EURO PEAN

SO CIETY O F
Original scientific paper CARDIOLOGY ®

European Journal of Preventive

Cardiology

Metabolically healthy obesity and 0(00) 1–11

! The European Society of
Cardiology 2015
cardiovascular events: A systematic Reprints and permissions:
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review and meta-analysis DOI: 10.1177/2047487315623884
ejpc.sagepub.com

Nathalie Eckel1,2, Karina Meidtner1, Tamara Kalle-Uhlmann*,

Norbert Stefan2,3,4 and Matthias B Schulze1,2

Abstract
Aims: Previous studies have provided inconsistent results about the cardiovascular risks for participants with metabol-
ically healthy obesity (MHO). These uncertainties might partly reflect the lack of a uniform definition of MHO. We
conducted a systematic review and meta-analysis to examine whether there is a suitable approach that identifies obese
participants who are not at an increased risk of cardiovascular events compared with healthy normal-weight participants.
Methods and results: Twenty-two prospective studies were eligible for the meta-analysis. Using random-effect models,
pooled relative risks (RRs) were calculated for the combined effects of obesity with the presence or absence of
metabolic syndrome, insulin resistance, hypertension, diabetes, hyperlipidaemia and any of these metabolic factors.
Participants with MHO defined by the absence of metabolic syndrome were at increased risk for cardiovascular
events compared with healthy normal-weight participants (pooled RR 1.45, 95% confidence interval (CI) 1.20–1.70),
but had lower risks than unhealthy normal-weight (RR 2.07, 95% CI 1.62–2.65) and obese (RR 2.31, 95% CI 1.99–2.69)
participants. The risk associated with participants who had MHO was particularly high over the long term. Similar risk
estimates were observed when MHO was defined by other approaches.
Conclusions: None of the approaches clearly identified an obese subgroup not at increased risk of cardiovascular
events compared with normal-weight healthy participants. A benign obese phenotype might be defined by strict defin-
itions, but insufficient studies exist to support this. More research is needed to better define MHO.

Keywords
Body mass index, cardiovascular risk, meta-analysis, metabolically healthy obesity, systematic review
Received 13 October 2015; accepted 3 December 2015

Introduction
Obesity, which is considered to be one of the most
important risk factors contributing to the overall
burden of diseases worldwide, has reached epidemic
levels.1–3 A body mass index (BMI) of 30 kg/m2 or 1
Department of Molecular Epidemiology, German Institute of Human
more is often used as a definition of obesity.2 It has Nutrition Potsdam-Rehbrücke, Germany
2
German Center for Diabetes Research, Germany
been established that this BMI is associated with 3
Institute of Diabetes Research and Metabolic Diseases of the Helmholtz
increased mortality and morbidity, particularly with Center München at the University of Tübingen, Germany
respect to cardiovascular disease (CVD).4-6 However, 4
Department of Internal Medicine IV, University Hospital of Tübingen,
a subgroup among obese individuals has recently been Germany
*
recognized that does not express metabolic disorders Deceased.
and cardiovascular (CV) risk factors.7,8 The prevalence
of this subgroup, which is considered to have metabol- Corresponding author:
Matthias B Schulze, German Institute of Human Nutrition Potsdam-
ically healthy obesity (MHO), ranges from 6 to 75%, Rehbrücke, Department of Molecular Epidemiology, Arthur-Scheunert-
largely depending on the definition used.9 However, no Allee 114-116, 14558 Nuthetal, Germany
uniform definition of what should be considered Email: mschulze@dife.de

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2 European Journal of Preventive Cardiology 0(00)
‘metabolically healthy’ has so far been established.
Investigators often define participants with MHO by
the absence of metabolic syndrome (MetS), the absence
of insulin resistance (IR), or, less often, the absence of
abdominal adiposity or high cardiorespiratory fitness
(CRF).10 Consequently, whether the MHO phenotype
modifies the risk of CVD remains controversial.10
Kramer et al.11 systematically reviewed studies on
MHO and concluded that this phenotype is not a
benign condition over the long term. However, their
meta-analysis was based on unadjusted risk estimates,
although smoking is known to be a strong confounder
for the obesity/mortality relationship.12 In addition,
only definitions of MHO based on MetS were con-
sidered, resulting in a limited number of only eight stu-
dies analysed. As the endpoint, Kramer et al.11
considered a mixture of total mortality and CVD,
although studies suggested stronger associations for
CVD mortality than for total mortality. Therefore the
purpose of our systematic review and meta-analysis was
to summarize the evidence of prospective studies
among apparently healthy populations about the CV
risk of participants with MHO by comparing different
approaches to the definition.
Methods
We conducted a systematic review according to the
guidelines recommended by the Meta-analysis of
Observational Studies in Epidemiology (MOOSE)
group13 (Supplementary Table S1, available online).
Data sources and searches
A systematic search of the literature was performed
from inception to 7 April 2014; this was limited to pub-
lications written in English or German. Two reviewers
independently analysed citations in PubMed on the
basis of their title and abstract. In cases of disagree-
ment, the decision was based on a third reviewer’s opin-
ion. A search with the same terms was repeated in the
Web of Science by one reviewer (Supplementary Table
S2, available online). A hand-search of references from
relevant publications was also performed.
Study selection
Studies were considered eligible if they: (a) reported
relative risks (RRs) for overall CVD mortality/inci-
dence or for a specific disease relating to the CV
system; (b) were stratified for BMI categories; (c)
were additionally stratified for another exposure and
reported estimates for joint effects; (d) had one refer-
ence group in the normal-weight healthy range; and (e)
had a prospective study design. We excluded a study if:
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(a) it used only patients or participants undergoing spe-
cific medical procedures; (b) it was not conducted in
adults; (c) the obese category started at <27.5 kg/m2;
(d) the investigated subgroup did not express metabolic
determinants; or (e) less than two studies were identified
that investigated the same subgroup. In addition, stu-
dies were excluded from the meta-analysis if the
authors did not provide CIs even after contacting
them via email.
Quality assessment
The quality of the included cohort studies was assessed
using the Newcastle Ottawa Scale (NOS).14 This quality
assessment tool judges studies on the basis of a star
system, ranging from zero to nine stars and including
the areas selection, comparability and outcome.
A study was considered to be of high quality if it
obtained at least six stars. In the section ‘comparabil-
ity’, we granted the study one star if adjustments were
made for sex (when appropriate), age and smoking, and
a second star if analyses were additionally adjusted for
multiple variables.
Data extraction and analysis
We extracted the first author’s name, year of publica-
tion, description of the study population (sample size,
age, country), follow-up time, outcome, description of
the additional exposure, BMI assessment, adjustment
variables and RRs for normal-weight and obese partici-
pants with and without the additional exposure vari-
able, including 95% CIs if available. Where the RRs
were not reported in tables or in the text, we estimated
the numbers from the presented figures.
Pooled RRs were calculated with CV events as out-
comes for the MHO, metabolically unhealthy normal-
weight (MUH-NW) and metabolically unhealthy
obesity (MUHO) phenotypes using metabolically
healthy normal-weight (MHNW) participants as the
reference. Among the identified subgroups, metabolic
health was defined as the absence of a particular risk
factor. Where more than one publication of the same
study population was identified with similar definitions
of phenotypes, the more recently published study was
included in the meta-analysis. Where studies reported
several different CV outcomes, we considered the more
inclusive outcome category (e.g. total coronary heart
disease rather than myocardial infarction (MI)).15 In
studies where only disjoint CV outcomes were reported,
we considered the more severe outcome (fatal instead of
non-fatal CVD).16 If such a judgement was not possible
(e.g. for MI versus heart failure),17 we exchanged out-
comes in sensitivity analyses. In addition to our ana-
lyses on any CV events, we also summarized individual
Eckel et al. 3

CV outcomes in the meta-analysis if at least three indi-
vidual studies reported associations. Where studies
reported estimates for different definitions of the meta-
bolic phenotype, the more conventional definition was
included. In the majority of cases we extracted the RR
that reflected the greatest degree of control for potential
confounders except where an adjustment was made to
explain a possible mediating effect18 or, in one study,
where the analyses were adjusted for waist circumfer-
ence (WC), which might be an over-adjustment.16 All
additional findings not included in the meta-analysis
are listed in Supplementary Table S3 (available online).
A random effects model was used to calculate overall
estimates for RRs. The Cochrane Q test was used to
evaluate the heterogeneity between studies and I2 was
used to calculate the magnitude of heterogeneity. I2
values <25, 25–75 and >75% were considered as low,
moderate and high heterogeneity, respectively.19
Subgroup analyses were conducted to evaluate the
potential source of heterogeneity and sensitivity ana-
lyses to evaluate the influence of single studies, which
differed in certain characteristics from the others.
A potential publication bias was examined by Egger’s
linear regression test.20 All analyses were performed
using the R package ‘meta’ incorporated in SAS
(Version 9.4, Enterprise Guide 6.1, SAS Institute Inc.,
Cary, NC, USA).
Results
Study selection and characteristics
Of 2947 citations identified from PubMed and 4528 from
Web of Science, 308 articles were identified for a full-text
evaluation after the removal of duplicates and screening
of titles and abstracts (Figure 1). Twenty-two publica-
tions fulfilled all the inclusion criteria for the
meta-analysis. Definitions of normal-weight and obese
subgroups were based on the following metabolic pheno-
types: MetS, IR, hypertension, diabetes, hyperlipidaemia
and the absence of any metabolic factor (Supplementary
Table S3, available online). In addition, seven studies
were identified that were not eligible for the meta-analysis
because the authors did not report CIs, but were system-
atically reviewed (Supplementary Table S4, available
online). Consequently, not enough studies were identified

Potentially relevant articles Potentially relevant articles

identified through Pubmed: identified through Web of Science:
n = 2,947 n = 4,528

Potentially eligible articles identified

for full-text screening: Studied excluded
n = 308 no additional exposure: 139
no CVD outcome: 32
no BMI categories: 27
no joint analysis: 21
obese category starts<27.5kg/m2: 16
Hand-search
no risk estimates: 10
n=2
no reference for BMI categories: 7
no normal-weight, healthy reference: 5
study population at risk: 1
only one study with same exposure
Articles included in review identified: 8
n = 32 meta-analysis: 1
at risk population: 1
population includes adolescents: 2
BMI measurement in midlife, outcome
Studies excluded in elderly: 1
No confidence Subgroup does not represent a
intervals: 7 metabolic determinant: 8
Not enough studies
in subgroup to be
pooled: 3

Articles included in meta-analysis

n = 22

Figure 1. Flow chart of literature search and criterion for inclusion and exclusion of studies.

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4 European Journal of Preventive Cardiology 0(00)

to be pooled in the meta-analysis for metabolic health
defined by anthropometric measurements and CRF.
The vast majority of the studies were conducted in
Caucasian populations (Europe, 10 studies15–17,21–28;
USA, seven studies18,29–34; Australia, one study35;
Canada, one study36; Iran, one study37; Japan, one
study38). Two studies were restricted to women30,31
and five to men.25,27,28,32,36 The sample size varied
substantially across the studies, ranging from 550 par-
ticipants23 to 71,527 participants.15 The duration of
follow-up ranged from 3.6 years15 to 30 years.25
The quality of each study according to the NOS is
summarized in the Supplementary Table S5 (available
online). All studies included in the meta-analysis
achieved at least six stars, indicating good quality.
Absence of MetS
Thirteen prospective studies were identified that inves-
tigated CV risk according to the presence or absence of
MetS in different strata of BMI (Supplementary Table
S3, available online). As one of these studies only
reported an RR for participants with MHO compared
with normal-weight healthy participants,33 the findings
from 12 studies were pooled for the MUH-NW and
MUHO phenotypes. The identified studies used either
the established National Cholesterol Adult Treatment
Panel III (ATP-III),18,23,31 the International Diabetes
Federation criteria17 or, more commonly, modified ver-
sions of MetS. The modifications were mainly a result
of different cut-offs,36,37 different numbers of inclusion
criteria,15,36 the exclusion of the WC criter-
ion,22,25,29–31,33,35,36 and/or additional inclusions of
less conventional criteria.25,29,30,36 The pooled RRs
of CV risks for MHO, MUH-NW and MUHO com-
pared with MHNW participants were 1.45 (95% CI
1.20–1.75), 2.07 (95% CI 1.62–2.65) and 2.31 (95%
CI 1.99–2.69), respectively. Heterogeneity was moder-
ate in the risk estimates of all three phenotypes (Figure
2). Pooling subsets of studies with separate findings for

(a) Study Risk Ratio RR 95%–CI (b) Study Risk Ratio RR 95%–CI

Aung,2014 4.40 [2.02;9.58] Aung,2014 3.90 [1.72; 8.83]

Hinnouho,2015 1.95 [1.37; 2.78] Hinnouho,2015 2.08 [1.66; 2.60]
Morkesal,2014 1.10 [0.88; 1.37] Morkedal,2014 1.90 [1.42; 2.54]
Thomsen,2014 1.45 [1.19; 1.76] Thomsen,2014 1.03 [0.82; 1.30]
Appleton,2013 1.16 [0.58; 2.30] Appleton,2013 1.15 [0.50; 2.64]
Ogorodnikova,2012 1.24 [0.98; 1.56] Hosseinpanah,2011 2.10 [1.36; 3.25]
Hosseinpanah,2011 1.07 [0.59; 1.95] Voulgari,2011 2.33 [1.25; 4.35]
Voulgari,2011 0.41 [0.11; 1.48] Arnlov,2010 1.63 [1.11; 2.39]
Arnlov,2010 1.95 [1.14; 3.34] Song,2007 3.40 [2.12; 5.45]
Song,2007 1.00 [0.59; 1.68] Meigs,2006 3.01 [1.68; 5.40]
Meigs,2006 1.48 [0.86; 2.53] Katzmarzyk,2005 2.06 [0.92; 4.62]
Katzmarzyk,2005 2.70 [1.40; 5.19] StPierre,2005 3.01 [1.70; 5.32]
StPierre,2005 1.53 [0.79; 2.98]
pooled RR 2.07 [1.62; 2.65]
pooled RR 1.45 [1.20; 1.75] Heterogeneity: I–squared=74.5%, tau-squared=0.124, p<0.0001
Heterogeneity: I–squared=58.6%, tau-squared=0.0556, p=0.004
0.2 0.5 1 2 5
0.2 0.5 1 2 5

(c) Study Risk Ratio RR 95%–CI

Aung,2014 5.20 [2.60; 10.41]

Hinnouho,2015 2.44 [1.85; 3.22]
Morkedal,2014 2.00 [1.72; 2.33]
Thomsen,2014 1.67 [1.44; 1.93]
Appleton,2013 2.23 [1.31; 3.79]
Hosseinpanah,2011 2.35 [1.71; 3.22]
Voulgari,2011 2.13 [1.36; 3.34]
Arnlov,2010 2.55 [1.82; 3.58]
Song,2007 3.30 [2.43; 4.48]
Meigs,2006 2.13 [1.43; 3.18]
Katzmarzyk,2005 2.83 [1.70; 4.72]
StPierre,2005 1.81 [1.02; 3.20]

pooled RR 2.31 [1.99; 2.69]

Heterogeneity: I–squared=62.3%, tau-squared=0.0373, p=0.0021

0.1 0.5 1 2 10

Figure 2. Meta-analyses of risk for cardiovascular events of participants with (a) metabolically healthy obesity, (b) metabolically
unhealthy normal weight and (c) metabolically unhealthy obesity compared with metabolically healthy normal-weight participants;
phenotypes defined by body mass index categories and the presence or absence of metabolic syndrome (based on varying definitions;
Supplementary Table S3, available online).

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Eckel et al. 5

men15,18,25,29,36 and women15,29,30 yielded significantly
increased risks for male participants with MHO
compared with those with MHNW (RR 1.96, 95% CI
1.54–2.48; I2 ¼ 11%), but not for female participants
with MHO (RR 1.32, 95% CI 0.83–2.10; I2 ¼ 56%).
Considering only studies with a short follow-up time
(<8 years) yielded an increased risk for MHO com-
pared with MHNW that was not statistically significant
and had low precision and high heterogeneity (RR 1.44,
95% CI 0.77–2.69; I2 ¼ 76%).15,23,29,37 Pooling only
those studies with long-term follow-up (>12 years)
revealed higher risks for participants with MHO
(RR 1.87, 95% CI 1.43–2.45; I2 ¼ 0%)22,25,36 than pool-
ing studies with medium follow-up times from 8
to 12 years (RR 1.26, 95% CI 1.03–1.53; I2 ¼
34%).17,18,30,31,33,35 In contrast, the risks for partici-
pants with MUH-NW and MUHO did not differ sub-
stantially between subsets of studies with different
follow-up times. Considering only the findings of stu-
dies that included C-reactive protein (CRP) in their
definition of MetS21,30,36 yielded an increased RR that
was not significant for participants with MHO com-
pared with those with MHNW (RR 1.24, 95% CI
0.84–1.83; I2 ¼ 0%). Pooling only studies with CVD
mortality as the outcome18,21,25 revealed higher risks
for participants with MHO (RR 2.13, 95% CI 1.32–
3.44; I2 ¼ 9.6%), whereas the results did not change
when we pooled only those studies that used total
CVD events as the outcome22,25,29,30,33,37. Several sensi-
tivity analyses (excluding studies that adjusted for par-
ticular MetS criteria,15,23 excluding one study that
calculated odds ratios instead of hazards ratios,35
excluding studies that included underweight participants
in the reference category17,23,25,29–31,36 and including the
finding for the outcome heart failure instead of MI in the
study by Morkedal et al.17) yielded similar results.
Including only studies that adjusted for physical activity
yielded a slightly lower pooled RR for participants with
MHO (Supplementary Table S6, available online).
Absence of IR
Figure 3 shows forest plots of risk estimates from stu-
dies that evaluated CV risks according to IR in the BMI
categories (Supplementary Table S3, available online).
Four studies used HOMA-IR based on quartiles to
define IR,21,25,31,33 whereas one study assessed
HOMA-IR according to a pre-defined cut-off point
(>2.5).16 The pooled RR indicated increased risks for
participants with MHO (RR 1.39, 95% CI 1.14–1.69)
and MUHO compared with MHNW participants,
although it was not statistically significant for MUH-
NW participants (RR 1.41, 95% CI 0.79–2.53). I2
indicated moderate heterogeneity for MUH-NW par-
ticipants, whereas it was low for MHO and MUHO.
A sensitivity analysis in which we substituted the find-
ing for fatal CVD events with that for non-fatal CVD
events in the study by Bo et al.16 yielded similar results.
Subgroup analyses indicated that pooled RRs were
higher for CVD mortality as outcome16,21,25 than for
total CVD events as outcome25,31,33 for both obese
phenotypes (Supplementary Table S6, available online).

(a) Study Risk Ratio RR 95%-CI (b) Study Risk Ratio RR 95%-CI
Bo,2013 2.95 [1.05: 8.31] Bo,2013 3.63 [1.34: 9.82]
Hinnouho,2013 1.04 [0.41: 2.65] Hinnouho,2013 0.54 [0.19: 1.53]
Ogoridnikova,2012 1.28 [1.01: 1.62] Arnlov,2010 1.15 [0.90: 1.46]
Arnlov,2010 1.98 [1.07: 3.41] Meigs,2006 1.89 [0.93: 3.84]
Meigs,2006 1.42 [0.87: 2.32]
pooled RR 1.41 [0.79: 2.53]
pooled RR 1.39 [1.14: 1.69] Heterogeneity: I-squared=65.3%, tau-squared=0.2152, p=0.0342
Heterogeneity: I-squared=0.6%, tau-squared=0.0004, p=0.4027
0.2 0.5 1 2 5
0.2 0.5 1 2 5

(c) Study Risk Ratio RR 95%-CI

Bo,2013 2.43 [1.03: 5.75]

Hinnouho,2013 2.63 [1.51: 4.59]
Arnlov,2010 2.56 [1.82: 3.59]
Meigs,2006 2.06 [1.35: 3.14]

pooled RR 2.40 [1.91: 3.02]

Heterogeneity: I-squared=0%, tau-squared=0, p=0.8622

0.2 0.5 1 2 5

Figure 3. Meta-analyses of risk for cardiovascular events of participants with (a) metabolically healthy obesity, (b) metabolically
unhealthy normal weight and (c) metabolically unhealthy obesity compared with metabolically healthy normal-weight individuals;
phenotypes defined by body mass index categories and a pre-defined cut-off for HOMA-IR.

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6 European Journal of Preventive Cardiology 0(00)
Absence of a single metabolic factor
Hypertension. Five studies were pooled in meta-analyses
that investigated CV risks in subgroups defined by BMI
categories and self-reported hypertension26,32 or mea-
sured high blood pressure (BP) at baseline24,28,30,32
(Supplementary Table S3, available online). The
pooled RRs compared with MHNW participants
were 1.77 (95% CI 1.20–2.59), 2.46 (95% CI
1.92–3.15) and 2.55 (95% CI 1.92–3.15) for MHO,
MUH-NW and MUHO participants, respectively. I2
indicated a high magnitude of heterogeneity
(Supplementary Figure S1, available online). Three sensi-
tivity analyses were conducted that did not change the
results: (a) the exclusion of one study with a different ref-
erence group in terms of BP24; (b) the exclusion of one
study that used BMI categories based on tertiles28; and
(3) the exclusion of one study that did not control
for smoking status32 (Supplementary Table S6, available
online). Three additional studies were not used in the meta-
analysis because the authors did not report the CIs.39-41
Point estimates for participants with MHO were also
increased in these studies compared with MHNW (RRs
1.65–2.2), except in the study by Rexrode et al.40 for the
endpoint haemorrhagic stroke incidence (RR 0.7)
(Supplementary Table S4, available online).
Diabetes. Four studies evaluated CV risks for partici-
pants with MHO, MUH-NW and MUHO compared
with those with MHNW defined by the presence or
absence of diabetes26,30,32,34 (Supplementary Table S3,
available online). Pooled RRs for all three phenotypes
were significantly increased compared with MHNW
(Supplementary Figure S2, available online).
However, the risk for participants with MHO (RR
1.65, 95% CI 1.19–2.30) was lower than for those
with MUH-NW and MUHO. Heterogeneity was high
for participants with MHO (I2 ¼ 87%) and MUHO
(I2 ¼ 83%), but moderate for those with MUH-NW
(I2 ¼ 39%). Performing two sensitivity analyses
(excluding one study that used the incidence of diabetes30
and excluding one study that did not control for smoking
status32) resulted in similar pooled RRs for participants
with MHO (Supplementary Table S6, available online).
Two studies were not included in the meta-analyses
because the authors did not report the CIs.41,42 Point esti-
mates for participants with MHO in these two studies
were similar to the pooled estimate (RR 1.9–2.2)
(Supplementary Table S4, available online).
Hyperlipidaemia. Three studies investigated CV risks in
groups stratified by BMI categories and the presence of
hyperlipidaemia26,30,32 (Supplementary Table S3, avail-
able online). Pooled RRs revealed similarly increased
risks for participants with MHO (1.69, 95% CI
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1.22–2.36) and MUH-NW, and a three times increased
risk for those with MUHO compared with MHNW
(Supplementary Figure S3, available online).
Heterogeneity was high for participants with MHO
and MUHO, but low for participants with MUH-NW
(I2 ¼ 0%). Point estimates of one study that was only
systematically reviewed41 were higher than the pooled
RRs for all three phenotypes (Supplementary Table S4,
available online).
Absence of all metabolic factors
Three studies were identified that examined CV risks for
participants with MHO, MUH-NW and MUHO com-
pared with those with MHNW with metabolic health
defined by the absence of all metabolic factors (hyperten-
sion, diabetes, hyperlipidaemia)27,30,38 (Supplementary
Table S3, available online). The pooled RR for partici-
pants with MHO was increased compared with those
with MHNW, but was not statistically significantly
(RR 1.49, 95% CI 0.80–2.76; I2 ¼ 70%), whereas the
risks for participants with MUH-NW and MUHO
were highly and statistically significantly increased (RR
2.13, 95% CI 1.43–3.17, I2 ¼ 85% and RR 3.32, 95%
2.19–5.03, I2 ¼ 75%, respectively) (Supplementary
Figure S4, available online). The study by Saito et al.38
differed in several respects from the others. The BMI was
self-reported, stroke incidence only was assessed and it
was conducted in Japanese participants, whereas the
other studies were conducted in Caucasian participants.
After removing this study from the analysis, the RR for
participants with MHO was not increased compared with
participants with MHNW (RR 1.01, 95% CI 0.47–2.19;
I2 ¼ 12% (Supplementary Table S6, available online).
Anthropometric measurements
Of three studies that examined joint associations for
BMI categories and another anthropometric measure-
ment for a CVD outcome, one study applied WC43 and
all studies applied the waist-to-hip ratio (WHR)43-45
(Supplementary Table S4, available online). As one
study evaluated both WC and WHR43 and another
reported findings separated for sex,44 five findings
were presented. Four findings (all among women) indi-
cated the highest risk for MUHO43–45 and one finding
observed the highest risk for MHO (in men).44
However, all except one finding44 indicated an
increased risk for MHO compared with the reference
(Supplementary Figure S5, available online).
CRF
Three publications with the same study population
were identified that reported findings for CVD
Eckel et al.
outcomes stratified for BMI categories and CRF32,46,47
(Supplementary Table S4, available online). Two pub-
lications indicated a slightly increased risk for fit, obese
participants compared with fit, normal-weight partici-
pants; the risk was more apparently increased in one
publication, where only mortality from heart failure
was used as the outcome (Supplementary Figure S6,
heart failure).
Publication bias
Evidence of publication bias on the Egger’s linear
regression test was only significant for the MUHO
phenotype defined by the presence of MetS
(Supplementary Table S7, available online).
Discussion
This systematic review and meta-analysis of prospective
studies suggests that obese participants classified by dif-
ferent metabolic parameters potentially reflecting a
‘metabolically healthy’ phenotype are still at an
increased risk for CV events compared with MHNW
participants. Nevertheless, their risk was lower than
that for MUHO participants, suggesting an intermedi-
ate risk state. Interestingly, their risk was also lower
than that of MUH-NW participants. The identified stu-
dies allowed the pooling of findings for six different
subgroups: absence of MetS, insulin sensitivity, absence
of hypertension, diabetes, hyperlipidaemia, or any of
these metabolic factors. None of these approaches
clearly detected an obese subgroup that was not at an
increased risk of CV events. Obese participants without
any metabolic disease were not at a significantly
increased risk; however, not enough studies were
detected to draw a firm conclusion. In addition, as sig-
nificant heterogeneity was observed in several analyses,
the results have to be interpreted with caution.
Subgroup analyses suggest that the risk associated
with the MHO phenotype increased with longer
follow-up times.
The most frequent approach investigators used to
define MHO was the absence of MetS. Our meta-
analysis was based on more studies, some recently
published,15,17,22,29,35 than previous meta-analyses11,48
or systematic reviews49 on the CVD risk for the
MHO phenotype. These previous meta-analyses dif-
fered in their methods from our study. Kramer
et al.11 pooled unadjusted RRs, whereas Fan et al.48
included studies that defined the reference as non-
obese participants. Nevertheless, our results in general
support their conclusions that participants with MHO
are at an increased risk compared with MHNW partici-
pants. Our pooled RR for participants with MHO was
higher than in the meta-analysis of Kramer et al.,11
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7
which might be explained by their non-adjustment for
smoking and by the different outcomes used (mixture of
total mortality and CV events vs. CV events only). In
their meta-analysis, participants with MHO were at a
significantly increased risk compared with MHNW par-
ticipants when they were followed up for at least 10
years; we confirmed this result for follow-ups of at
least 8 years. Fan et al.48 and Roberson et al.49 found
no difference in pooling or reviewing their findings
when metabolic health was defined by either MetS or
insulin sensitivity. In line with this approach, we found
increased risks for participants with MHO compared
with MHNW participants, but lower risks compared
with MUHO participants, no matter which of these
two approaches was used. Fan et al.48 did not detect
a sex difference, whereas we observed greater risks
among male participants with MHO than among
female participants with MHO. However, as they
used fixed effect models, their finding was mainly
driven by one study.42 The lack of a standard definition
for MetS makes comparisons of study results difficult
and might be one reason for the observed high hetero-
geneity. Different definitions may result in widely
varying prevalence estimates of MHO.50 Pooling only
the RRs of three studies with a rather strict definition of
MetS (definition proposed by Karelis et al.,21 IR syn-
drome features,36 National Cholesterol Adult
Treatment Panel III criteria with additional stratifica-
tion for CRP levels30) suggests a risk that is not
increased for participants with MHO compared with
MHNW participants. All of these definitions added
CRP levels as a criterion. Interestingly, it has already
been suggested that CRP levels should be added to the
definition of MetS51,52 and markers of inflammation
have been proposed to distinguish between MHO and
MUHO.53,54 Thus more studies should examine
whether more rigorous approaches, e.g. adding CRP
levels or other biomarkers to MetS, might be useful
in detecting a benign obese phenotype. For example,
it has been suggested that relatively high levels of adi-
ponectin,55 low levels of hepatic enzymes56 and rela-
tively low liver fat contents8 are associated with a pre-
defined MHO phenotype, but we did not find any lon-
gitudinal studies of CV risks. The definitions with CRP
as an additional criterion were also stricter in terms of
the number of criteria that had to be met to be classified
as ‘metabolically healthy’. Classifying participants by
MetS leads to a heterogeneous ‘healthy’ subgroup as
usually up to two components may be present with a
participant still classified as ‘metabolically healthy’.
This might be a further reason for the conflicting results
in previous studies. Not surprisingly, our meta-analysis
indicated that it is not possible to identify a benign
obese phenotype by the absence of one of the MetS
components hypertension, diabetes or hyperlipidaemia.
8 European Journal of Preventive Cardiology 0(00)
Although BP, cholesterol and glucose levels have been
shown to mediate a substantial amount of the CV risk
of obesity, it was not fully explained by these factors in
two earlier meta-analyses.57,58 However, our results
suggest a not significantly increased risk compared
with MHNW participants among those obese partici-
pants who did not express any of these metabolic fac-
tors. This was particularly apparent after removing one
study within a Japanese population that assessed stroke
incidence only,38 thereby limiting the analysis to two
studies. Thus more studies are necessary to confirm
this finding. Another explanation for inconsistent
results might be that MHO is a transient state rather
than a permanent state, which has already been sug-
gested by studies that evaluated the persistence of
MHO over time35,59,60 and is strongly supported by
our results.
Abdominal visceral fat is known to be one of the
main health hazards of obesity.4,61 Therefore a favour-
able fat distribution, marked by low WC or WHR,
might identify a subgroup not at increased risk
among people with a large general body fat content.10
The few studies identified that investigated joint asso-
ciations of obesity based on BMI and other anthropo-
metric measurements (WC and WHR) did not provide
enough evidence for an obese benign phenotype defined
by these measures, consistent with a systematic review
on all-cause mortality62 and collaborative analyses on
CV risks.63
Another approach to determining metabolic health
might be CRF. As a result of the limited number of
identified studies, we were not able to reach a conclu-
sion as to whether fit obese participants were not at an
increased risk compared with normal-weight fit partici-
pants. A recent meta-analysis on the joint associations
of CRF and obesity on all-cause mortality concluded
that obesity is not a risk factor among fit participants.64
However, although the pooled RR, which was based on
findings from only three different study populations,
was not statistically significant, it still pointed to a
slightly increased risk (pooled RR 1.21, 95% CI
0.95–1.52). Therefore further research is necessary to
examine whether CRF is useful in identifying partici-
pants with MHO.
To our knowledge, this is the first systematic review
that considered the full range of possible definitions for
MHO. Its strengths are the extensive literature search,
investigations of comprehensive subgroups and the
inclusion of only prospective studies with the reference
groups that are considered to be the healthiest
(MHNW). However, some limitations should be
noted. First, as in all systematic reviews, the possibility
of publication and selection bias cannot be excluded.
However, the results of statistical tests did not provide
evidence for publication bias and selection bias was
Downloaded from cpr.sagepub.com at Middle East Technical Univ on December 26, 2015
reduced by an independent title and abstract screening
by two reviewers. Second, our literature search included
only terms such as obesity and BMI that were stated in
the title. However, we also scanned reference lists of
numerous relevant articles to minimize the chance of
bias in the search process. Third, in addition to the
aforementioned reasons for heterogeneity in the defin-
itions of the phenotypes, the studies also differed in
adjustments for covariates, exclusion criteria and def-
initions for BMI categories. Moreover, different CVD
outcomes were summarized. Statistical tests confirmed
a high heterogeneity in numerous analyses. We per-
formed various sensitivity analyses to examine the
robustness of our results, although we cannot exclude
the possibility that different combinations of outcomes
and definitions might alter the results. Fourth, for sev-
eral subgroups we identified only a limited number of
studies, making it difficult to draw firm conclusions.
Fifth, most studies that met our inclusion criteria ori-
ginated from predominantly Caucasian populations.
Thus more studies are needed from diverse populations
to examine possible differences in ethnicity. Sixth, we
included only studies that used BMI to indicate obesity,
although other anthropometric measurements also cor-
relate with CV risk. However, studies on MHO intend
to stratify participants identified to be obese based on
their BMI.10 Finally, study quality is a further potential
bias which might lead to inaccurate conclusions in
meta-analyses. For example, self-reported data of
weight are likely to be under-reported,65 which might
result in the misclassification of participants to incor-
rect BMI categories. However, a quality assessment
revealed the high quality of all studies included in the
meta-analysis and only one study used self-reported
weight.38
In conclusion, this meta-analysis of prospective stu-
dies suggests that obese participants with metabolic
phenotypes considered to be ‘healthy’ are still at an
increased risk for CV events compared with MHNW
participants. None of the previous approaches to clas-
sify MHO clearly detected an obese subgroup not at
increased risk. More strict criteria, such as the simul-
taneous absence of high BP, dyslipidaemia and
hyperglycaemia might identify a benign obese pheno-
type; however, not enough studies were detected to
draw a firm conclusion. Thus more systematic assess-
ments of various CV risk factors are still needed to
verify the concept of MHO and special attention
should be paid to possible differences caused by sex
and ethnicity.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Eckel et al.
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this
article: This study was supported by a grant from the German
Federal Ministry of Education and Research (BMBF) to the
German Center for Diabetes Research (DZD).
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