metabolic syndrome are available. How-

ever, post hoc analyses and subanalyses of statin trials havesuggested that these agents can modify lipid levels signifi-

cantly in patients with the metabolic syndrome and reduce

the risk of coronary events. In a comparative trial of

atorvastatin versus simvastatin in hypercholesterolemia,

improvements in LDL-C, TG, and non-HDL-C levels in a

subset of 212 patients with the metabolic syndrome were

similar to those for the total study population. However,

importantly, after 36 weeks of treatment, almost half of the

subset no longer met the cr iteria for the metabolic syndrome

(Hunninghake et al., 2003). For patients with the metabolic

syndrome who were included in efficacy trials of rosuvas-

tatin 10 mg for treating hypercholesterolemia, this treatment

improved lipid profiles to a similar ext ent as in those without the syndrome (Ballantyne et al., 2003). In addition, 64% of

patients with TG z200 mg/dl met their NCEP ATP III non-

HDL-C goals. In a post-hoc analysis of the Scandinavian

Simvastatin Survival Study (4S), patients with elevated

LDL-C as well as high TG and low HDL-C levels were

compared with those with isolated LDL-C elevation. The

former group had an increased incidence of comorbidity at

baseline, including metabolic syndrome characteristics, such

as hypertension, elevated glucose, and increased BMI. A

greater benefit with simvastatin (significantly greater reduc-

tion of major coronary events) was seen in this group

compared with the isolated LDL-C elevation group ( P =.03;Ballantyne et al., 2001). Men with the metabolic syndrome

who were included in the WOSCOPS study and received

pravastatin had a similar CHD risk reduction to that in

pravastatin-treated men without the syndrome (Sattar et al.,

2003). In the Anglo-Scandinavian Cardiac Outcomes Trial–

Lipid Lowering Arm (ASCOT-LLA), patients with the

metabolic syndrome were one of the prespecified subgroups

for analysis (Sever et al., 2003). The reduction in major

cardiovascular events with atorvastatin compared with

placebo was significantly reduced in the overall study group

(36%, P =.0005), but not in the metabolic syndrome subgroup

(23%); however, this may reflect inadequate power.

Diabetes is frequently present in patients with the

metabolic syndrome, and subgroup analyses from the land-

mark statin trials have shown that intensive cholesterol

lowering can reduce the incidence of cardiovascular events

in patients with diabetes (Heart Protection Study [HPS],

2003; Pyorala et al., 1997; Sacks et al., 2000). The HPS

included almost6000 patients with diabetes (90% with Type 2diabetes), half of whom had no evidence of either coronary or

other occlusive arterial disease. Simvastatin reduced the rate

of first major vascular events by about a quarter compared

with placebo, even in those without manifest coronary disease

or high cholesterol concentrations (HPS, 2003). However, in

the lipid-lowering trial component of the Antihypertensive

and Lipid-Lowering treatment to prevent Heart Attack Trial

(ALLHAT-LLT) and in ASCOT-LLA, no significant benefit

of statin therapy was observed among patients with diabetes

(ALLHAT, 2002; Sever et al., 2003). In the ALLHAT study,

in which 35% of patients had diabetes, there was no overall

significant effect of pravastatin on CHD compared withusual care, possibly reflecting the modest difference in

LDL-C levels between the pravastatin and placebo groups

compared with other landmark trials (ALLHAT, 2002). In a

substudy of the LIPID trial, however, pravastatin effectively

reduced the increased risk of recurrent CHD and death

among subjects wit h diabetes (by 21%) and impaired fasting

glucose (by 26%; Keech et al., 2003). The nonsignificant

reduction in coronary event rates with atorvastatin versus

placebo in the diabetes subgroup of the ASCOT-LLA study

(16%) is consistent with the results for the ASCOT-LLA

metabolic syndrome subgroup. However, the total number

of events in the diabetes subgroup was only 84, limiting the

robustness of the analysis (Sever et al., 2003). In contrast,the Collaborative Atorvastatin Diabetes Study (CARDS), in

which patients with Type 2 diabetes and no previous history

of heart disease or stroke were randomized to receive

atorvastatin 10 mg daily or placebo was halted halfway

through its 4-year course because of a clearly beneficial

effect of atorvastatin on coronary outcomes (Colhoun et al.,

2004). These results lend support to the view that all

patients with Type 2 diabetes should receive a statin as a

matter of routine.

In addition to the data from long-term trials, efficacy

studies of statin therapy in patients with diabetes have

demonstrated significant improvements in the atherogeniclipoprotein profile that is characteristic of both diabetes and

metabolic syndrome patients (reviewed by Chaiyakunapruk,

Boudreau, & Ramsey, 2001). Clinical trials of statins in

individuals with mixed hyperlipidemia or hypertriglyceride-

mia have also shown improvements in HDL-C and TG in

addition to lowered LDL-C levels (Bakker-Arkema et al.,

1996; Stein, Lane, & Laskarzewski, 1998; Stein et al., 2000).

In a pooled analysis of 2689 participants stratified according

to TG levels, significant and dose-dependent reductions in

TG of 22 – 45% were observed for subjects with TG N250 t o

b400 mg/dl with all statins examined (Stein et al., 1998).

Furthermore, the relatively constant ratio between LDL-C




reductions and TG lowering indicates that statins with the

greatest LDL-C lowering capacity are likely to be the most

effective in decreasing TG levels in these patients.

The high levels of TG associated with the metabolic

syndrome may make it appropriate to provide combination

therapy of statins plus fibrates to some patients (Vega et al.,

2003; Xydakis & Ballantyne, 2002). Careful monitoring of patients on such regimens is warranted in the light of

adverse events associated with cerivastatin and gemfibrozil

co-administration that contr ibuted to the former’s with-

drawal (Furberg & Pitt, 2001). However, other fibrate–statin

regimens appear to be better tolerated. Indeed, in the Lipids

in Diabetes Study (LDS) of cerivastatin and micronized

fenofibrat e, no cases of myositis or rhabdomyolysis were

reported (Holman et al., 2003). The addition of fenofibrate

200 mg/day to simvastatin 10 mg/day has proved safe and

effective in patients with combined hyperlipidemia and

the metabolic syndrome (Vega et al., 2003). Rosuvastatin

in combination with fenofibrate has also proved safeand effective in patients with diabetes and elevated LDL-C

and TG levels (Durrington, Tuomilehto, Hamann, Kallend,

& Smith, 2004). The recently initiated Action to Control

Cardiovascular Risk in Diabetes (ACCORD) trial will

pr ov id e fu rt he r in fo rm at ion on th e us ef ul ne ss of

adding fibrates to the lipid-lowering regimen of patients

with diabetes.

Niacin is highly effective for raising HDL-C levels

(NCEP ATP III; Expert Panel on Detection and Evaluation,

and Treatment of High Blood Cholesterol in Adults, 2001)

and has beneficial effects on other components of the

atherogenic lipid triad, including lowering TG levels,

increasing LDL particle size, and reducing the concentrationof small LDL particles (McKenney, McCormick, Schaefer,

Black, & Watkins, 2001; Pan, Lin, Kesala, Van, & Charles,

2002). The HDL Atherosclerosis Treatment Study (HATS)

investigated the effects of combined treatment with 10 to 20

mg simvastatin and 2 to 4 mg niacin in CHD patients with

low HDL-C levels, who also had many other characteristics

of the metabolic syndrome (Brown et al., 2001; Zhao et al.,

2004). Combination therapy was associated with the

regression of proximal coronary stenosis and a reduced

frequency of cardiovascular events.

Inhibitors of cholesteryl ester transfer protein, for

example, torcetrapib, may also be useful in the treatment of the metabolic syndrome. A recent study examined the

effects of torcetrapib, alone and in combination with

atorvastatin, on plasma lipoprotein levels in patients with

HDL-C levels b1.0 mmol/l (40 mg/dl; Brousseau et al.,

2004). Treatment with 120 mg/day torcetrapib as mono-

therapy increased HDL-C levels by 46% and by 61% when

used in combination with 20 mg/day atorvastatin. Addi-

tionally, torcetrapib reduced LDL-C levels both when given

as monotherapy and in combination with atorvastatin.

Although the available evidence indicates that treating the

dyslipidemia associated with the metabolic syndrome with

lipid-lowering therapy is likely to be highly beneficial, there

is a need for information from prospective, randomized trials

in this patient group to determine its role in optimal disease

management. One such trial is the COmparative study

with rosuvastatin in subjects with METabolic Syndrome

(COMETS; Stalenhoef, Ballantyne, Sarti, Wilpshaar, &

Southworth, 2003), in which the comparative effects of

rosuvastatin (10–20 mg/day), atorvastatin (10–20 mg/day),and placebo on lipids and lipoproteins, glucose metabolism,

insulin resistance, and inflammatory markers were assessed

(Stalenhoef et al., 2004). The first results from this study

show that rosuvastatin lowered LDL-C significantly more

than atorvastatin after 6 and 12 weeks of treatment.

Rosuvastatin also produced significantly greater improve-

ments in HDL-C and non-HDL-C and enabled a significantly

higher proportion of patients to reach European and NCEP

ATP III LDL-C goals, compared with atorvastatin.

Statin therapy might have a beneficial effect far beyond

that expected from the treatment of dyslipidemias. In

addition to their lipid-modifying properties, statins haved pleiotropicT effects that may be beneficial for other aspects

of the metabolic syndrome (Bellosta et al., 2000; Liao, 2002;

Rosenson, 2004; Rosenson & Tangney, 1998; Sowers,

2003). Recent studies suggest that statins may reduce

oxidative stress and the susceptibility of LDL to oxidation

by several mechanisms (Rosenson, 2004). Promotion of NO

release by statins may reduce endothelial dysfunction,

thereby limiting lesion development, improving plaque

stabilization, inhibiting platelet aggregation, improving

blood flow, and protecting against ischemia (Laufs, 2003).

Statins have the potential to ameliorate the prothrombotic

state by mechanisms that include reducing platelet aggrega-

tion and promoting fibrinolytic activity through the reductionof PAI-1 levels (Liao, 2002; Rosenson & Tangney, 1998;

Sowers, 2003). The deleterious impact of the proinflamma-

tory state characteristic of the metabolic syndrome may be

lessened by the action of statins in reducing the number and

activit y of inflammatory cells as well as lowering levels of

CRP (Liao, 2002; Sowers, 2003). Data from the Pravastatin

Inflammation/CRP Evaluation (PRINCE) study and sub-

analyses of the Cholesterol and Recurrent Events (CARE)

trial and Air Force/Texas Coronary Atherosclerosis Preven-

tion Study (AFCAPS/TexCAPS) provide evidence for an

anti-inflammatory class effect of statins that may be

independent of their lipid-modifying properties (Albert,Danielson, Rifai, & Ridker, 2001; Ridker et al., 2001;

Ridker et al., 1999). However, a recent study reporting a mild

but significant correlation (.33, P =.004) between statin-

mediated CRP and LDL-C reductions indicates the need for

further investigation of the mechanisms involved (Ansell,

Watson, Weiss, & Fonarow, 2003).

6. Conclusions

The metabolic syndrome is a multifactorial disease that is

becoming more prevalent in parallel with trends in the




epidemiology of underlying contributory factors, such as

sedentary lifestyles, obesity, and diabetes, as well as in-

creasing longevity. Early recognition of the metabolic

syndrome and prompt amelioration of risk factors through

optimal interventions is essential to minimize the morbi-

dity and mortality associated with this condition. Significant

tracking (longitudinal stability) effects of cardiovascular risk factors, particularly BMI, cholesterol levels, and blood

pressure (Ulmer, Kelleher, Diem, & Concin, 2003), endorse

early intervention to address obesity and its consequences in

children and young adults, as well as in the middle-aged and

older populations.

The metabolic syndrome is amenable to treatment;

however, a multifaceted approach is required to minimize

CHD risk, including lifestyle changes and appropriate

pharmacotherapy. The efficacy of statins in treating dysli-

pidemia is well established, and retrospective studies have

indicated that these benefits are also evident in patients with

the metabolic syndrome. In addition to their effects on thelipid profile, statins may also improve other abnormalities

associated with the metabolic syndrome, for example, by

reducing oxidative stress and inflammatory and thrombo-

genic responses. Further studies are required to fully

elucidate the role of statins in the management of the

metabolic syndrome, thereby minimizing the risk of the

development of CHD.

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