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Prevalence of Atherosclerotic Vascular Disease Among Subjects With the Metabolic Syndrome With or Without Diabetes Mellitus: the METS- GREECE Multicentre Study

Posted on: Friday, 7 January 2005, 03:00 CST

Key words: Diabetes mellitus * Dyslipidaemia * Hypertension * Mediterranean * Metabolic syndrome * Uric acid * Vascular disease

SUMMARY

Aims: To estimate the prevalence of vascular disease (coronary heart disease/stroke/peripheral arterial disease) in individuals with the metabolic syndrome (MetSyn) with or without diabetes mellitus (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 areas (54%, 25% and 21%, respectively). The National Cholesterol Education Program - Adult Treatment Panel III definition of the MetSyn was used.

Results: The age-adjusted prevalence of the MetSyn was 23.6% [95% confidence interval (CI) = 22.4%-25.1%]; this was similar in men and women. The fully adjusted prevalence of vascular disease in those with the MetSyn (n = 984) was 29.4%, significantly higher than in those without (n = 3169, 9.6%, p < 0.0001), while subjects without both the MetSyn and DM had the lowest vascular 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), which was similar to that in subjects with DM without the MetSyn (n = 134, 25.4%), but lower than in those with both the MetSyn and DM (n = 310, 40.7%, p < 0.0001 vs. all). In comparison to those without the MetSyn [odds ratio (OR) = 1], the ORs of prevalent vascular disease, after multivariate analysis for age, sex and components of the MetSyn, and antiatherosclerotic drugs were: all MetSyn = 1.94 (95% CI = 1.35-2.47), with both MetSyn 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 disease was markedly increased in the presence of the MetSyn. Those with both the MetSyn and DM had the highest prevalence of vascular disease, followed by those with the MetSyn without DM. Probably MetSyn without DM should be considered as a coronary heart disease-risk equivalent in future guidelines. This initiative would reset treatment targets and potentially provide additional benefit in patients with the MetSyn.

Introduction

The clustering of risk factors called the metabolic syndrome (MetSyn) confers an increased risk of vascular disease morbidity and mortality1,2 and all-cause mortality2, even in the absence of clinically evident vascular disease and/or diabetes mellitus (DM)23. The recently published National Health and Nutrition Examination Survey (NHANES) II Mortality Study4 showed a significant increase [hazard ratio (HR) = 1.37; 95% confidence interval (CI) = 1.02- 1.85] in cardiovascular mortality in subjects with the MetSyn. However, all-cause mortality was not significantly increased. There was a near linear association ( p = 0.007) between the number of diagnostic criteria for the MetSyn and mortality from cardiovascular disease4.

Among the NHANES III participants aged 50 years and older5, the MetSyn was a significant [odds ratio (OR) = 2.07; 95% CI = 1.66- 2.59] univariate predictor of prevalent coronary heart disease (CHD). However, after adjusting for blood pressure, high-density lipoprotein cholesterol (HDL-C) and DM, the MetSyn was not a significant multivariate predictor of prevalent CHD. In another recent study from the same cohort6, the MetSyn was significantly related in multivariate analysis to self-reported myocardial infarction (MI), stroke and Ml/stroke, in both men and women. The 14- year follow-up of the San Antonio Heart Study7 showed that non- diabetic subjects with the MetSyn had about a 2-fold increase in risk for cardiovascular disease (adjusted for age, sex and ethnicity) compared with those without the MetSyn.

Recent data from the Strong Heart Study in nondiabetic American Indians with the MetSyn showed that cardiovascular disease risk did not increase as a function of the MetSyn8. Therefore, there is controversial evidence regarding the incremental risk for vascular disease associated with the MetSyn in the absence of DM. Because the overall prevalence of the MetSyn is increasing globally, it is vital to examine the relationship between the MetSyn and vascular disease in various ethnic subgroups and different populations9.

Within the population-based cross-sectional METS-GREECE Multicentre Study (prevalence of the METabolic Syndrome in GREECE)10'11, we investigated the prevalence of all vascular disease in subjects with the MetSyn with or without DM, in comparison to those without the MetSyn. This study, therefore, provides an insight into the association between vascular disease and the MetSyn in a Mediterranean country (Greece). The diagnosis of the MetSyn was based on the National Cholesterol Educational Program (NCEP) Adult Treatment 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 Care Centres and the Working Groups for the Identification and Treatment of the Metabolic Syndrome of the Greek Atherosclerosis Society and the Greek Society of General Practitioners, participated in the study. The study received ethical approval (the master regional consent was granted by the Hippocration Hospital) and informed consent was obtained from all subjects before enrolment.

Definition of the MetSyn

Participants having three or more of the following criteria (according to the NCEP ATP III report13), were defined as having the MetSyn:

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

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

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

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

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

Definition of DM

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

Study Design - Study Cohort

This was a cross-sectional analysis of a representative sample of Greek adults (4153 participants older than 18years). All subjects were Caucasian men (49%) and women (51%), living in urban (54%), semi-urban (25%) and rural (21%) areas. We established representation in relation to residence (urban area > 50 000 inhabitants, semi-urban area 5000-50000 and rural areas < 5000, in accordance with the 2001 National Census. This was conducted at the beginning of 2001 and the census results have been accessible online since December 2001(14). We assigned the specific number of subjects to each investigator consistent with the population of the city, town or village where they practice. We established representation in relation to age and sex as follows: each investigator, in cooperation with the Civil Authorities, visited subjects in their home. Entire neighbourhoods with residents of different socio- economic status were screened by the 'door-to-door' method. Only a few eligible subjects did not wish to be enrolled (n = 31). These were not of a different gender and age from those enrolled (n = 4153). It is very unlikely that this small number of persons affected the reported prevalence of vascular disease.

For each enrolled subject, the personal and family medical history was obtained by a structured interview, drug treatment was recorded and he/she had a physical examination at home. Subjects were then invited to have the laboratory tests at the local hospital after a 12 h fast, at which time a second physical examination was performed.

Definition and Diagnosis of Vascular Disease

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

The presence of vascular disease was established based on physical examination and personal medical history. Prevalent CHD was diagnosed by the presence of stable angina (WHO chest pain questionnaire), positive exercise tolerance test, coronary angiography with at least one substantial coronary artery stenosis or history of hospitalisation for MI, coronary bypass artery grafting or percutaneous transluminal angioplasty. Subjects were considered to have a stroke if they had been discharged from a hospital with this diagnosis. Only those with confirmation of a non- haemorrhagic stroke by a CT or MRI scan were considered. PAD was established by physical examination and the presence of intermittent claudication. If a subject had more than one vascular disease manifestation he/she was considered only once (adjustment for overlap).

PROCAM Risk Calculator Estimates

The PROCAM 10-year CHD risk calculator15 estimates should be interpreted with caution since they represent 10-year probabilities in primary prevention subjects and our results refer to the cross- sectional prevalence of vascular disease in all subjects (primary and secondary prevention).

Laboratory-based Assessment

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

Statistical Analysis

First a univariate analysis was performed and then we used a logistic regression model to determine the multivariate association of the MetSyn after adjusting for all cofounders, component conditions and other vascular disease risk factors. All ORs were calculated for all subjects with the MetSyn, those with the MetSyn and DM and those with the MetSyn but no DM. The component conditions were included as categorical variables. All analyses were carried out with SPSS 11.0 software package (SPSS, Inc., Chicago, IL). The prevalence of the MetSyn in the general population and vascular disease in those with or without the MetSyn as well as the 95% CIs were derived using the SPSS frequency and explore procedures. Significance for differences among groups was assessed by SPSS Cross tabs, interval by interval, Pearson's R. The ORs and 95% CI for prevalent vascular disease between groups and subjects without the MetSyn (OR = 1), was assessed with the Pearson Chi-Square method. A sex-specific model for vascular disease was also examined. Mean and standard deviation (SD) of the numerical variables are reported. A two-sided p value < 0.05 was considered significant.

Results

Characteristics of the study population are provided in Table 1 and lipid values in Table 2. There were no significant differences in smoking habits among the evaluated subject groups (Table 1).

Prevalence of the MetSyn in the General Population

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

Prevalence of Vascular Disease According to the Presence of the MetSyn and DM

The age-, sex-adjusted prevalence of CHD, stroke and PAD 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 the MetSyn (n = 984) had a vascular disease prevalence of 29.4%, 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 the MetSyn (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%), but significantly lower than that of participants (n = 310) with both the MetSyn and DM (40.7%, p < 0.0001). In the group of patients with DM but no MetSyn (n = 134), 58 had Type 1 DM and 76 were effectively treated patients with Type 2 DM.

Vascular Disease Components Overlap

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

Lipid Values

All the lipid values of subjects with the MetSyn were significantly different from those of subjects without the MetSyn (Table 2). A substantial percentage (64%) of patients with the MetSyn had high12 LDL-C levels > 3.4mmol/L and even more (69%) had a nonHDL-C > 4.1 mmol/L, despite the fact that 36% of them were on lipid lowering drug treatment (31% on statins and 5% on fibrates). Anti-atherosclerotic medications used in the study population are reported in Table 3.

Odds Ratios (ORs) for Prevalent Vascular Disease

Univariate and multivariate associations of the MetSyn and component conditions with prevalent vascular disease are shown in Table 4. In subjects with the MetSyn, compared with people without the MetSyn (OR = 1), the fully adjusted OR of prevalent vascular disease, after logistic regression for age, sex, smoking, anti- atherogenic drugs (listed in Table 3), hypertension, high triglycerides and low HDL-C, regardless of diabetic state was 1.94 (95% CI = 1.35-2.47), in subjects with both the MetSyn and DM this was 3.04 (95% CI = 1.98-4.11) and in people with the MetSyn but without DM it was 1.48 (95% CI = 1.12-1.92). In this latter group, the MetSyn was significantly associated with vascular 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 sex difference was not statistically significant.

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)

Table 2. Measured lipid parameters (mean value 1 standard deviation) in all groups (4153 adults aged > 18 years) according to the presence 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

Table 3. All anti-antherosclerotic 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)

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 for anti-atherosclerotic medications (listed in Table 3) and current smoking, age, sex and MetSyn components

Subjects with the MetSyn but without DM with all five MetSyn components had a fully adjusted OR of prevalent vascular disease of 2.78 (95% CI = 2.10-3.81), in comparison with those without the MetSyn (data not shown in Table 4). Among the component conditions only abdominal obesity was not independently related to prevalent vascular disease. Low HDL-C was significantly associated with vascular disease and had the greatest OR of any of the component conditions (OR = 1.36, 95% CI = 1.07-1.75). High triglycerides (OR = 1.22,95% CI = 1.09-139) and hypertension (OR = 1.06, 95% CI = 1.01- 1.14) were also independently and significantly related to vascular disease (Table 4). In the sex-specific analysis, high triglycerides were more associated with vascular disease in women (OR = 1.59, 95% CI = 1.17-2.05) than in men (OR = 1.18, 95% CI = 1.01-1.42). After adjustment for age, sex, hypertension, high triglycerides, low HDL- C and non-HDL-C there was a significant association between the MetSyn and vascular disease (OR = 1.72, 95% CI = 1.07-2.51) (not shown in Table 4) only in the subjects with the MetSyn and DM. However, this relationship may have been masked by the fact that 36% of those with the MetSyn were on lipid lowering drugs (31% on statins and 5% on fibrates) and other anti-atherosclerotic medications. Therefore, in the multivariate analyses, ORs were adjusted for drug treatment, which are more representative (Table 4).

Prevalence of the MetSyn and its Individual Diagnostic Features in Subjects with Vascular Disease

The prevalence of the MetSyn was significantly higher (p < 0.0001) among subjects with (n = 594) than without prevalent vascular disease (n = 3559): 48.1% vs. 19.6%. The same relationship applied to the diagnostic features (p < 0.0001 for all), except for central obesity (62.2% vs. 55.9%, p = 0.3).

PROCAM Risk Calculator Estimates

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

Discussion

Our results suggest that in a Mediterranean population, the MetSyn identifies a substantial additional vascular risk (CHD/ stroke/PAD) in men and women, even in those without DM. Both vascular disease prevalence and the percentage of subjects with vascular disease having more than one manifestation were similar in subjects with the MetSyn but without DM and those with DM but without the MetSyn. Furthermore, the adjusted prevalent vascular disease in those with the MetSyn but no DM was almost 50% greater than that of those with neither the MetSyn nor DM (Table 4), underlining the high risk associated with the MetSyn. These findings suggest that the MetSyn should probably be added to the list of CHD equivalents, even in the absence of DM. In favour of this suggestion is the fact that a considerable proportion of the subjects with the MetSyn and their physicians were unaware of the diagnosis and the patients were undertreated".

We found a significant cross-sectional association between the diagnostic features of the MetSyn12 and vascular disease, except for abdominal obesity. It is possible that the strength and significance of these associations would be enhanced if these features were modelled as continuous variables. In our analysis, there was a lack of association between abdominal obesity and prevalent vascular disease. This is in agreement with the data from the Women's Ischemia Syndrome E\valuation (WISE) Study16 and previous studies1,6, but differs from others that showed linear relationships between CHD and either body mass index (BMI) or waist-to-hip ratio independent of the BMI17, after adjusting for other risk factors. It is possible that the association of abdominal obesity with vascular disease was diluted because of the impact of other components, such as hypertriglyceridaemia6 or medication. Some, but not all studies, showed a significant association between high triglycride levels and CHD; a meta-analysis of 17 prospective studies reported a significant relationship, after adjusting for other risk factors9'18. This relationship was stronger in women, as with our findings. Hypertension and low HDL-C have been reported to have a clear association with vascular disease1,5,6.

The increased vascular disease prevalence in subjects with the MetSyn19, may be explained by the components12 that define the MetSyn in association with other, not routinely measured factors. For example, impaired fibrinolysis, oxidative stress, high LDL-C levels, increased small dense LDL particles, hypercoagulability, inflammation and hyperinsulinaemia20. It was also reported21 that the MetSyn is associated with higher levels of oxidized LDL-C, apolipoprotein-B, urate, leptin, fibrinogen, leukocytes, erythrocyte sedimentation rate and soluble endothelial adhesion molecules and lower apolipoprotein-A concentrations. Furthermore, in women with the MetSyn, a substantial residual CHD risk remained after controlling for all five MetSyn components. This was partly due to increased levels of LDL-C, small dense LDL particles or C-reactive protein22,23. All these parameters cannot be assessed in each patient in everyday clinical practice. However, LDL-C and non-HDL-C (total cholesterol minus HDL-C] are easily calculated.

Although LDL-C is not considered a component of the MetSyn, many of patients have raised levels of LDL-C. In our study, 64% of the subjects with the MetSyn had a LDL-C level > 3.4mmol/L (Table 2), despite the fact that 36% of them were on lipid lowering drugs (31% on statins and 5% on fibrates). This argues for whether elevated LDL- C might be considered a modifying component of the MetSyn, especially in the presence of elevated triglycerides (indicating small dense LDL particles with increased atherogenicity24). The contribution of high LDL-C levels to vascular disease risk in subjects with the MetSyn was highlighted by a retrospective analysis of the landmark statin trials. The placebo data from the Scandinavian Simvastatin Survival Study (4S) and the Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)25 showed that the relative risk of major coronary events 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 subjects without the MetSyn. Moreover, patients with the MetSyn had an increased risk of major coronary events irrespective of their Framingham-calculated 10-year risk score25. These data demonstrate that the MetSyn is associated with an increased vascular risk in hypercholesterolaemic patients with CHD in 4S and in those with 'average' LDL-C levels and low HDL-C but without CHD in AFCAPS/ TexCAPS25. It appears that the MetSyn is associated with vascular events that are not 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 response to therapy. Within 4S, subsequent analysis based on the LDL-C level suggests that simvastatin therapy was more effective among those with the MetSyn than those without it26. In the West of Scotland Coronary Prevention Study (WOSCOPS)27, the MetSyn continued to predict CHD events (HR = 1.30, 95% CI = 1.00-1.67, p = 0.045) in a multivariate model incorporating conventional risk factors. Men with 4 or 5 features of the MetSyn had a 3.7-fold increase in risk for CHD compared with men with none. A projection of pooled observational data28 suggested that optimal control of LDL-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 are in accordance with those of WOSCOPS27. However, there are several limitations when comparing WOSCOPS and our findings. WOSCOPS used a modified NCEP definition of the MetSyn, replacing waist circumference [WC) with BMI. However, WC seems to be a stronger predictor than BMI of obesity-related health risks, especially CHD, both in men29 and women29,30 and it is more closely associated with the level of exercise30. Increased exercise may not alter BMI and risk assessment will remain unaffected31. In contrast, WC was shown to change with increased exercise, indicating changes in abdominal obesity, which allows fora more accurate risk assessment for type 2 DM and CHD31. Results from the Heart and Estrogen/progestin Replacement Study (HERS) show that both BMI and WC are associated with mortality among postmenopausal women with established CHD, but WC may be more important than BMI. This may be largely mediated by other cardiac risk factors32. Even in South and Southeast Asia, where body build is different from that of Caucasians, a modified WC value that is more applicable to Asian populations (90 cm for men and 85 cm for women) is used rather than the BMP33,34. Furthermore, in the 14924 adult participants of the NHANES III within the three BMI categories, those with high WC values were increasingly likely to have hypertension, DM, dyslipidaemia and the MetSyn compared with those with normal WC values35. We report the BMI values in Table 1 to facilitate comparisons with other studies.

We could not use the Framingham risk score (FRS) to compare our findings with those of the AFCAPS/TexCAPS study25 for several reasons. First, the FRS is only applicable in subjects free of CHD and our population included patients with CHD or CHD equivalents, while in AFCAPS/TEXCAPS and WOSCOPS the majority of the participants were free of CHD and very few (1% in WOSCOPS)27 had DM. second, it is not appropriate to compare 10-year probabilities for MI with cross-sectional prevalence (in AFCAPS/TEXCAPS and WOSCOPS the prospective 5-year data were compared with the FRS prediction), especially when they include PAD, as in our study. Third, the FRS does not include impaired fasting glucose, high triglycerides and abdominal obesity as risk factors. Thus, from the five components of the MetSyn, only HDL-C and hypertension will be considered by the FRS, probably providing false low results. For subjects with DM, the UKPDS risk calculator36 is ideal. However, we cannot use two different scoring systems within the same study. The PROCAM risk calculator15 might apply, though it does not include impaired fasting glucose. Estimates of the PROCAM risk (Table 1) provide an indicative level of risk for the CHD-free subjects. However, these scores should be interpreted with caution because they represent 10- year probabilities and our results refer to the cross-sectional prevalence of vascular disease.

The case for assessing non-HDL-C levels is probably convincing37. In individuals with triglycerides ≥ 2.3 mmol/L (probably the majority of subjects with the MetSyn), non-HDL-C is a secondary treatment target12. Non-HDL-C includes cholesterol in LDL and triglyceride-rich lipoproteins. In our study, 69% of subjects with the MetSyn had a non-HDL-C level > 4.1 mmol/L (Table 1). The Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) suggested that non-HDL-C at baseline and on-treatment may be a more practical predictor of CHD risk that is already available from the lipid profile18. In the Lipid Research Clinics (LRC) follow- up study, non-HDL-C level was a better predictor of CHD death than LDL-C39. In the GREACE Study40,41, non-HDL-C was a better predictor than LDL-C of both risk for clinical events in untreated patients and statin-induced clinical benefit in treated patients with CHD. Probably, non-HDL-C in such patients should be the primary treatment target39'41. Therefore, non-HDL-C may be incorporated in the definition of the MetSyn. Moreover, in our study, after adjusting for non-HDL-C, the ORs in subjects with the MetSyn (especially those without DM) were not significantly higher than those of subjects without the MetSyn. This finding supports the concept that adding the LDL-C variable influenced the relationship between risk and the MetSyn. This interpretation also supports the need to lower LDL-C levels to guideline recommendations12 in patients with the MetSyn.

Our results relating vascular risk with the number of MetSyn components are consistent with the findings of other studies4'27'42- 43. Thus, in our study those with all five features (NCEP ATP III)12 of the MetSyn had a greater OR than those with three features required to make a diagnosis of the MetSyn. However, other studies42'13 considered different factors from those defined in the NCEP ATP III12. Nevertheless, in the NHANES II survey4 the association between the number of MetSyn criteria and cardiovascular disease mortality was near linear (p = 0.007).

Several studies2'3'6'7'4'1 and our data from a Mediterranean Country suggest that the MetSyn, even in the absence of DM, is associated with an increased vascular risk. This will reset the LDL- C and non-HDL-C treatment targets and may result in additional clinical benefit in these subjects. There is evidence that treating the MetSyn or DM with statins or fibrates will result in a reduction in vascular events22"26,4"0. Therefore, a wider use of these drugs should result in a reduction of vascular events in these patients. Furthermore, all abnormal lipid variables may represent an increased risk51.

Study Limitations

As a cross-sectional study, the present analysis is limited in its ability to elucidate causal rel\ationships between risk factors and outcomes. It is also likely that the exact incidence of vascular disease was higher since fatal events were not included and silent vascular disease manifestations were not detected. For example, the prevalence of PAD is increased 3-fold if asymptomatic patients are included by measuring the ankle-brachial pressure index52. Moreover, primary or secondary vascular disease prevention interventions may have attenuated the association of risk factors with vascular disease manifestations. We are also aware that some subgroups are small (e.g. no MetSyn + DM; n = 134).

Conclusions

The MetSyn is significantly associated with CHD/stroke/PAD risk, even in the absence of DM and after adjusting the ORs for age, sex and features of the MetSyn. Probably the MetSyn, even without DM, should be considered as a CHD-risk equivalent. This will increase awareness and set lower targets for both LDL-C and non-HDL-C for these individuals. This initiative is likely to substantially increase the benefit from treatment.

Acknowledgement

This study was conducted independently; no company or institution supported it financially. Some of the authors have attended conferences and participated in other trials sponsored by various pharmaceutical companies.

We thank the Greek Atherosclerosis Society and the following 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), Posnahidou DN (HC), Prokopidis D (GP), Protopapas N (HC), Psaltoglou I (HC), Sarigianni M (GH), Satsoglou EA (GH), Sekeri ZP (HC), Sfakianakis M (HC), Tsakiris K (HC), Tsiknaki SB (HC), Vasilopoulou D (HC). (UH = University Hospital, GH = General Hospital, GP = General Practice, HC = Health Center).

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

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

Published Online: 21 September 2004

doi: 10.1185/030079904X5599

Vasilios G. Athyros1,3,7,8, Dimitri P. Mikhailidis4,7, Athanasios A. Papageorgiou3,7,8, Triandafillos P. Didangelos2,3, Emmanuel S. Ganotakis5,7,8, Athanasios N. Symeonidis8, Stella S. Daskalopoulou4,7, Anna I. Kakafika3,7 and Moses Elisaf6,7,8 for the METS-GREECE Collaborative Group

1 Atherosclerosis and Metabolic Syndrome Units, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece

2 Diabetes Center, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece

3 Second Prop. Department of Internal Medicine, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece

4 Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College Medical School, London, UK

5 Department of Internal Medicine, Medical School, University of Crete, Heraklion, Greece

6 Department of Internal Medicine, Medical School, University of loannina, Greece

7 Working Group for the Identification and Treatment of Metabolic Syndrome of the Greek Atherosclerosis Society, Athens, Greece

8 Working 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: athyros@med.auth.gr

Copyright Librapharm Nov 2004

Source: Current Medical Research and Opinion

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