The prevalence of the metabolic syndrome in Greece: The MetS-Greece Multicentre Study

ORIGINAL ARTICLE

Prevalence of atheroscleroticvascular disease amongsubjects with the metabolicsyndrome with or withoutdiabetes mellitus: the METS-GREECE Multicentre StudyVasilios G. Athyros1,3,7,8, Dimitri P. Mikhailidis4,7, AthanasiosA. Papageorgiou3,7,8, Triandafillos P. Didangelos2,3,Emmanuel S. Ganotakis5,7,8, Athanasios N. Symeonidis8,Stella S. Daskalopoulou4,7, Anna I. Kakafika3,7 and MosesElisaf6,7,8 for the METS-GREECE Collaborative Group1Atherosclerosis and Metabolic Syndrome Units, Aristotelian University,

Hippocration Hospital, Thessaloniki, Greece2Diabetes Center, Aristotelian University, Hippocration Hospital,

Thessaloniki, Greece3Second Prop. Department of Internal Medicine, Aristotelian University,

Hippocration Hospital, Thessaloniki, Greece4Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and

University College Medical School, London, UK5Department of Internal Medicine, Medical School, University of Crete,

Heraklion, Greece6Department of Internal Medicine, Medical School, University of Ioannina,

Greece7Working Group for the Identification and Treatment of Metabolic Syndrome

of the Greek Atherosclerosis Society, Athens, Greece8Working Group for the Identification and Treatment of Metabolic Syndrome

of the Greek Society of General Practitioners, Thessaloniki, Greece

Address for correspondence: Professor Vasilios G. Athyros, 15 Marmara St, Thessaloniki, 55132,Greece. Tel.: +30-2310-45423; Fax: +30-2310-445220; email: [email protected]

Key words: Diabetes mellitus – Dyslipidaemia – Hypertension – Mediterranean – Metabolicsyndrome – Uric acid – Vascular disease

Paper 2757 1691

CURRENT MEDICAL RESEARCH AND OPINION®

VOL. 20, NO. 11, 2004, 1691–1701

© 2004 LIBRAPHARM LIMITED

0300-7995

doi:10.1185/030079904X5599

Aims: To estimate the prevalence of vasculardisease (coronary heart disease/stroke/peripheralarterial disease) in individuals with the metabolicsyndrome (MetSyn) with or without diabetesmellitus (DM) when compared with subjects

without the MetSyn.Patients and methods: A cross-sectional

analysis of a representative sample of Greek adults(n = 4153), men and women (49% and 51%,respectively), living in urban, semi-urban and rural

S U M M A R Y

Introduction

The clustering of risk factors called the metabolicsyndrome (MetSyn) confers an increased risk of vasculardisease morbidity and mortality1,2 and all-cause mortality2,even in the absence of clinically evident vascular diseaseand/or diabetes mellitus (DM)2,3. The recently publishedNational Health and Nutrition Examination Survey(NHANES) II Mortality Study4 showed a significantincrease [hazard ratio (HR) = 1.37; 95% confidenceinterval (CI) = 1.02–1.85] in cardiovascular mortality insubjects with the MetSyn. However, all-cause mortalitywas not significantly increased. There was a near linearassociation ( p = 0.007) between the number ofdiagnostic criteria for the MetSyn and mortality fromcardiovascular disease4.

Among the NHANES III participants aged 50 yearsand older5, the MetSyn was a significant [odds ratio(OR) = 2.07; 95% CI = 1.66–2.59] univariate predictorof prevalent coronary heart disease (CHD). However,after adjusting for blood pressure, high-density lipo-protein cholesterol (HDL-C) and DM, the MetSyn wasnot a significant multivariate predictor of prevalentCHD. In another recent study from the same cohort6,the MetSyn was significantly related in multivariateanalysis to self-reported myocardial infarction (MI),stroke and MI/stroke, in both men and women. The 14-year follow-up of the San Antonio Heart Study7 showedthat non-diabetic subjects with the MetSyn had about a2-fold increase in risk for cardiovascular disease(adjusted for age, sex and ethnicity) compared withthose without the MetSyn.

Recent data from the Strong Heart Study in non-diabetic American Indians with the MetSyn showed

that cardiovascular disease risk did not increase as afunction of the MetSyn8. Therefore, there is contro-versial evidence regarding the incremental risk forvascular disease associated with the MetSyn in theabsence of DM. Because the overall prevalence of theMetSyn is increasing globally, it is vital to examine therelationship between the MetSyn and vascular disease invarious ethnic subgroups and different populations9.

Within the population-based cross-sectional METS-GREECE Multicentre Study (prevalence of theMETabolic Syndrome in GREECE)10,11, we investigatedthe prevalence of all vascular disease in subjects with theMetSyn with or without DM, in comparison to thosewithout the MetSyn. This study, therefore, provides aninsight into the association between vascular disease andthe MetSyn in a Mediterranean country (Greece). Thediagnosis of the MetSyn was based on the NationalCholesterol Educational Program (NCEP) AdultTreatment Panel III (ATP III)12 definition.

Study design and methods

The study was carried out during 2003 in Greece. Forty-seven investigators, from four hospitals, 22 Health CareCentres and the Working Groups for the Identificationand Treatment of the Metabolic Syndrome of the GreekAtherosclerosis Society and the Greek Society ofGeneral Practitioners, participated in the study. Thestudy received ethical approval (the master regionalconsent was granted by the Hippocration Hospital) andinformed consent was obtained from all subjects beforeenrolment.

1692 Vascular disease and metabolic syndrome © 2004 LIBRAPHARM LTD – Curr Med Res Opin 2004; 20(11)

areas (54%, 25% and 21%, respectively). TheNational Cholesterol Education Program – AdultTreatment Panel III definition of the MetSyn wasused.

Results: The age-adjusted prevalence of theMetSyn was 23.6% [95% confidence interval(CI) = 22.4%–25.1%]; this was similar in men andwomen. The fully adjusted prevalence of vasculardisease in those with the MetSyn (n = 984) was29.4%, significantly higher than in those without(n = 3169, 9.6%, p < 0.0001), while subjectswithout both the MetSyn and DM had the lowestvascular disease prevalence (n = 3035, 8.9%).Subjects with the MetSyn but no DM (n = 674)had a vascular disease prevalence of 24.1%( p < 0.0001 vs. those without the MetSyn), whichwas similar to that in subjects with DM withoutthe MetSyn (n = 134, 25.4%), but lower than inthose with both the MetSyn and DM (n = 310,

40.7%, p < 0.0001 vs. all). In comparison to thosewithout the MetSyn [odds ratio (OR) = 1], the ORsof prevalent vascular disease, after multivariateanalysis for age, sex and components of theMetSyn, and antiatherosclerotic drugs were: allMetSyn = 1.94 (95% CI = 1.35–2.47), with bothMetSyn and DM = 3.04 (95% CI = 1.98–4.11) and with MetSyn but no DM = 1.48 (95% CI = 1.12–1.92).

Conclusions: The prevalence of vascular diseasewas markedly increased in the presence of theMetSyn. Those with both the MetSyn and DM hadthe highest prevalence of vascular disease,followed by those with the MetSyn without DM.Probably MetSyn without DM should be consideredas a coronary heart disease-risk equivalent infuture guidelines. This initiative would resettreatment targets and potentially provide additionalbenefit in patients with the MetSyn.

Definition of the MetSyn

Participants having three or more of the followingcriteria (according to the NCEP ATP III report13), weredefined as having the MetSyn:

1. Abdominal obesity: waist circumference(WC) > 102 cm in men and > 88 cm in women.

2. Hypertriglyceridaemia: triglycerides ≥ 1.7mmol/L(150 mg/dL).

3. Low HDL-C: < 1.0 mmol/L (40 mg/dL) in menand < 1.3 mmol/L (50 mg/dL) in women.

4. High blood pressure: ≥ 130/85 mmHg or use ofantihypertensive medication.

5 . High fasting plasma venous glucose: ≥ 6.1mmol/L(110 mg/dL) or treatment for DM.

Definition of DM

The 1997 American Diabetes Association criteria13 wereused to define DM. We considered a subject to haveDM when the fasting plasma venous glucose was≥ 7 mmol/L (126 mg/dL) in two consecutive assess-ments or if they were on treatment for DM.

Study Design – Study Cohort

This was a cross-sectional analysis of a representativesample of Greek adults (4153 participants older than18 years). All subjects were Caucasian men (49%) andwomen (51%), living in urban (54%), semi-urban (25%)and rural (21%) areas. We established representation inrelation to residence (urban area > 50 000 inhabitants,semi-urban area 5000–50000 and rural areas < 5000, inaccordance with the 2001 National Census. This wasconducted at the beginning of 2001 and the censusresults have been accessible online since December200114. We assigned the specific number of subjects toeach investigator consistent with the population of thecity, town or village where they practice. We establishedrepresentation in relation to age and sex as follows: eachinvestigator, in cooperation with the Civil Authorities,visited subjects in their home. Entire neighbourhoodswith residents of different socio-economic status werescreened by the ‘door-to-door’ method. Only a feweligible subjects did not wish to be enrolled (n = 31).These were not of a different gender and age from thoseenrolled (n = 4153). It is very unlikely that this smallnumber of persons affected the reported prevalence ofvascular disease.

For each enrolled subject, the personal and familymedical history was obtained by a structured interview,drug treatment was recorded and he/she had a physicalexamination at home. Subjects were then invited tohave the laboratory tests at the local hospital after a 12h

fast, at which time a second physical examination wasperformed.

Definition and Diagnosis of VascularDisease

The definition of vascular disease included CHD, strokeand/or peripheral arterial disease (PAD).

The presence of vascular disease was establishedbased on physical examination and personal medicalhistory. Prevalent CHD was diagnosed by the presenceof stable angina (WHO chest pain questionnaire),positive exercise tolerance test, coronary angiographywith at least one substantial coronary artery stenosis orhistory of hospitalisation for MI, coronary bypass arterygrafting or percutaneous transluminal angioplasty. Sub-jects were considered to have a stroke if they had beendischarged from a hospital with this diagnosis. Onlythose with confirmation of a non-haemorrhagic strokeby a CT or MRI scan were considered. PAD wasestablished by physical examination and the presence ofintermittent claudication. If a subject had more thanone vascular disease manifestation he/she was con-sidered only once (adjustment for overlap).

PROCAM Risk Calculator Estimates

The PROCAM 10-year CHD risk calculator15 estimatesshould be interpreted with caution since they represent10-year probabilities in primary prevention subjects andour results refer to the cross-sectional prevalence ofvascular disease in all subjects (primary and secondaryprevention).

Laboratory-based Assessment

After an overnight 12 h fast, total cholesterol, HDL-C,triglycerides and transaminases were assessed using anOlympus AU 560 auto-analyser and respective reagents(Olympus Diagnostica GmbH, Clare, Ireland). Fastingplasma venous glucose was measured with the GOD-PAP method using an Olympus AU 560 auto-analyserand respective reagents (Medicon Hellas, Athens,Greece). All hospital laboratories used in the studyparticipated in an internal and external quality controlscheme.

Statistical Analysis

First a univariate analysis was performed and then we useda logistic regression model to determine the multivariateassociation of the MetSyn after adjusting for allcofounders, component conditions and other vasculardisease risk factors. All ORs were calculated for allsubjects with the MetSyn, those with the MetSyn and

© 2004 LIBRAPHARM LTD – Curr Med Res Opin 2004; 20(11) Vascular disease and metabolic syndrome Athyros et al. 1693

DM and those with the MetSyn but no DM. Thecomponent conditions were included as categoricalvariables. All analyses were carried out with SPSS 11.0software package (SPSS, Inc., Chicago, IL). Theprevalence of the MetSyn in the general population andvascular disease in those with or without the MetSyn aswell as the 95% CIs were derived using the SPSSfrequency and explore procedures. Significance fordifferences among groups was assessed by SPSS Crosstabs, interval by interval, Pearson’s R. The ORs and 95%CI for prevalent vascular disease between groups andsubjects without the MetSyn (OR = 1), was assessed withthe Pearson Chi-Square method. A sex-specific model forvascular disease was also examined. Mean and standarddeviation (SD) of the numerical variables are reported. Atwo-sided p value < 0.05 was considered significant.

Results

Characteristics of the study population are provided inTable 1 and lipid values in Table 2. There were nosignificant differences in smoking habits among theevaluated subject groups (Table 1).

Prevalence of the MetSyn in the GeneralPopulation

The age-standardised prevalence of the MetSyn in allparticipants (n = 4153) was 23.6% (95% CI =22.4%–25.1%), increasing with age. This was similar inboth genders (men: 95% CI = 22.3%–25.2%; women:CI = 21.4%–25.0%) ( p = 0.3). The prevalence of theMetSyn increased with age ( p for trend < 0.0001).There was a 14.7-fold increase in OR for having theMetSyn in the age group > 70 years old compared withthat of those 19 years–29 years old ( p < 0.0001). Therewas no impact of family history of premature CHD onthe prevalence of the MetSyn.

Prevalence of Vascular Disease Accordingto the Presence of the MetSyn and DM

The age-, sex-adjusted prevalence of CHD, stroke andPAD is reported in Table 1. The age-, sex- and overlap-adjusted prevalence of vascular disease in all participants(n = 4153) was 14.3% (Table 1). All subjects with theMetSyn (n = 984) had a vascular disease prevalence of29.4%, significantly higher than that of people (n =3169) without the MetSyn (9.6%, p < 0.0001).Participants without both the MetSyn and DM (n =3035) had the lowest vascular disease prevalence(8.9%), while subjects with DM but without theMetSyn (n = 134) had a vascular disease prevalence of

25.4% ( p < 0.0001). This was similar to that of people(n = 674) with the MetSyn without DM (24.1%), butsignificantly lower than that of participants (n = 310)with both the MetSyn and DM (40.7%, p < 0.0001). Inthe group of patients with DM but no MetSyn (n =134), 58 had Type 1 DM and 76 were effectivelytreated patients with Type 2 DM.

Vascular Disease Components Overlap

The concomitant presence of CHD, stroke and PAD inthe MetSyn group, with or without DM, was higherthan in those without the MetSyn (Table 1). Thus, thesum total of CHD, stroke and PAD was 38.6% in theMetSyn group, while the corresponding value in thosewithout the MetSyn was 10.2%. Due to patients in theMetSyn group having more than one of CHD, stroke orPAD, the prevalence of vascular disease, when countedas the presence of CHD, stroke and/or PAD was 29.4%.In contrast, this figure was 9.6% for those without theMetSyn.

Lipid Values

All the lipid values of subjects with the MetSyn weresignificantly different from those of subjects withoutthe MetSyn (Table 2). A substantial percentage (64%)of patients with the MetSyn had high12 LDL-Clevels > 3.4 mmol/L and even more (69%) had a non-HDL-C > 4.1 mmol/L, despite the fact that 36% ofthem were on lipid lowering drug treatment (31% onstatins and 5% on fibrates). Anti-atheroscleroticmedications used in the study population are reported inTable 3.

Odds Ratios (ORs) for Prevalent VascularDisease

Univariate and multivariate associations of the MetSynand component conditions with prevalent vasculardisease are shown in Table 4. In subjects with theMetSyn, compared with people without the MetSyn(OR = 1), the fully adjusted OR of prevalent vasculardisease, after logistic regression for age, sex, smoking,anti-atherogenic drugs (listed in Table 3), hypertension,high triglycerides and low HDL-C, regardless of diabeticstate was 1.94 (95% CI = 1.35–2.47), in subjects withboth the MetSyn and DM this was 3.04 (95% CI =1.98–4.11) and in people with the MetSyn but withoutDM it was 1.48 (95% CI = 1.12–1.92). In this lattergroup, the MetSyn was significantly associated withvascular disease in both men (OR = 1.31, 95% CI =1.07–1.64) and women (OR = 1.43, 95% CI =1.14–1.91) (data not shown in Table 4). This sexdifference was not statistically significant.


© 2

004 L

IBR

AP

HA

RM

LTD

– Curr M

ed

Res O

pin

2004; 2

0(11)

Vascular disease and metabolic syndrom

eAthyros

et al.1695

stcejbus llA(n )3514 =

lla nySteM(n )489 =

MD + nySteM(n )013 =

MD on + nySteM(n )476 =

stcejbus lla nySteM oN(n )9613 =

tneserp MD + nySteM oN(n )431 =

MD on + nySteM oN(n )5303 =

*)sraey( egA 3.74 ± 3.85 4.81 ± 7.21 1.16 ± 0.11 0.75 ± 3.31 9.34 ± 8.55 6.81 ± 4.34 1.81 ± 4.81 3.94 1.15 4.94 4.05 1.35 2.15 0.94 )%( elam redneG

m/gk( IMB 2 *) 6.52 ± 4.92 7.2 ± 4.3 6.92 ± 6.3 3.92 ± 9.2 3.42 ± 9.32 5.2 ± 4.42 8.3 ± 5.2 73 23 73 54 23 14 83 )%( srekoms tnerruC 32 82 42 91 62 12 32 )%( srekoms xE 04 04 93 63 24 83 93 )%( dekoms reveN

)%( MACORP ksir raey-01 7.8 2.02 1.22 7.81 3.8 8.91 0.8 )%( LGF hgiH 2.81 9.35 001 1.73 2.7 001 3.5

)%( HA 6.73 7.38 7.68 3.28 3.32 8.74 2.22 )%( GT hgiH 7.52 6.76 2.07 7.21 7.6 0.31

)%( C-LDH woL 7.42 3.45 3.15 5.45 6.51 2.5 0.61 )%( ytisebo lartneC 8.65 2.88 8.48 7.98 1.74 8.62 1.84

)%( nySteM 6.32 001 001 001 0 0 0 )%( MD 6.01 5.13 001 0 2.4 001 0

)%( DHC 3.9 9.32 2.53 7.81 7.5 9.81 1.5 )%( ekortS 1.4 0.9 2.31 2.7 2.3 7.9 9.2

)%( DAP 3.2 7.5 3.01 6.3 3.1 5.1 3.1 )%( DcsaV 3.41 4.92 7.04 1.42 6.9 4.52 9.8

DcsaV 1 > htiw DcsaV8.32 9.8 )%( noitatsefinam 7.03 3.81 6.51 9.5 3.3

m/gk ni )xedni ssam ydob( IMB dna sraey ni egA* 2 seulav naem ni desserpxe era ± noitaived dradnats 1

p nySteM eht tuohtiw stcejbus sv 10.0 <

rotaluclac ksir )yduts retsnuM ralucsavoidraC evitcepsorP( MACORP fo ksir raey-01 ehT 51 poleved ot stcejbus noitneverp yramirp fo ytilibaborp raey-01 sesserpxe ti esuaceb noituac htiw deterpretni eb dluohs ces dna yramirp( stcejbus lla ni esaesid ralucsav fo ecnelaverp lanoitces-ssorc ot refer stluser ruo dna esaesid traeh yranoroc )noitneverp yradno

esoculg :GFI[ ])MD( sutillem setebaid ro )GFI( esoculg gnitsaf deriapmi[ slevel esoculg amsalp suonev gnitsaf hgih = LGF hgiH ≥ 9.6–1.6 521–011( L/lomm esoculg :MD ;)d/gm ≥ 0.7 621( L/lomm = HA ,])Ld/gm erusserp doolb[ noisnetrepyh lairetra ≥ 58/031 7.1 > sedirecylgirt = GT hgih ,]gHmm 051( L/lomm 0.1 < loretselohc nietorpopil ytisned hgih fo slevel wol = C-LDH wol ,)Ld/gm 04( L/lomm nem rof )Ld/gm

3.1 < dna 05( L/lomm 201 > ecnerefmucric tsiaw = ytisebo lartnec ,nemow rof )Ld/gm 88 > dna nem rof mc ( emordnys cilobatem = nySteM ,nemow rof mc ≥ lartnec ,C-LDH wol ,GT hgih ,HA ,GFI fo 3 )DAP/ekorts/DHC( esaesid ralucsav = DcsaV ,esaesid lairetra larehpirep = DAP ,esaesid yretra yranoroc = DHC ,)ytisebo

Table 1. Characteristics of the study population (4153 adults aged > 18 years with or without the metabolic syndrome (MetSyn) and with or without diabetes mellitus (DM)

1696Vascular disease and m

etabolic syndrome

© 2

004 L

IBR

AP

HA

RM

LTD

– Curr M

ed

Res O

pin

2004; 2

0(11)

llA (n )3514 =

lla :nySteM(n )489 =



lla :nySteM oN(n )9613 =

MD + nySteM oN(n )431 =


)L/lomm( CT 4.5 ± 9.5 0.1 ± 9.5 *2.1 ± 0.6 *2.1 ± 2.5 *2.1 ± 0.5 9.0 ± 2.5 6.0 ± 9.0 )L/lomm( C-LDL 5.3 ± 8.3 9.0 ± 7.3 *30.1 ± 9.3 *1.1 ± 3.3 *0.1 ± 1.3 8.0 ± 3.3 6.0 ± 9.0 )L/lomm( C-LDH 3.1 ± 2.1 3.0 ± 1.1 *3.0 ± 2.1 *3.0 ± 3.1 *3.0 ± 1.1 3.0 ± 3.1 *2.0 ± 3.0

)L/lomm( C-LDH-noN 2.4 ± 8.4 9.0 ± 8.4 *2.1 ± 9.4 *2.1 ± 9.3 *2.1 ± 9.3 8.0 ± 9.3 5.0 ± 9.0 )L/lomm( GT 5.1 ± 2.2 7.0 ± 1.2 *0.1 ± 2.2 *3.1 ± 3.1 *1.1 ± 4.1 6.0 ± 3.1 *5.0 ± 6.0

*p nySteM eht tuohtiw stcejbus fo puorg evitcepser eht fo eulav eht sv 100.0 <H ,loretselohc nietorpopil ytisned-wol = C-LDL ,loretselohc latot = CT ,sutillem setebaid = MD ,emordnys cilobatem eht = nySteM = GT ,loretselohc nietorpopil ytisned-hgih = C-LD

sedirecylgirt

Table 2. Measured lipid parameters (mean value ± 1 standard deviation) in all groups (4153 adults aged > 18 years) according to the presence or absence of the metabolic syndrome(MetSyn) and diabetes mellitus (DM). 70% of subjects with DM had the MetSyn; 64% of subjects with the MetSyn had LDL-C > 3.4 mmol/L and 69% non-HDL-C > 4.1 mmol/L

llA (n )3514 =

lla :nySteM(n )489 =



lla :nySteM oN(n )9613 =

MD + nySteM oN(n )431 =


%2 %11 %2 *%52 *%24 *%13 %9 snitatS %3 %9 %3 %2 %11 %5 %4 setarbiF %0 *%42 %1 %0 *%13 *%01 %3 nimrofteM %0 %9 %1 < %0 *%63 *%11 %3 saerulynohpluS %0 *%34 %2 %0 *%42 *%8 %3 nilusnI %7 *%71 %8 *%92 *%63 *%13 %31 srotibihni ECA %6 %01 %6 *%81 *%22 *%02 %9 sBCC

*p nySteM tuohtiw stcejbus fo puorg evitcepser eht fo eulav eht sv 100.0 < srekcolb lennahc muiclac = BCC ,emyzne nisnetoigna = ECA

Table 3. All anti-atherosclerotic medication used in the study population (percentage of subjects on medication) in all groups (4153 adults aged > 18 years) according to the presence or absence of the metabolic syndrome (MetSyn) and diabetes mellitus (DM)


Subjects with the MetSyn but without DM with allfive MetSyn components had a fully adjusted OR ofprevalent vascular disease of 2.78 (95% CI =2.10–3.81), in comparison with those without theMetSyn (data not shown in Table 4). Among thecomponent conditions only abdominal obesity was notindependently related to prevalent vascular disease. LowHDL-C was significantly associated with vascular diseaseand had the greatest OR of any of the componentconditions (OR = 1.36, 95% CI = 1.07–1.75). Hightriglycerides (OR = 1.22, 95% CI = 1.09–139) andhypertension (OR = 1.06, 95% CI = 1.01–1.14) werealso independently and significantly related to vasculardisease (Table 4). In the sex-specific analysis, hightriglycerides were more associated with vascular diseasein women (OR = 1.59, 95% CI = 1.17–2.05) than inmen (OR = 1.18, 95% CI = 1.01–1.42). Afteradjustment for age, sex, hypertension, high triglycerides,low HDL-C and non-HDL-C there was a significantassociation between the MetSyn and vascular disease(OR = 1.72, 95% CI = 1.07–2.51) (not shown in Table4) only in the subjects with the MetSyn and DM.However, this relationship may have been masked by thefact that 36% of those with the MetSyn were on lipidlowering drugs (31% on statins and 5% on fibrates) andother anti-atherosclerotic medications. Therefore, in the

multivariate analyses, ORs were adjusted for drugtreatment, which are more representative (Table 4).

Prevalence of the MetSyn and itsIndividual Diagnostic Features in Subjectswith Vascular Disease

The prevalence of the MetSyn was significantly higher( p < 0.0001) among subjects with (n = 594) thanwithout prevalent vascular disease (n = 3559): 48.1%vs. 19.6%. The same relationship applied to the diag-nostic features ( p < 0.0001 for all), except for centralobesity (62.2% vs. 55.9%, p = 0.3).

PROCAM Risk Calculator Estimates

These are shown in Table 1 for subjects of primary CHDprevention only.

Discussion

Our results suggest that in a Mediterranean population,the MetSyn identifies a substantial additional vascularrisk (CHD/stroke/PAD) in men and women, even in

Odds ratio 95% CI P

Univariate model MetSyn all (n = 984) 3.69 3.08–4.73 < 0.0001 MetSyn + DM (n = 310) 5.64 4.43–6.89 < 0.0001 MetSyn + no DM (n = 674) 2.78 2.27–3.42 < 0.0001 Age 1.08 1.06–1.10 < 0.0001 Female gender 0.75 0.63–0.86 < 0.0001 Abdominal obesity* 1.01 0.72–1.36 0.4592 High triglycerides* 1.22 1.09–139 0.0041 High blood pressure* 1.06 1.01–1.14 0.0354 Low HDL-C* 1.36 1.07–1.75 0.0021 High LDL-C* 1.42 1.09–1.95 0.0002 High non-HDL-C* 1.56 1.14–2.12 < 0.0001 Multivariate model (adjusted for age, sex, smoking, anti-atherosclerotic drugs and MetSyn components) MetSyn all (n = 984) 1.94 1.35–2.47 < 0.0001 MetSyn + DM (n = 310) 3.04 1.98–4.11 < 0.0001 MetSyn + no DM (n = 674) 1.48 1.12–1.92 0.0191 Multivariate model (adjusted for age, sex, smoking, anti-atherosclerotic drugs, MetSyn components and non-HDL-C) MetSyn all (n = 984) 1.17 0.80–1.56 0.3942 MetSyn + DM (n = 310) 1.68 1.02–2.40 0.0364 MetSyn + no DM (n = 674) 1.01 0.57–1.43 0.6375

Abbreviations as in Table 1 *Component conditions and vascular risk factors as defined in the text

Table 4. Univariate and multivariate cross-sectional associations of prevalent vascular disease [odds ratio (OR) and 95%confidence interval (CI)] with the metabolic syndrome (MetSyn) (n = 984), component conditions and other vascular risk

factors, in comparison to subjects without the MetSyn (n = 3169; OR = 1). In multivariate analyses ORs were adjusted foranti-atherosclerotic medications (listed in Table 3) and current smoking, age, sex and MetSyn components

those without DM. Both vascular disease prevalence andthe percentage of subjects with vascular disease havingmore than one manifestation were similar in subjectswith the MetSyn but without DM and those with DMbut without the MetSyn. Furthermore, the adjustedprevalent vascular disease in those with the MetSyn butno DM was almost 50% greater than that of those withneither the MetSyn nor DM (Table 4), underlining thehigh risk associated with the MetSyn. These findingssuggest that the MetSyn should probably be added tothe list of CHD equivalents, even in the absence of DM.In favour of this suggestion is the fact that a con-siderable proportion of the subjects with the MetSynand their physicians were unaware of the diagnosis andthe patients were undertreated11.

We found a significant cross-sectional associationbetween the diagnostic features of the MetSyn12 andvascular disease, except for abdominal obesity. It ispossible that the strength and significance of theseassociations would be enhanced if these features weremodelled as continuous variables. In our analysis, therewas a lack of association between abdominal obesity andprevalent vascular disease. This is in agreement with thedata from the Women’s Ischemia Syndrome Evaluation(WISE) Study16 and previous studies1,6, but differs fromothers that showed linear relationships between CHDand either body mass index (BMI) or waist-to-hip ratioindependent of the BMI17, after adjusting for other riskfactors. It is possible that the association of abdominalobesity with vascular disease was diluted because of theimpact of other components, such as hypertri-glyceridaemia6 or medication. Some, but not all studies,showed a significant association between high tri-glyceride levels and CHD; a meta-analysis of 17prospective studies reported a significant relationship,after adjusting for other risk factors9,18. This relationshipwas stronger in women, as with our findings. Hyper-tension and low HDL-C have been reported to have aclear association with vascular disease1,5,6.

The increased vascular disease prevalence in subjectswith the MetSyn19, may be explained by the compo-nents12 that define the MetSyn in association with other,not routinely measured factors. For example, impairedfibrinolysis, oxidative stress, high LDL-C levels,increased small dense LDL particles, hypercoagulability,inflammation and hyperinsulinaemia20. It was alsoreported21 that the MetSyn is associated with higherlevels of oxidized LDL-C, apolipoprotein-B, urate,leptin, fibrinogen, leukocytes, erythrocytesedimentation rate and soluble endothelial adhesionmolecules and lower apolipoprotein-A concentrations.Furthermore, in women with the MetSyn, a substantialresidual CHD risk remained after controlling for all fiveMetSyn components. This was partly due to increasedlevels of LDL-C, small dense LDL particles or C-

reactive protein22,23. All these parameters cannot beassessed in each patient in everyday clinical practice.However, LDL-C and non-HDL-C (total cholesterolminus HDL-C) are easily calculated.

Although LDL-C is not considered a component ofthe MetSyn, many of patients have raised levels of LDL-C. In our study, 64% of the subjects with the MetSynhad a LDL-C level > 3.4 mmol/L (Table 2), despite thefact that 36% of them were on lipid lowering drugs(31% on statins and 5% on fibrates). This argues forwhether elevated LDL-C might be considered a modi-fying component of the MetSyn, especially in thepresence of elevated triglycerides (indicating smalldense LDL particles with increased atherogenicity24).The contribution of high LDL-C levels to vasculardisease risk in subjects with the MetSyn was highlightedby a retrospective analysis of the landmark statin trials.The placebo data from the Scandinavian SimvastatinSurvival Study (4S) and the Air Force/Texas CoronaryAtherosclerosis Prevention Study (AFCAPS/Tex-CAPS)25 showed that the relative risk of major coronaryevents associated with the MetSyn, after excluding DM,was 1.5 (95% CI = 1.2–1.8) and 1.4 (95% CI =1.04–1.9), respectively, in comparison to subjectswithout the MetSyn. Moreover, patients with theMetSyn had an increased risk of major coronary eventsirrespective of their Framingham-calculated 10-year riskscore25. These data demonstrate that the MetSyn isassociated with an increased vascular risk inhypercholesterolaemic patients with CHD in 4S and inthose with ‘average’ LDL-C levels and low HDL-C butwithout CHD in AFCAPS/TexCAPS25. It appears thatthe MetSyn is associated with vascular events that arenot entirely accounted for by risk scoring programs25.Not only does the MetSyn influence the risk of CHD,but it also appears to be a major factor in the responseto therapy. Within 4S, subsequent analysis based on theLDL-C level suggests that simvastatin therapy was moreeffective among those with the MetSyn than thosewithout it26. In the West of Scotland Coronary Preven-tion Study (WOSCOPS)27, the MetSyn continued topredict CHD events (HR = 1.30, 95% CI = 1.00–1.67,p = 0.045) in a multivariate model incorporating con-ventional risk factors. Men with 4 or 5 features of theMetSyn had a 3.7-fold increase in risk for CHDcompared with men with none. A projection of pooledobservational data28 suggested that optimal control ofLDL-C in subjects with the MetSyn prevented 46.2%and 38.1% of CHD-related events, in men and women,respectively.

Our findings regarding the contribution of LDL-C arein accordance with those of WOSCOPS27. However,there are several limitations when comparing WOSCOPSand our findings. WOSCOPS used a modified NCEPdefinition of the MetSyn, replacing waist circumference


(WC) with BMI. However, WC seems to be a strongerpredictor than BMI of obesity-related health risks,especially CHD, both in men29 and women29,30 and it ismore closely associated with the level of exercise30.Increased exercisemay not alter BMI and risk assessmentwill remain unaffected31. In contrast, WC was shown tochange with increased exercise, indicating changes inabdominal obesity, which allows for a more accurate riskassessment for type 2 DM and CHD31. Results from theHeart and Estrogen/progestin Replacement Study(HERS) show that both BMIand WC are associated withmortality amongpostmenopausal women with establishedCHD, but WC may be more important than BMI. Thismay be largely mediated by other cardiac risk factors32.Even in South and Southeast Asia, where body build isdifferent from that of Caucasians, a modified WC valuethat is more applicable to Asian populations (90 cm formen and 85 cm for women) is used rather than theBMI33,34. Furthermore, in the 14 924 adult participants ofthe NHANES III within the three BMI categories, thosewith high WC values were increasingly likely to havehypertension, DM, dyslipidaemia and the MetSyncomparedwith those with normal WC values35. We reportthe BMI values in Table 1 to facilitate comparisons withother studies.

We could not use the Framingham risk score (FRS) tocompare our findings with those of theAFCAPS/TexCAPS study25 for several reasons. First,the FRS is only applicable in subjects free of CHD andour population included patients with CHD or CHDequivalents, while in AFCAPS/TEXCAPS andWOSCOPS the majority of the participants were freeof CHD and very few (1% in WOSCOPS)27 had DM.Second, it is not appropriate to compare 10-yearprobabilities for MI with cross-sectional prevalence (inAFCAPS/TEXCAPS and WOSCOPS the prospective5-year data were compared with the FRS prediction),especially when they include PAD, as in our study.Third, the FRS does not include impaired fastingglucose, high triglycerides and abdominal obesity as riskfactors. Thus, from the five components of the MetSyn,only HDL-C and hypertension will be considered by theFRS, probably providing false low results. For subjectswith DM, the UKPDS risk calculator36 is ideal.However, we cannot use two different scoring systemswithin the same study. The PROCAM risk calculator15

might apply, though it does not include impaired fastingglucose. Estimates of the PROCAM risk (Table 1)provide an indicative level of risk for the CHD-freesubjects. However, these scores should be interpretedwith caution because they represent 10-yearprobabilities and our results refer to the cross-sectionalprevalence of vascular disease.

The case for assessing non-HDL-C levels is probablyconvincing37. In individuals with triglycerides

≥ 2.3 mmol/L (probably the majority of subjects withthe MetSyn), non-HDL-C is a secondary treatmenttarget12. Non-HDL-C includes cholesterol in LDL andtriglyceride-rich lipoproteins. In our study, 69% ofsubjects with the MetSyn had a non-HDL-C level> 4.1 mmol/L (Table 1). The Atorvastatin ComparativeCholesterol Efficacy and Safety Study (ACCESS)suggested that non-HDL-C at baseline and on-treatment may be a more practical predictor of CHDrisk that is already available from the lipid profile38. Inthe Lipid Research Clinics (LRC) follow-up study, non-HDL-C level was a better predictor of CHD death thanLDL-C39. In the GREACE Study40,41, non-HDL-C was abetter predictor than LDL-C of both risk for clinicalevents in untreated patients and statin-induced clinicalbenefit in treated patients with CHD. Probably, non-HDL-C in such patients should be the primarytreatment target39,41. Therefore, non-HDL-C may beincorporated in the definition of the MetSyn. Moreover,in our study, after adjusting for non-HDL-C, the ORs insubjects with the MetSyn (especially those withoutDM) were not significantly higher than those of subjectswithout the MetSyn. This finding supports the conceptthat adding the LDL-C variable influenced the relation-ship between risk and the MetSyn. This interpretationalso supports the need to lower LDL-C levels to guide-line recommendations12 in patients with the MetSyn.

Our results relating vascular risk with the number ofMetSyn components are consistent with the findings ofother studies4,27,42,43. Thus, in our study those with all fivefeatures (NCEP ATP III)12 of the MetSyn had a greaterOR than those with three features required to make adiagnosis of the MetSyn. However, other studies42,43

considered different factors from those defined in theNCEP ATP III12. Nevertheless, in the NHANES IIsurvey4 the association between the number of MetSyncriteria and cardiovascular disease mortality was nearlinear ( p = 0.007).

Several studies2,3,6,7,44 and our data from a Mediter-ranean Country suggest that the MetSyn, even in theabsence of DM, is associated with an increased vascularrisk. This will reset the LDL-C and non-HDL-C treat-ment targets and may result in additional clinical benefitin these subjects. There is evidence that treating theMetSyn or DM with statins or fibrates will result in areduction in vascular events22–26,45–50. Therefore, a wideruse of these drugs should result in a reduction of vas-cular events in these patients. Furthermore, all abnormallipid variables may represent an increased risk51.

Study Limitations

As a cross-sectional study, the present analysis is limitedin its ability to elucidate causal relationships betweenrisk factors and outcomes. It is also likely that the exact


incidence of vascular disease was higher since fatalevents were not included and silent vascular diseasemanifestations were not detected. For example, theprevalence of PAD is increased 3-fold if asymptomaticpatients are included by measuring the ankle-brachialpressure index52. Moreover, primary or secondaryvascular disease prevention interventions may haveattenuated the association of risk factors with vasculardisease manifestations. We are also aware that somesubgroups are small (e.g. no MetSyn + DM; n = 134).

Conclusions

The MetSyn is significantly associated withCHD/stroke/PAD risk, even in the absence of DM andafter adjusting the ORs for age, sex and features of theMetSyn. Probably the MetSyn, even without DM,should be considered as a CHD-risk equivalent. Thiswill increase awareness and set lower targets for bothLDL-C and non-HDL-C for these individuals. Thisinitiative is likely to substantially increase the benefitfrom treatment.

Acknowledgement

This study was conducted independently; no companyor institution supported it financially. Some of theauthors have attended conferences and participated inother trials sponsored by various pharmaceuticalcompanies.

We thank the Greek Atherosclerosis Society and thefollowing for the collection of the data: Akritopoulos P(GH), Apousidou VP (GH), Arseniou A (Griva HC),Athanasiou PI (HC), Batou ND (HC), Bouloukos VI(UH), Bourdouvalis IA (HC), Dimopoulou SP (HC),Dionisopoulou SG (GH), Georaki AN (HC),Giapoutsidis V (GP), Giouleme O (UH), Hartaba VG(HC), Kalaitzidou EL (GP), Karaleftheri MP (HC),Karotsis AL (GP), Kapousouzi MI (HC), Kesidou NI(HC), Kiourtzidou BL (HC), Kouroudi AI (HC),Lazaridou PG (HC), Liakou K (HC), Matsou AT (HC),Messios R (HC), Notaridis G (HC), Patroklou S (HC), Paulidou H (HC), Pehlivanidis AN (UH),Petridis DI (HC), Polychronidis E (HC), PosnahidouDN (HC), Prokopidis D (GP), Protopapas N (HC), Psaltoglou I (HC), Sarigianni M (GH), SatsoglouEA (GH), Sekeri ZP (HC), Sfakianakis M (HC),Tsakiris K (HC), Tsiknaki SB (HC), Vasilopoulou D(HC). (UH = University Hospital, GH = GeneralHospital, GP = General Practice, HC = HealthCenter).

References1. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity

and mortality associated with the metabolic syndrome. DiabetesCare 2001;24:683-9

2. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolicsyndrome and total and cardiovascular disease mortality inmiddle-aged men. J Am Med Assoc 2002;288:2709-16

3. Trevisan M, Liu J, Bahsas FB, Menotti A. Syndrome X andmortality: a population-based study. Am J Epidemiol1998;148:958-66

4. Ford ES. The metabolic syndrome and mortality fromcardiovascular disease and all-causes: findings from the NationalHealth and Nutrition Examination Survey II Mortality Study.Atherosclerosis 2004;73:307-12

5. Alexander CM, Landsman PB, Teutsch SM, Haffner SM; ThirdNational Health and Nutrition Examination Survey (NHANESIII); National Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, diabetes, and prevalence ofcoronary heart disease among NHANES III participants age50 years and older. Diabetes 2003;52:1210-4

6. Ninomiya JK, L’Italien G, Criqui MH, Whyte JL, Gamst A, ChenRS. Association of the metabolic syndrome with history ofmyocardial infarction and stroke in the third national health andnutrition examination survey. Circulation 2004;109:42-6

7. Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP.NCEP versus WHO metabolic syndrome in relation to all causeand cardiovascular mortality in the San Antonio Heart Study(SAHS) [abstract]. Diabetes 2003;52:A221-28.Resnick HE, Jones K, Ruotolo G, et al. Insulin resistance, themetabolic syndrome, and risk of incident cardiovascular diseasein nondiabetic American Indians. The Strong Heart Study.Diabetes Care 2003;26:861-7

9. Deedwania PC. Metabolic syndrome and vascular disease: isnature or nurture leading the new epidemic of cardiovasculardisease? Circulation 2004;109:2-4

10. Athyros VG, Bouloukos VI, Pehlivanidis AN, et al. for the MetS-GREECE Collaborative Group. The prevalence of the METabolicSyndrome in GREECE-The MetS – GREECE Multicenter Study.Diab Obesity Metab 2004 [in press]

11. Athyros VG, Elisaf M, Mikhailidis DP. Undertreatment ofdyslipidaemia in Greece. Atherosclerosis 2004 [in press]

12. Adult Treatment Panel III. The third report of the NationalCholesterol Education Program (NCEP) expert panel ondetection, evaluation, and treatment of high blood cholesterol inadults. J Am Med Assoc 2001;285:2486-97

13. Expert Committee on the Diagnosis and the Classification ofDiabetes Mellitus. Report of the expert committee on thediagnosis and the classification of diabetes mellitus. DiabetesCare 1997;20:1183-97

14. Greek population data set. Available from http://www.kethi.gr/greek/statistika/Apasxolisi/APOGRAFI_01.htm [accessed 13 Aug 2004]

15. PROCAM risk calculator. Available from: http://chdrisk.uni-muenster.de/risk.php [accessed 13 August 2004]

16. Kip KE, Marroquin OC, Kelley DE, et al. Clinical importance ofobesity vs the metabolic syndrome in cardiovascular risk inwomen: a report from the Women’s Ischemia Syndrome Evalua-tion (WISE) study. Circulation 2004;109:706-13

17. Daly P, Solomon C, Manson J. Risk modification in the obesepatient. In: Manson J, Ridker P, Gaziano J, editors. Prevention ofmyocardial infarction. New York: Oxford University Press; 1996.pp. 203-40

18. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factorfor cardiovascular disease independent of high-densitylipoprotein cholesterol: a meta-analysis population-basedprospective studies. J Cardiovasc Risk 1996;3:213-9

19. Olijhoek JK, van der Graaf Y, Banga JD, Algra A, Rabelink TJ,Visseren FLJ for the SMART Study Group. The MetabolicSyndrome is associated with advanced vascular damage in patientswith coronary heart disease, stroke, peripheral arterial disease orabdominal aortic aneurysm. Eur Heart J 2004;25:342-8

20. Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP.Clustering of procoagulation, inflammation, and fibrinolysisvariables with metabolic factors in insulin resistance syndrome.Am J Epidemiol 2000;152:897-907


21. Bonora E, Kiechl S, Willeit J, et al. Metabolic syndrome:epidemiology and more extensive phenotypic description. Cross-sectional data from the Bruneck Study. Int J Obes Relat MetabDisord 2003;27:1283-9

22. Onat A, Ceyhan K, Basar O, Erer B, Toprak S, Sansoy V.Metabolic syndrome: major impact on coronary risk in apopulation with low cholesterol levels – a prospective and cross-sectional evaluation. Atherosclerosis 2002;165:285-92

23. Daskalopoulou SS, Mikhailidis DP, Elisaf M. Prevention andtreatment of the metabolic syndrome. Angiology 2004 [in press]

24. Kwiterovich Jr PO. Clinical relevance of the biochemical,metabolic, and genetic factors that influence low-densitylipoprotein heterogeneity. Am J Cardiol 2002;90:30i-47

25. Girman CJ, Rhodes T, Mercuri M, et al. for the 4S Group andthe AFCAPS/TexCAPS Research Group. The metabolicsyndrome and risk of major coronary events in the ScandinavianSimvastatin Survival Study (4S) and the Air Force/TexasCoronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol 2004;93:136-41

26. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR,Kjekshus J. Influence of low high-density lipoprotein cholesteroland elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation2001;104:3046-51

27. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome withand without C-reactive protein as a predictor of coronary heartdisease and diabetes in the West of Scotland Coronary PreventionStudy. Circulation 2003;108:414-9

28. Wong ND, Pio JR, Franklin SS, L’Italien GJ, Kamath TV,Williams GR. Preventing coronary events by optimal control ofblood pressure and lipids in patients with the metabolicsyndrome. Am J Cardiol 2003;91:1421-6

29. Janssen I, Katzmarzyk PT, Ross R. Waist circumference and notbody mass index explains obesity-related health risk. Am J ClinNutr 2004;79:379-84

30. Lofgren I, Herron K, Zern T, et al. Waist circumference is abetter predictor than body mass index of coronary heart diseaserisk in overweight premenopausal women. J Nutr2004;134:1071-6

31. Ross R, Katzmarzyk PT. Cardiorespiratory fitness is associatedwith diminished total and abdominal obesity independent ofbody mass index. Int J Obes 2003;27:204-10

32. Kanaya AM, Vittinghoff E, Shlipak MG, et al. Association of totaland central obesity with mortality in postmenopausal womenwith coronary heart disease. Am J Epidemiol 2003;158:1161-70

33. Ramachandran A, Snehalatha C, Satyavani K, et al. Metabolicsyndrome in urban Asian Indian adults – a population study using modified ATP III criteria. Diabetes Res Clin Pract2003;60:199-204

34. Lee WY, Park JS, Noh SY, Rhee EJ, Kim SW, Zimmet PZ.Prevalence of the metabolic syndrome among 40 698 Koreanmetropolitan subjects. Diabetes Res Clin Pract 2004;65:143-9

35. Janssen I, Katzmarzyk PT, Ross R. Body mass index, waistcircumference, and health risk evidence in support of currentNational Institutes of Health guidelines. Arch Intern Med2002;162:2074-9

36. UKPDS risk calculator. Available from: http://www.dtu.ox.ac.uk/index.html?maindoc=/ukpds/ [Accessed 13 August 2004]

37. Ballantyne CM, Hoogeveen RC. Role of lipid and lipoprotein pro-files in risk assessment and therapy. Am Heart J 2003:146:227-33

38. Ballantyne CM, Andrews TC, Hsia JA, Kramer JH, Shear C;ACCESS Study Group. Atorvastatin Comparative CholesterolEfficacy and Safety Study. Correlation of non-high-density lipo-protein cholesterol with apolipoprotein B: effect of 5 hydroxy-methylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol 2001;88:265-9

39. Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipo-protein cholesterol level as a predictor of cardiovascular diseasemortality. Arch Intern Med 2001;161:1413-9

40. Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatmentwith atorvastatin to the National Cholesterol EducationalProgram goals versus usual care in secondary coronary heartdisease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study. Curr Med Res Opin2002;18:220-8

41. Athyros VG, Papageorgiou A, Symeonidis A, Elisaf M. Non-highdensity lipoprotein cholesterol and coronary events during long-term statin treatment. Atherosclerosis 2003;168:397-8

42. Klein BE, Klein R, Lee KE. Components of the metabolicsyndrome and risk of cardiovascular disease and diabetes inBeaver Dam. Diabetes Care 2002;25:1790-4

43. Nakanishi N, Takatorige T, Fukuda H, et al. Components of themetabolic syndrome as predictors of cardiovascular disease andtype 2 diabetes in middle-aged Japanese men. Diabetes Res ClinPract 2004;64:59-70

44. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolicsyndrome on mortality from coronary heart disease, cardio-vascular disease, and all causes in United States Adults.Circulation 2004 Aug 23 [Epub ahead of print]

45. Athyros VG, Papageorgiou AA, Symeonidis AN, et al. for theGREACE study collaborative Group. Early benefit fromstructured care with atorvastatin in patients with coronary heartdisease and diabetes mellitus. Angiology 2003;54:679-90

46. Robins SJ, Rubins HB, Faas FH, et al.; Veterans Affairs HDLIntervention Trial (VA-HIT). Insulin resistance and cardio-vascularevents with low HDL cholesterol: the Veterans Affairs HDLIntervention Trial (VA-HIT). Diabetes Care 2003;26:1513-7

47. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin,and cardiovascular disease: subgroup analysis from the Depart-ment of Veterans Affairs high-density lipoprotein interventiontrial (VA-HIT). Arch Intern Med 2002;162:2597-604

48. MRC/BHF Heart Protection Study of cholesterol lowering withsimvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003;361:2005-16

49. Sever PS, Dahlof B, Poulter NR, et al.; ASCOT investigators.Prevention of coronary and stroke events with atorvastatin inhypertensive patients who have average or lower-than-averagecholesterol concentrations, in the Anglo-Scandinavian CardiacOutcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multi-centre randomised controlled trial. Lancet 2003;361:1149-58

50. UK HDL-C Consensus Group. Role of fibrates in reducingcoronary risk: a UK consensus. Curr Med Res Opin 2004;20:241-7

51. Milionis HJ, Daskalopoulou SS, Elisaf M, Mikhailidis DP. Thepredictive value of lipid markers. Curr Pharm Des 2004 [inpress]

52. Fowkes FG, Housley E, Cawood EH, Macintyre CC, RuckleyCV, Prescott RJ. Edinburgh Artery Study: prevalence ofasymptomatic and symptomatic PAD in the general population.Int J Epidemiol 1991;20:384-92


CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2757_3, Accepted for publication: 03 September 2004Published Online: 21 September 2004

doi:10.1185/030079904X5599

Documents

The prevalence of the metabolic syndrome in Greece: The MetS-Greece Multicentre Study