Journal of the American College of Cardiology

2007 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 49, No. 4, 2007

ISSN 0735-1097/07/$32.00
doi:10.1016/j.jacc.2006.09.032

REVIEW AND META-ANALYSIS

Metabolic Syndrome and Risk of

Incident Cardiovascular Events and Death
A Systematic Review and Meta-Analysis of Longitudinal Studies
Apoor S. Gami, MD,* Brandi J. Witt, MD,* Daniel E. Howard, MD, Patricia J. Erwin, MLS,
Lisa A. Gami, RN,* Virend K. Somers, MD, PHD, FACC,* Victor M. Montori, MD, MSC
Rochester, Minnesota
Objectives

The purpose of this research was to assess the association between the metabolic syndrome (MetSyn) and cardiovascular events and mortality by meta-analyses of longitudinal studies.

Background

Controversy exists regarding the cardiovascular risk associated with MetSyn.

Methods

We searched electronic reference databases through March 2005, studies that referenced Reavens seminal
article, abstracts presented at meetings in 2003 to 2004, and queried experts. Two reviewers independently
assessed eligibility. Longitudinal studies reporting associations between MetSyn and cardiovascular events or
mortality were eligible. Two reviewers independently used a standardized form to collect data from published
reports. Authors were contacted. Study quality was assessed by the control of selection, detection, and attrition
biases.

Results

We found 37 eligible studies that included 43 cohorts (inception 1971 to 1997) and 172,573 individuals. Random effects meta-analyses showed MetSyn had a relative risk (RR) of cardiovascular events and death of 1.78
(95% confidence interval [CI] 1.58 to 2.00). The association was stronger in women (RR 2.63 vs. 1.98, p
0.09), in studies enrolling lower risk (10%) individuals (RR 1.96 vs. 1.43, p 0.04), and in studies using factor
analysis or the World Health Organization definition (RR 2.68 and 2.06 vs. 1.67 for National Cholesterol Education Program definition and 1.35 for other definitions; p 0.005). The association remained after adjusting for
traditional cardiovascular risk factors (RR 1.54, 95% CI 1.32 to 1.79).

Conclusions

The best available evidence suggests that people with MetSyn are at increased risk of cardiovascular
events. These results can help clinicians counsel patients to consider lifestyle interventions, and should fuel
research of other preventive interventions. (J Am Coll Cardiol 2007;49:40314) 2007 by the American
College of Cardiology Foundation

The metabolic syndrome (MetSyn), also termed the insulin

resistance syndrome, is the concurrence in an individual of
multiple metabolic abnormalities associated with cardiovascular disease. Cross-sectional surveys indicate that, in the
U.S., one-third of adults (1) and an alarming proportion of
children (2) have the MetSyn. It represents a global public
health problem (3,4). Since 1988, when Reaven (5) first
systematically described it, an abundance of research has
advanced an understanding of the pathophysiology, epidemiology, prognostic implications, and therapeutic strategies

From the *Division of Cardiovascular Diseases, Department of Internal Medicine,

Mayo Medical Libraries, Division of Hypertension, Division of Endocrinology,
Nutrition, and Metabolism, and Knowledge and Encounter Research Unit, Mayo
Clinic College of Medicine, Rochester, Minnesota. Dr. Gami had full access to all of
the data in this study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Manuscript received June 26, 2006; revised manuscript received September 1, 2006,
accepted September 27, 2006.

related to the MetSyn. Despite this progress, fundamental

uncertainties persist regarding the MetSyn, as highlighted
by recent national and international diabetes organizations
doubt regarding even its existence (6).
Reavens (5) first definition of the MetSyn included these
components: hyperglycemia, abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol concentration, and hypertension. Its pathogenesis, unified by
the putative mechanism of insulin resistance, was thought to
be related to interactions between sedentary lifestyle, diet,
and genetic factors. In 1998, the American Diabetes Association proposed that MetSyn is comprised of glucose
intolerance, central obesity, dyslipidemia (including increased triglycerides, decreased high-density lipoprotein
cholesterol concentration, and increased small dense lowdensity lipoprotein cholesterol concentration), hypertension, increased prothrombotic and antifibrinolytic factors,
and risk for atherosclerotic disease; but, it did not propose

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Gami et al.
Meta-Analysis of Metabolic Syndrome

specific definitions or thresholds

for these processes (7). In 1999,
the World Health Organization
CI confidence interval
(WHO) codified specific compoMetSyn metabolic
nents and thresholds for the
syndrome
MetSyn (8), and in 2003 the
NCEP National
U.S. National Cholesterol EduCholesterol Education
cation Program (NCEP) reProgram
defined the MetSyn in an atRR relative risk
tempt to simplify the clinical
WHO World Health
application of its criteria and imOrganization
prove its recognition (9). Despite
these efforts, there exists no genuine consensus of the unique components that comprise the
MetSyn (4,10). Burgeoning information regarding its
pathophysiology adds to the uncertainty (11).
Only recently have there been studies assessing the risk of
incident cardiovascular disease events attributable to the
MetSyn. These studies had different populations, definitions of MetSyn, methods, and results. Because of this
variability and the current controversy regarding its implications (6), we propose that a systematic review and metaanalysis of the existing data will provide the current best
evidence. In addition to providing an overall estimate of
risk, the tools of meta-analysis allow an evaluation of
differences between studies that could clarify the prognostic
implications of how MetSyn is defined, in which settings it
may be informative, and other issues related to its clinical
use (12,13).
We performed a meta-analysis of longitudinal studies
that assessed any cardiovascular event outcomes or mortality
in people with clustering of 3 or more coronary risk factors
(regardless of whether this was termed the MetSyn) compared with people without that phenotype. We expected to
capitalize on the high heterogeneity between studies to
identify likely explanations for it in factors related to
population characteristics, outcome and exposure ascertainment, and study quality. The reporting of this systematic
review follows current standards (14).
Abbreviations
and Acronyms

Methods
Study eligibility. Eligible studies: 1) were randomized
trials or cohort studies; 2) reported a risk estimate (or
frequency data from which one could be calculated) for
MetSyn, its synonyms, or clustering of 3 or more coronary
risk factors; and 3) reported a single or combined cardiovascular event outcome or mortality. There were no exclusion criteria or language restrictions.
Search strategy. A content expert and a masters level
medical librarian with extensive meta-analytical experience
collaborated to design the search strategies. We searched
the following electronic databases on March 1, 2005: Ovid
MEDLINE (from 1966), Ovid EMBASE (from 1988),
Web of Science (from 1993), and Cochrane Library (from
inception). Our search of Web of Science included a match

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between terms for cardiovascular outcomes and publications

that cited Reavens article (5). Figure 1 shows the strategy
for MEDLINE (the other strategies are available from the
authors).
We hand-searched conference proceedings from the 2003
and 2004 annual scientific sessions of the European Society
of Cardiology, American Heart Association, American
College of Cardiology, and American Diabetes Association
for relevant abstracts to identify full peer-reviewed publications not yet indexed. We queried experts of endocrinology
and cardiology, and we reviewed bibliographies of retrieved
publications to further increase our yield of potentially
relevant articles.
Study selection. Using a high threshold for exclusion, one
investigator examined all abstracts and selected articles for
full text examination. Two investigators independently used
piloted, standardized forms to assess the eligibility of all full
text articles. We collaborated with translation services to
examine articles in languages other than English. We
assessed interobserver agreement by the phi and kappa
statistics (15,16), and we resolved differences by consensus.
Data collection. Two investigators independently used
piloted, standardized forms to abstract data from included
studies and other publications reporting their methods. We
contacted original study authors in order to obtain missing
data.
For each study, we recorded the year of cohort inception,
the setting (community subjects vs. medical patients), participant characteristics related to the MetSyn, and the
number of participants with prevalent coronary heart disease
and diabetes mellitus. Exposure data collected included the
definitions and criteria for MetSyn and its components, the
number of participants with and without MetSyn for each
definition, and the duration of follow-up. Outcome data
collected included the definitions of cardiovascular outcomes, the numbers of participants with and without
MetSyn who did and did not have the outcome(s), the
multivariable adjusted risk estimate (relative risk [RR],
hazard ratio, or odds ratio) for MetSyn and for different
numbers of its components for each outcome, and the
variables incorporated into the multivariable analyses. When
a study reported only risk estimates for different numbers of
MetSyn components, rather than a risk estimate for MetSyn
or 3 or more components, we used the risk estimate for 3
components to reflect that of the MetSyn (an approach that
would underestimate the risk).
Quality assessment. We measured the quality, or internal
validity, of studies by assessing their control of selection
bias, detection bias, and attrition bias (17). For control of
selection bias, we assessed if multivariable risk estimates
incorporated age, gender, smoking, and coronary heart
disease history, when applicable. For control of detection
bias, we assessed if the outcome assessors were unaware
(either explicitly or de facto due to temporal relationships)
of subjects MetSyn status. For control of attrition bias, we
assessed the extent of loss to follow-up.

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Figure 1

405

Literature Search Strategy Used for the MEDLINE Database

Loss to follow-up is traditionally represented as a proportion of the total initial study population, but this
approach does not provide sufficient information about how
loss to follow-up in a study affects the reliability of its risk
estimate. In this study, we describe attrition bias by the ratio
of the number of subjects lost to follow-up to the number of
outcome events in the study (loss-events ratio). This is a
direct measure of how influential loss to follow-up could be
for a risk estimate in a given study, and we arbitrarily
considered a loss-events ratio 10% as satisfactory control
of attrition bias.
Statistical analysis. The results of each cohort study were
reported as an RR, hazard ratio, odds ratio, or dichotomous frequency data. We treated hazard ratios as RRs.
Because event rates were not sufficiently low in some
high-risk study populations, we did not assume that odds
ratios were comparable to RRs. We algebraically converted odds ratios and frequency data into RRs. When
available, we used the adjusted risk estimates from
multivariate models.
We performed separate meta-analyses with the DerSimonian and Laird (18) random effects model to obtain the
pooled RR for each outcome and the pooled RR for the
primary end point of incident cardiovascular events and death.

For the latter, when studies reported multiple outcomes, we

incorporated them into subsequent analyses based on the
following hierarchical list of outcomes (from broader to
more specific cardiovascular outcomes, followed by all-cause
mortality): cardiovascular events, coronary heart disease
events, cardiovascular death, coronary heart disease death,
and all-cause death. Similarly, when studies reported results
based on multiple MetSyn criteria, we incorporated them
based on the following hierarchical list of criteria: NCEP,
modified NCEP, WHO, modified WHO, and other criteria. We used the Cochrans Q test to assess between-study
differences and the I2 statistic to quantify the proportion of
observed inconsistency across study results not explained by
chance (19). We proposed pre-defined subgroup analyses to
test the effect of methodology and participant characteristics
on the strength of association. Heterogeneity between
subgroups was calculated with Cochrans Q test (20), and
comparisons of risk estimates between subgroups were made
with a test of interaction (21).
Using the same methods, we performed an additional
meta-analysis of studies that reported a risk estimate for
MetSyn that was adjusted in multivariable models for any or
all of the components that make up the syndrome. This
analysis aimed to quantify the additive cardiovascular risk

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attributable to the MetSyn above that which is conferred by

its component risk factors.
The presence of publication bias was investigated graphically by the method of Sterne and Egger (22), and its
implications for our results were assessed by the fail-safe n
(23) and the trim-and-fill method (24).
All analyses were performed with Comprehensive Meta
Analysis Version 2 (Biostat, Englewood, New Jersey) (25).

Data Synthesis
Search results and study inclusion. Our initial search
identified 4,198 unique publications, which were narrowed
by preliminary review to 104 potentially relevant original
articles. The search of conference proceedings and query of
experts did not identify additional articles. Sixty-seven
articles were excluded (some for multiple reasons) because of
cross-sectional study design (n 10), lack of measurement
or report of outcome data for MetSyn, its synonyms, or
clustering of 3 or more coronary risk factors (n 61), or
lack of measurement of cardiovascular events or death (n
2). There were 37 eligible reports (interobserver raw agreement 96%, 0.93, 0.91). One article that studied the
same cohort as another included article was excluded (26),
and 1 article presented results for 2 independent studies
(27). In another study, the investigators performed 11
cohort studies (by applying modified MetSyn criteria to
existing baseline subject data from 11 prior epidemiologic
studies that assessed mortality during long-term follow-up)
and reported a pooled result for 7 of those cohorts (28).
Ultimately, our meta-analysis included 36 reports that
described 37 studies including 43 unique cohorts (Fig. 2)
(27 62).

Figure 2

Flowchart of Article Inclusion

*The 36 included articles described 37 studies that included 43 unique cohorts.

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Qualitative summary. Table 1 summarizes the characteristics of the included studies. They were all published since
1998, included cohorts with inception between 1971 and
1997, and had follow-up from 2.2 to 18.8 years. Sample
sizes ranged from 133 to 41,056 participants (total
172,537), and there was a wide range of prevalence of
cardiovascular disease and diabetes mellitus at inception.
The MetSyn was defined by WHO criteria in 6 studies
(36,41,47,48,51,61), NCEP criteria in 12 studies
(39,40,42,43,47,5355,57,59,61,62), modified WHO criteria
in 4 studies (28,39,54,58), and modified NCEP criteria in 10
studies (27,39,44 46,49,50,56,60). Most modifications substituted body mass index for waist circumference or waist-to-hip
ratio, or omitted the proteinuria component of the WHO
criteria. A few studies added additional components, such as
C-reactive protein (45) and uric acid (38,52). Factor analysis
was used in 5 studies (31,33,34,39,52) to create a novel
variable, or factor, comprised of statistical loadings of highly
inter-correlated participant characteristics (analogous to clustered risk factors in the MetSyn), which was then used as a
parameter in regression models for incident cardiovascular disease. The factors in these studies were nearly
identical to the components in WHO and NCEP definitions of MetSyn. Some studies developed MetSyn
criteria using threshold values for its components based
on the extreme tertiles to quintiles of their distribution
(30,32,35,37). One study that presumably had a predominantly Japanese population used a lower threshold for
systemic obesity (a body mass index 25 kg/m2) in its
modified WHO criteria (58), but no other studies modified their criteria to account for ethnic differences.
Eleven studies assessed cardiovascular events (which in
some studies included cardiovascular death), 18 studies

Table 1

Characteristics of Cohort Studies of Metabolic Syndrome and Incident Cardiovascular Disease and Death
Cohort
Inception Year

Follow-Up,
yrs

Setting

Sample
Size, n

Mean
Age, yrs

Men,
%

CVD,
%

DM,
%

MS Criteria

MS,
%

Outcomes

Anderson et al., 2004 (46)

1994

2.8

2,035

65

76

100

30

Modified NCEP

66

CHD events

Bonora et al., 2003 (a) (41)

1990

5.0

888

59

51

10

23

WHO
NCEP

34
18

CHD events

Study Author, Year

Controlled
Selection Bias

Controlled
Attrition Bias

Bonora et al., 2004 (b) (47)

1988

4.3

559

63

45

100

WHO

91

CV events

Bruno et al., 2004 (48)

1991

8.2

1,565

69

43

24

100

WHO

76

Death
CV death

Corsetti et al., 2004 (49)

1994

2.2

766

58

77

100

Modified NCEP

36

CHD events

Ford, 2004 (50)

1976

13.5

2,431

50

46

18

Modified NCEP

26

Death
CV death
CHD death

Gimeno Orna et al., 2004 (51)

1994

4.6

318

65

41

21

100

WHO

77

CV events
CHD events

Girman et al., 2004 (a) (27)

1988

5.4

1,991

59

81

100

Modified NCEP

21

CHD events

Girman et al., 2004 (b) (27)

1986

5.0

3,188

58

85

Modified NCEP

46

CHD events

CHD events

Godsland et al., 2004 (52)

1971

10.6

649

47

100

Factor analysis

NA

Holvet et al., 2004 (53)

1997

5.0

3,033

74

48

13

19

NCEP

38

CHD events

Hsia et al., 2003 (42)

1997

2.8

294

65

100

37

NCEP

60

CHD death
CV events
CHD events

NA

8.5

9,522

56

46

Modified WHO

15

Death
CV death

Hunt et al., 2004 (54)

1984

12.7

2,815

43

43

11

NCEP
Modified WHO

25
25

Death
CV death

Isomaa et al., 2001 (36)

1990

6.9

4,483

54

48

38

WHO

46

Death
CV death

Katzmarzyk et al., 2004 (55)

1979

10.2

19,223

43

100

NCEP

20

Death
CV death

Kaukua et al., 2001 (37)

1979

10.0

133

56

53

32

100

Other

54

Death
CV death

Klein et al., 2002 (38)

1988

4.8

2,957

62

43

Other

19

CV events

Lakka et al., 2002 (39)

1984

11.6

1,209

52

100

NCEP
Modified NCEP
Modified WHO-1
Modified WHO-2
Factor analysis

9
14
14
13
NA

Death
CV death
CHD death

Hu et al., 2004 (28)

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Characteristics of Cohort Studies of Metabolic Syndrome and Incident Cardiovascular Disease and Death

Lehto et al., 2000 (33)

1982

7.2

902

58

55

15

100

Factor analysis

NA

CHD death

Lempianin et al., 1999 (31)

1986

7.0

1,069

69

37

20

Factor analysis

NA

CHD events

Malik et al., 2004 (56)

1976

13.0

6,255

50

46

27

13

Modified NCEP

27

Death
CV death
CHD death

Marroquin et al., 2004 (57)

1996

3.5

755

58

38

32

NCEP

57

Death
CV events

McNeill et al., 2005 (62)

1987

11.0

12,089

54

43

NCEP

23

CHD events

Gami et al.
Meta-Analysis of Metabolic Syndrome

407

Continued on next page

408

Table 1

Continued

Study Author, Year

Cohort
Inception Year

Follow-Up,
yrs

Setting

Sample
Size, n

Mean
Age, yrs

Men,
%

CVD,
%

DM,
%

MS Criteria

MS,
%
7

Outcomes
CV events

Controlled
Selection Bias

Controlled
Attrition Bias

Nakanishi et al., 2004 (58)

1994

7.0

6,182

48

100

Modified WHO

Onat et al., 2002 (40)

1997

3.0

2,398

49

50

NCEP

33

CHD events

Pyrl et al., 2000 (34)

1971

18.8

970

48

100

Factor analysis

NA

CV events
CHD events

Resnick et al., 2003 (43)

1989

7.6

2,283

55

43

NCEP

35

CV events

Ridker et al., 2003 (44)

1992

10.1

14,719

54

Modified NCEP

24

CV events
CHD events

Rutter et al., 2004 (59)

1991

6.9

3,037

54

45

NCEP

24

CV events

Sattar et al., 2003 (45)

1989

4.9

6,447

55

100

Modified NCEP

26

CHD events

Schillaci, 2004 (60)

1988

4.1

1,742

50

55

Modified NCEP

34

CV events
CHD events

100

12

Death

Sprecher et al., 2000 (35)

1987

8.2

6,428

62

81

Stern et al., 2004 (61)

1984

78

2,570

Tenkanen et al., 1994 (29)

1981

5.0

2,035

47

100

Trevisan et al., 1998 (30)

1978

7.0

4,056

47

55

Wilson et al., 1999 (32)

1971

16.0

3,577

49

20

Other

WHO
NCEP

Other
Other

Other

19

CHD death
CHD events

CV events

CHD events

15

Death
CV death
CHD death

X
36

Gami et al.
Meta-Analysis of Metabolic Syndrome

Continued

Data are for subjects included in analyses of incident cardiovascular disease (CVD) or death, and may differ from the characteristics of the total study populations. Definitions for metabolic syndrome, outcomes, and biases are in the Methods section.
C community; CHD coronary heart disease; CV cardiovascular; DM diabetes mellitus; M medical; MS metabolic syndrome; NA not applicable; NCEP National Cholesterol Education Program; WHO World Health Association; X unknown.

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assessed coronary heart disease events (which in some

studies included coronary heart disease death), 10 studies
assessed cardiovascular deaths, 7 studies assessed coronary
heart disease death, and 12 studies assessed all-cause death
(Table 1, outcomes). The loss-events ratio ranged from 0%
to 990%, and in 23 studies it was less than 10% (Table 1,
attrition bias). Age, gender, smoking, and prevalent cardiovascular disease were simultaneously controlled for, when
necessary, in half of the studies (Table 1, selection bias). Not
shown in the table, detection bias was controlled for in all
studies. Selection, detection, and attrition biases were concomitantly limited in 12 studies (29,34,39,43,45,46,48,53,
55,56,60,62).
Meta-analyses. Separate meta-analyses for each outcome
(cardiovascular events, coronary heart disease events, cardiovascular death, coronary heart disease death, and all-cause
death) demonstrated that the magnitude of risk for the
different outcomes assessed in the studies was similar (Fig.
3). This supported our strategy for subsequent analyses to
pool the risk estimates for studies reporting different outcomes based on the hierarchies described earlier. The overall
pooled RR for incident cardiovascular events and death for
people with the MetSyn was 1.78 (95% confidence interval
[CI] 1.58 to 2.00) (Fig. 4).
In the 7 studies that provided separate risk estimates for
both genders, the risk of incident cardiovascular events and
death was higher for women compared with men (RR 2.63
vs. 1.98, p 0.09). Other within-study subgroups were not
analyzed, because the studies only rarely reported risk
estimates for subgroups other than gender.
Significant heterogeneity existed between studies (I2
82%), and we conducted the planned between-study subgroup analyses to investigate its sources. The RR of cardiovascular events and death was significantly different between
the WHO criteria, NCEP criteria, factor analysis, and other
criteria (2.06 vs. 1.67 vs. 2.68 vs. 1.35, p 0.005).

Figure 3

409

Variability between studies that used other definitions

were due to chance (I2 0%), as was nearly all of the
variability between studies that used factor analysis (I2
4%); however, there were still large inconsistencies between
studies using WHO and NCEP criteria (both I2 75%).
This heterogeneity was not explained by use of different
obesity metrics (body mass index vs. waist circumference or
waist-to-hip ratio vs. either) (p 0.7).
We compared subgroups and studies that included only
diabetic patients with those that excluded diabetic patients
(RR 1.51 vs. 1.69), those that included only coronary heart
disease patients to those that excluded coronary heart
disease patients (RR 2.68 vs. 1.94), and studies that included community subjects with those that included medical
patients (RR 1.69 vs. 1.70), but these comparisons did not
explain the heterogeneity between studies (all p 0.10).
The background risk of the study populations (as determined by the event rate in the subjects without MetSyn) was
a significant source of heterogeneity (p 0.047), and
MetSyn posed a greater risk in populations with background
event rates 10% compared with populations with background event rates 10% (RR 1.96 vs. 1.43, p 0.04).
Attrition bias (p 0.02) but not selection bias (p 0.4)
contributed to heterogeneity. Studies with high attrition
(10% loss-events ratio) had a significantly higher risk of
cardiovascular events and death than those with low attrition (RR 2.31 vs. 1.63, p 0.001).
Figure 5 shows the results of the meta-analysis of studies
that simultaneously adjusted for MetSyn and its components. The pooled results showed an increased risk of
cardiovascular disease or death in patients with MetSyn,
even after controlling for its component risk factors (RR
1.54, 95% CI 1.32 to 1.79). The results of the studies were
homogeneous (p 0.23); furthermore, the observed inconsistency (I2 32%) suggested that most of the variability
between these studies was due to chance.

RR and 95% CI for Metabolic Syndrome and Incident Cardiovascular Events and Death, by Specific Outcomes

The diamonds represent the pooled relative risk (RR) and 95% confidence interval (CI) for studies that assessed
each outcome. Some studies assessed more than 1 outcome. CHD coronary heart disease; CV cardiovascular.

410

Figure 4

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RR and 95% CI for Metabolic Syndrome and Incident Cardiovascular Events and Death

Studies are listed in chronological order by year that their cohorts were created (except for the last study listed, which includes multiple cohorts). Results are for available analyses of incident cardiovascular disease and death, and may differ from the results of the total study populations. Boxes represent the relative risk (RR), and
lines represent the 95% confidence interval (CI) for studies. The diamond represents the pooled RR, and its width represents its 95% CI.

Sensitivity analyses. We performed 3 sensitivity analyses

to test how robust the results of our meta-analysis were in
relation to its design and assumptions.
In the first, we included studies that had cohorts without
prevalent cardiovascular disease and assessed incident coronary
heart disease events (Fig. 6). After removal of 2 outliers
(29,44), the pooled RR was 1.49 (95% CI 1.37 to 1.61), and
there was no inconsistency (test of homogeneity p 0.8; I2
0%). The first outlier (44) did not control for gender or
smoking and had a very high loss-events ratio (161%), both of
which introduce bias that could have increased its risk estimate.
The other outlier (29) was designed as a study of risk factor
clustering, rather than MetSyn per se, and thus the components and their thresholds were dissimilar from the other
studies (e.g., it did not incorporate any measure of obesity).
In the second sensitivity analysis, we included only the 12
studies (listed earlier) that simultaneously limited selection,

detection, and attrition biases, since these are well recognized

and important contributors to systematic error in observational
studies. The results of this analysis were similar to those of the
overall analysis (RR 1.58, 95% CI 1.34 to 1.87), with similar
inconsistency across studies (I2 75%).
For the last sensitivity analysis, we re-analyzed the
original data after excluding 1 study (28), which itself was a
meta-analysis and potentially introduced error related to the
unreported but possible heterogeneity of its included cohorts. Removing this study did not account for the underlying heterogeneity among studies (I2 81%) and did not
change the general results (RR 1.83, 95% CI 1.62 to 2.07).
Publication bias. The funnel plot was asymmetric (Fig. 7,
blue), suggesting small-study bias (either the absence of or
inability to find studies with smaller or negative risk
estimates) or unexplained heterogeneity. The fail-safe n for
our pooled analysis is 3,846, which is reassuring since it is

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Figure 5

411

RR and 95% CI for Metabolic Syndrome and Incident Cardiovascular Events and Death in Studies
That Simultaneously Included Metabolic Syndrome and Some of its Components Into Multivariable Models

All studies excluded people with prevalent cardiovascular disease, and 1 study (45) excluded women. Other covariates included race (62), study site (in a multicenter
study) (62), body mass index (45), C-reactive protein (45), creatinine (60), left ventricular hypertrophy (60), and cigarette smoking (45,60,62). The boxes represent the
relative risk (RR) for individual studies and are proportional to their weight in the analysis, and the lines represent their 95% confidence intervals (CIs). The diamond represents the pooled RR, and its width represents its 95% CI. BP hypertension or elevated systolic or diastolic blood pressure; Glu fasting hyperglycemia; X covariate included.

very unlikely that there are over 100 unpublished or undiscovered studies for every 1 study we found. The trim-andfill method imputed missing studies and recalculated our
pooled risk estimate (Fig. 7, red). The imputed RR was 1.68
(95% CI 1.48 to 1.91), which is similar to our original risk
estimate, suggesting that the apparent publication bias in
this area is insufficient to affect our results or interpretations
in a meaningful way.

Figure 6

Discussion
This study found that the current evidence, drawn from a
large number of longitudinal studies that included 172,573
people, indicates a significantly increased risk of cardiovascular events and death in people with the MetSyn. The data
demonstrate that the cardiovascular risk conferred by the
MetSyn was a third higher in women than it was in men.

RR and 95% CI for Incident Coronary Heart Disease Events in Patients Without Prevalent Cardiovascular Disease

Results are for available analyses of incident coronary heart disease events, and may differ from the results of the total study populations. Boxes represent the relative
risk (RR) for individual studies and are proportional to their weight in the analysis, and the lines represent their 95% confidence interval (CI). The diamonds represent the
pooled RR, and its width represents its 95% CI.

412

Figure 7

Gami et al.
Meta-Analysis of Metabolic Syndrome

JACC Vol. 49, No. 4, 2007

January 30, 2007:40314

Publication Bias and Its Potential Impact

The blue circles represent individual studies, the blue lines are the funnel plot, and the blue diamond is the relative risk (RR) and 95% confidence interval for the metaanalysis. The red circles represent imputed studies, and the red lines represent the adjusted funnel plot. The red diamond is the RR and 95% confidence interval for the
meta-analysis, after adjusting for publication bias. Log (RR) logarithm of the RR; SE standard error.

The best evidence came from the studies in which people

without coronary heart disease were followed for incident
coronary heart disease events, which except for 2 outlying
studies showed a slightly attenuated but similar and highly
homogeneous risk compared with the overall analysis. The
most compelling evidence comes from our pooled analysis of
studies that simultaneously adjusted in multivariable models
for both MetSyn and its components. The analysis of these
methodologically rigorous and statistically homogeneous
studies demonstrates that the MetSyn confers cardiovascular risk beyond that which is associated with its component
risk factors.
Our findings may shed light on important methodologic
issues that created difficulty in making strong inferences
from previous studies results. We found that many of these
cohort studies were methodologically limited by a high
degree of attrition bias. Subjects who were originally enrolled but then were lost to follow-up can affect the risk
estimate, especially if the numbers lost are a large proportion
of (or in some of the studies we included, multiples of) the
number of outcome events. We found that this attrition bias
was a significant source of variability in study results and
markedly overestimated the cardiovascular risk associated
with the MetSyn, while studies that limited this bias had a
pooled risk similar to that of the overall analysis.
The data reveal that definitions of MetSyn based on
factor analysis were far more predictive of cardiovascular
events and death than were other definitions. Since factors
are created by integrating highly correlated risk factors in
the specific population being studied, this may be expected.
It should be recognized, however, that factors are statistical
phenomena that cannot be applied readily to clinical prac-

tice. Our findings show that the WHO-based criteria were

better than NCEP-based criteria in predicting cardiovascular events and death, and that the substitution of body mass
index for waist circumference or waist-to-hip ratio in these
criteria did not appear to affect their robustness.
Limitations of our review include the inherent assumptions of meta-analysis. Since individual patient data were
unavailable, we used aggregate data as reported in published
articles (or as provided by their authors). This commonly
used approach may not detect and cannot solve methodologic problems affecting the primary studies. Also, our
interpretations of between-study subgroup analyses may be
less valid than within-study subgroup analyses, and there is
a risk of type I error due to multiple testing in our analyses.
The strengths of our review include its exhaustive search
strategy, which likely captured most relevant studies. Also,
the success in procuring data from most study authors
overcame the lack of key data in published reports. The
principal strengths of our study are the fundamental
strengths of meta-analysis, which overcome selective and
potentially biased inclusion and weighing of articles results
when interpreting the evidence, which can occur with
narrative reviews.
Our findings are applicable to clinical practice. Only few
of the studies in our analysis were published before development of the 2003 NCEP guidelines designed to aid
clinicians in recognizing and targeting MetSyn. Whether
the association between MetSyn and cardiovascular risk is
sufficient to support aggressive intervention for these patients was subject of debate, but the strength of the evidence
about the association is now even clearer. Clinicians can use
this evidence as motivation when counseling patients. Of

JACC Vol. 49, No. 4, 2007

January 30, 2007:40314

note, our analyses neither support nor refute the role of

insulin resistance or any other mechanism as mediators of
the observed association between MetSyn and cardiovascular risk. Furthermore, our analyses do not yield therapeutic
inferences.
These studies were conducted in diverse populations,
including many rural and urban regions of the U.S., Norway, Sweden, Finland, the Netherlands, Scotland, England,
Spain, Italy, Poland, Turkey, and Japan. People in developing countries, where obesity and its comorbidities are
becoming more prevalent, are underrepresented in the
current data. Only 1 original article included in our study
used criteria apparently modified to account for different
ethnic characteristics (58). The 2005 International Diabetes
Federation Consensus (63), which provides a worldwide
definition of the MetSyn that applies different measures
of obesity for different ethnicities, should be incorporated
in future research. Also requiring further study are
children and young adults, in whom identification of
MetSyn may have the greatest impact on public health if
it leads to successful interventions to prevent cardiovascular disease.
Given the cumulative results of these studies, investigators should design and conduct large randomized trials of
aggressive dietary, lifestyle, and pharmacologic interventions
in people with MetSyn. Our findings suggest that in
addition to targeting individual cardiovascular risk factors,
primary prevention trials should study interventions that
address the MetSyn as 1 entity.
Acknowledgments

The authors thank the many study authors who generously

provided additional information for this research (17,28,34,
38 41,44,46,48,51,5359).
Reprint requests and correspondence: Dr. Apoor S. Gami,
Division of Cardiovascular Diseases, Mayo Clinic College of
Medicine, 200 First Street SW, Rochester, Minnesota 55905.
E-mail: [email protected].

REFERENCES

1. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the

metabolic syndrome among U.S. adults. Diabetes Care 2004;27:
2444 9.
2. de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger
JW, Rifai N. Prevalence of the metabolic syndrome in American
adolescents: findings from the Third National Health and Nutrition
Examination Survey. Circulation 2004;110:2494 7.
3. James PT, Rigby N, Leach R. The obesity epidemic, metabolic
syndrome and future prevention strategies. Eur J Cardiovasc Prev
Rehabil 2004;11:3 8.
4. Jorgensen ME, Borch-Johnsen K. The metabolic syndromeis one
global definition possible? Diabet Med 2004;21:1064 5.
5. Reaven GM. Banting lecture 1988. Role of insulin resistance in human
disease. Diabetes 1988;37:1595 607.
6. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome:
time for a critical appraisal: joint statement from the American
Diabetes Association and the European Association for the Study of
Diabetes. Diabetes Care 2005;28:2289 304.

Gami et al.
Meta-Analysis of Metabolic Syndrome

413

7. American Diabetes Association. Consensus Development Conference

on Insulin Resistance. November 5 6, 1997. Diabetes Care 1998;21:
310 4.
8. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of
diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.
Diabet Med 1998;15:539 53.
9. Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive summary of the Third Report of The
National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III). JAMA 2001;285:2486 97.
10. Lim HS, Patel JV, Lip GY. Metabolic syndrome: a definition in
progress. Circulation 2004;110:e35.
11. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic
syndrome: a comprehensive perspective based on interactions between
obesity, diabetes, and inflammation. Circulation 2005;111:1448 54.
12. Dickersin K, Berlin JA. Meta-analysis: state-of-the-science. Epidemiol Rev 1992;14:154 76.
13. Berlin JA. Invited commentary: benefits of heterogeneity in metaanalysis of data from epidemiologic studies. Am J Epidemiol 1995;
142:3837.
14. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis
Of Observational Studies in Epidemiology (MOOSE) Group. JAMA
2000;283:2008 12.
15. Cook RJ, Farewell VT. Conditional inference for subject-specific and
marginal agreement: two families of agreement measures. Can J Stat
1995;23:333 44.
16. Cohen J. A coefficient of agreement for nominal scales. Educ Psychol
Meas 1960;20:37 46.
17. Sackett DL. Bias in analytic research. J Chronic Dis 1979;32:51 63.
18. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials 1986;7:177 88.
19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring
inconsistency in meta-analyses. BMJ 2003;327:557 60.
20. Cochran W. The combination of estimates from different experiments.
Biometrics 1954;10:10129.
21. Altman DG, Bland JM. Interaction revisited: the difference between
two estimates. BMJ 2003;326:219.
22. Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis:
guidelines on choice of axis. J Clin Epidemiol 2001;54:1046 55.
23. Rosenthal R. The file drawer problem and tolerance for null results.
Psychol Bull 1979;86:638 41.
24. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method
of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56:455 63.
25. Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive
Meta Analysis Version 2. Englewood, NJ: Biostat, 2005.
26. Katzmarzyk PT, Church TS, Janssen I, Ross R, Blair SN. Metabolic
syndrome, obesity, and mortality: impact of cardiorespiratory fitness.
Diabetes Care 2005;28:3917.
27. Girman CJ, Rhodes T, Mercuri M, et al. The metabolic syndrome and
risk of major coronary events in the Scandinavian Simvastatin Survival
Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol 2004;93:136 41.
28. Hu G, Qiao Q, Tuomilehto J, et al. Prevalence of the metabolic
syndrome and its relation to all-cause and cardiovascular mortality in
nondiabetic European men and women. Arch Intern Med 2004;164:
1066 76.
29. Tenkanen L, Pietila K, Manninen V, Manttari M. The triglyceride
issue revisited. Findings from the Helsinki Heart Study. Arch Intern
Med 1994;154:2714 20.
30. Trevisan M, Liu J, Bahsas FB, Menotti A. Syndrome X and mortality:
a population-based study. Am J Epidemiol 1998;148:958 66.
31. Lempiainen P, Mykkanen L, Pyorala K, Laakso M, Kuusisto J. Insulin
resistance syndrome predicts coronary heart disease events in elderly
nondiabetic men. Circulation 1999;100:123 8.
32. Wilson PW, Kannel WB, Silbershatz H, DAgostino RB. Clustering
of metabolic factors and coronary heart disease. Arch Intern Med
1999;159:1104 9.
33. Lehto S, Ronnemaa T, Pyorala K, Laakso M. Cardiovascular risk
factors clustering with endogenous hyperinsulinaemia predict death

414

34.

35.
36.
37.
38.
39.
40.

41.
42.
43.

44.

45.

46.
47.

48.
49.

Gami et al.
Meta-Analysis of Metabolic Syndrome
from coronary heart disease in patients with type II diabetes.
Diabetologia 2000;43:148 55.
Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K. Insulin
resistance syndrome predicts the risk of coronary heart disease and
stroke in healthy middle-aged men: the 22-year follow-up results of
the Helsinki Policemen Study. Arterioscler Thromb Vasc Biol 2000;
20:538 44.
Sprecher DL, Pearce GL. How deadly is the deadly quartet? A
post-CABG evaluation. J Am Coll Cardiol 2000;36:1159 65.
Isomaa B, Almgren P, Toumi T, et al. Cardiovascular morbidity and
mortality associated with the metabolic syndrome. Diabetes Care
2001;24:6839.
Kaukua J, Turpeinen A, Uusitupa M, Niskanen L. Clustering of
cardiovascular risk factors in type 2 diabetes mellitus: prognostic
significance and tracking. Diabet Obes Metab 2001;3:1723.
Klein BEK, Klein R, Lee KE. Components of the metabolic syndrome
and risk of cardiovascular disease and diabetes in Beaver Dam.
Diabetes Care 2002;25:1790 4.
Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged
men. JAMA 2002;288:2709 16.
Onat A, Ceyhan K, Basar O, Erer B, Toprak S, Sansoy V. Metabolic
syndrome: major impact on coronary risk in a population with low
cholesterol levelsa prospective and cross-sectional evaluation. Atherosclerosis 2002;165:28592.
Bonora E, Kiechl S, Willeit J, et al. Carotid atherosclerosis and
coronary heart disease in the metabolic syndrome: prospective data
from the Bruneck study. Diabetes Care 2003;26:12517.
Hsia J, Bittner V, Tripputi M, Howard BV. Metabolic syndrome and
coronary angiographic disease progression: the Womens Angiographic Vitamin & Estrogen trial. Am Heart J 2003;146:439 45.
Resnick HE, Jones K, Ruotolo G, et al. Insulin resistance, the
metabolic syndrome, and risk of incident cardiovascular disease in
nondiabetic American Indians: the Strong Heart Study. Diabetes Care
2003;26:8617.
Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the
metabolic syndrome, and risk of incident cardiovascular events: an
8-year follow-up of 14 719 initially healthy American women. Circulation 2003;107:3917.
Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and
without C-reactive protein as a predictor of coronary heart disease and
diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003;108:414 9.
Anderson JL, Horne BD, Jones HU, et al. Which features of the
metabolic syndrome predict the prevalence and clinical outcomes of
angiographic coronary artery disease? Cardiology 2004;101:18593.
Bonora E, Targher G, Formentini G, et al. The metabolic syndrome
is an independent predictor of cardiovascular disease in type 2 diabetic
subjects. Prospective data from the Verona Diabetes Complications
Study. Diabet Med 2004;21:52 8.
Bruno G, Merletti F, Biggeri A, et al. Metabolic syndrome as a
predictor of all-cause and cardiovascular mortality in type 2 diabetes:
the Casale Monferrato study. Diabetes Care 2004;27:2689 94.
Corsetti JP, Zareba W, Moss AJ, Sparks CE. Apolipoprotein B
determines risk for recurrent coronary events in postinfarction patients
with metabolic syndrome. Atherosclerosis 2004;177:36773.

JACC Vol. 49, No. 4, 2007

January 30, 2007:40314
50. Ford ES. The metabolic syndrome and mortality from cardiovascular
disease and all-causes: findings from the National Health and Nutrition Examination Survey II Mortality Study. Atherosclerosis 2004;
173:309 14.
51. Gimeno Orna JA, Lou Arnal LM, Molinero Herguedas E, Boned
Julian B, Portilla Cordoba DP. [Metabolic syndrome as a cardiovascular risk factor in patients with type 2 diabetes]. Rev Esp Cardiol
2004;57:50713.
52. Godsland IF, Bruce R, Jeffs JAR, Leyva F, Walton C, Stevenson JC.
Inflammation markers and erythrocyte sedimentation rate but not
metabolic syndrome factor score predict coronary heart disease in high
socioeconomic class males: the HDDRISC study. Int J Cardiol
2004;97:54350.
53. Holvoet P, Kritchevsky SB, Tracy RP, et al. The metabolic syndrome,
circulating oxidized LDL, and risk of myocardial infarction in wellfunctioning elderly people in the health, aging, and body composition
cohort. Diabetes 2004;53:1068 73.
54. Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP.
National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular
mortality in the San Antonio Heart Study. Circulation 2004;110:
12517.
55. Katzmarzyk PT, Church TS, Blair SN. Cardiorespiratory fitness
attenuates the effects of the metabolic syndrome on all-cause and
cardiovascular disease mortality in men. Arch Intern Med 2004;164:
10927.
56. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic
syndrome on mortality from coronary heart disease, cardiovascular
disease, and all causes in United States adults. Circulation 2004;110:
124550.
57. Marroquin OC, Kip KE, Kelley DE, et al. Metabolic syndrome
modifies the cardiovascular risk associated with angiographic coronary
artery disease in women: a report from the Womens Ischemia
Syndrome Evaluation. Circulation 2004;109:714 21.
58. Nakanishi N, Takatorige T, Fukuda H, et al. Components of the
metabolic syndrome as predictors of cardiovascular disease and type 2
diabetes in middle-aged Japanese men. Diabetes Res Clin Pract
2004;64:59 70.
59. Rutter MK, Meigs JB, Sullivan LM, DAgostino RB Sr., Wilson PW.
C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation
2004;110:380 5.
60. Schillaci G, Pirro M, Vaudo G, et al. Prognostic value of the metabolic
syndrome in essential hypertension. J Am Coll Cardiol 2004;43:181722.
61. Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner
SM. Does the metabolic-syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease?
Diabetes Care 2004;27:2676 81.
62. McNeill AM, Rosamond WD, Girman CJ, et al. The metabolic
syndrome and 11-year risk of incident cardiovascular disease in the
atherosclerosis risk in communities study. Diabetes Care 2005;28:
38590.
63. Alberti KG, Zimmet P, Shaw J. The metabolic syndromea new
worldwide definition. Lancet 2005;366:1059 62.