Monounsaturated fatty acids, olive oil and health status: a systematic review and meta-analysis of cohort studies
Lipids in Health and Disease
Monounsaturated fatty acids, olive oil and health status: a systematic review and meta-analysis of cohort studies
Lukas Schwingshackl 0
Georg Hoffmann 0
0 Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna , Althanstraße 14 (UZAII), A-1090 Vienna , Austria
Background: The aim of the present meta-analysis of cohort studies was to focus on monounsaturated fat (MUFA) and cardiovascular disease, cardiovascular mortality as well as all-cause mortality, and to distinguish between the different dietary sources of MUFA. Methods: Literature search was performed using the electronic databases PUBMED, and EMBASE until June 2nd, 2014. Study specific risk ratios and hazard ratios were pooled using a inverse variance random effect model. Results: Thirty-two cohort studies (42 reports) including 841,211 subjects met the objectives and were included. The comparison of the top versus bottom third of the distribution of a combination of MUFA (of both plant and animal origin), olive oil, oleic acid, and MUFA:SFA ratio in each study resulted in a significant risk reduction for: all-cause mortality (RR: 0.89, 95% CI 0.83, 0.96, p = 0.001; I2 = 64%), cardiovascular mortality (RR: 0.88, 95% CI 0.80, 0.96, p = 0.004; I2 = 50%), cardiovascular events (RR: 0.91, 95% CI 0.86, 0.96, p = 0.001; I2 = 58%), and stroke (RR: 0.83, 95% CI 0.71, 0.97, p = 0.02; I2 = 70%). Following subgroup analyses, significant associations could only be found between higher intakes of olive oil and reduced risk of all-cause mortality, cardiovascular events, and stroke, respectively. The MUFA subgroup analyses did not reveal any significant risk reduction. Conclusion: The results indicate an overall risk reduction of all-cause mortality (11%), cardiovascular mortality (12%), cardiovascular events (9%), and stroke (17%) when comparing the top versus bottom third of MUFA, olive oil, oleic acid, and MUFA:SFA ratio. MUFA of mixed animal and vegetable sources per se did not yield any significant effects on these outcome parameters. However, only olive oil seems to be associated with reduced risk. Further research is necessary to evaluate specific sources of MUFA (i.e. plant vs. animal) and cardiovascular risk.
Monounsaturated fatty acids; Olive oil; Cohort studies; Meta-analysis; Cardiovascular disease
The most common monounsaturated fatty acids (MUFA)
in daily nutrition is oleic acid, followed by palmitoleic acid,
and vaccenic acid. Moreover, oleic acid represents the
topmost MUFA provided in the diet (~90% of all MUFA). No
dietary recommendations for MUFA are given by the
National Institute of Medicine, the United States
Department of Agriculture, the European Food and Safety
Authority and the American Diabetes Association. In
contrast, the Academy of Nutrition and Dietetics as well as
the Canadian Dietetic Association both promote <20%
MUFA of daily total energy consumption, while the
American Heart Association sets a limit of 20% MUFA in
their respective guidelines [
]. One reason for specific
MUFA recommendations might be their potential benefit
in the primary and secondary prevention of cardiovascular
diseases. However, previous meta-analyses of cohort
studies reported inconsistent results of MUFA on coronary
heart disease (CHD). Jakobsen et al. [
] observed that
replacement of SFA by MUFA marginally increased the risk
of coronary events, whereas no significant effects on
coronary death could be observed. These results are in strong
discrepancy with another meta-analysis of cohort studies,
were Mente et al. [
] reported a significant correlation
between MUFA intake and a decrease in the relative risk for
CHD. Skeaff and Miller [
] did not observe any effects of
MUFA-rich diets on relative risks of CHD events and
CHD death. Likewise, the most recent meta-analysis by
Chowdhury et al. including nine cohort studies found no
significant associations between MUFA intake, circulating
MUFA and risk of CHD [
One explanation for these inconclusive data might be
that different sources of MUFA were not taken into
account. Adopting a western diet means that MUFA is
predominantly supplied by foods of animal origin, while
in south European countries, extra virgin olive oil is the
most dominant source of this type of fatty acid [
Results of the recently published PREDIMED trial
demonstrated major cardiovascular benefits of olive oil and
nuts when compared to a low-fat diet [
]. As a major
outcome parameter, the risk of stroke was reduced, an
event which has not been included in the meta-analyses
mentioned above. In addition, a recent cohort study
observed a significant association between dietary olive oil,
higher plasma oleic acid and reduced risk of stroke [
Extra virgin olive oil is regarded to be the genuine driver
of the Mediterranean diet and was found to be
associated with a 26% reduced risk of all-cause mortality in
the Spanish branch of the EPIC study [
]. The aim of
the present meta-analysis of cohort studies was to focus
on MUFA and CVD (combining CHD and stroke),
cardiovascular mortality, and all-cause mortality, and to
distinguish between the different dietary sources of MUFA
(e.g. olive oil).
Materials and methods
Queries of literature were performed using the electronic
databases PUBMED, and EMBASE (until 2nd June 2014,
respectively) with no restrictions to language, and calendar
date using the following search terms: (“dietary fat” OR
“fatty acids” OR “monounsaturated fat” OR “mufa” OR
“olive oil” OR “oleic acid” OR “mediterranean diet”) AND
(“cardiovascular disease” OR “myocardial infarction” OR
“coronary heart disease” OR “stroke” OR “mortality”) AND
(“incidence” OR “cohort” OR “follow-up” OR “prospective”
OR “risk ratio” OR “hazard ratio” OR “rate ratio”).
Moreover, the reference lists from retrieved articles, systematic
reviews, and meta-analyses were checked to search for
further relevant studies. This systematic review was
planned, conducted, and reported in adherence to
standards of quality for reporting meta-analyses [
Literature search was conducted independently by both authors,
with disagreements resolved by consensus.
Studies were included in the meta-analysis if they met
all of the following criteria: (i) cohort study design; (ii)
data related to dietary consumption of MUFA, MUFA:
SFA ratio, olive oil, and oleic acid; (iii) the primary
outcomes were: all-cause mortality, CVD mortality, combined
CVD events (cardiovascular mortality, cardiovascular
morbidity (non-fatal myocardial infarction, angina, stroke,
heart failure, peripheral vascular events)); the secondary
outcomes were: coronary heart disease, and stroke; (iv)
adjusted relative risks (RRs), and hazard ratios (HRs) with
corresponding 95% confidence intervals (95% CIs) or the
data necessary to calculate these; (v) when a study
appeared to have been published in duplicate, the version
containing the most comprehensive information was
Data extraction and quality assessment
The following data were extracted from each study: the
first author’s last name, year of publication, study origin,
outcome parameter, sample size, study length, age at
entry, sex, specification of MUFA, adjustment factors,
quality score, and risk estimates (HR, RR; highest vs.
lowest category) with their corresponding 95% CIs. If
separate risk estimates for males and females or separate
risk estimates for ages were available in one study, the data
were pooled and treated as one study. When a study
provided several risk estimates, the maximally adjusted model
was chosen. To assess the study quality, a 9-point scoring
system according to the Newcastle-Ottawa Scale (NOS)
was used. Hence, the full score was 9, and a high-quality
study in the present analysis was defined by a threshold
of ≥ 7 points [
]. Data extraction and quality assessment
were performed by one author (L.S).
The meta-analysis was performed by combining the
multivariable adjusted RR or HR of the highest
compared with the lowest MUFA, MUFA:SFA ratio, oleic
acid, or olive oil category based on random effects model
using DerSimonian-Laird method, which incorporated
both within and between study variability [
ensure a transparent approach to meta-analysis and
interpretation of findings in this review, RR/HR estimates
for association of fatty acids and primary/secondary
outcomes that were often differently reported by each study
(such as per-unit or per-1-SD change or comparing
quintiles, quartiles, thirds, and other groupings) were
transformed, using methods previously described [
These transformed estimates consistently corresponded
to the comparison of the top versus bottom third of
MUFA, MUFA:SFA ratio, olive oil, and oleic acid
distribution in each study. To evaluate the weighting of each
study, the standard error for the logarithm HR/RR of
each study was calculated and regarded as the estimated
variance of the logarithm HR/RR using an inverse
variance method [
]. Studies were grouped according to
the different clinical outcomes (all-cause mortality,
cardiovascular mortality, combined cardiovascular events,
coronary heart disease, and stroke). Subgroup analysis was
performed for total MUFA, MUFA:SFA ratio, oleic acid,
and olive oil. Heterogeneity was estimated by the
Cochrane Q test together with the I2 statistic. An I2 value
>50% indicates substantial heterogeneity across studies
]. The heterogi command in STATA was used to
calculate the confidence intervals for the heterogeneity
estimates. Funnel plots were used to assess potential
publication bias. To determine the presence of publication
bias, we assessed the symmetry of the funnel plots in
which mean differences were plotted against their
corresponding standard errors. In addition, Egger test was
performed to test for potential publication bias [
Sensitivity analyses were performed assuming statistical
heterogeneity with the metaan command in STATA [
analyses were conducted using the Review Manager by
the Cochrane Collaboration (version 5.2) and STATA 13.0
(Stata-Corp, College Station, TX).
Dr. Goldbourt (personal communication) provided the
23 year follow-up all-cause mortality and cardiovascular
mortality data of the Israeli civil cohort for the highest
vs. lowest quintile MUFA: SFA ratio [
Literature search and study characteristics
A total of 32 cohort studies (42 reports) met the
inclusion criteria and were included in the meta-analysis
]. Full search strategy for PUBMED is given
in the Additional file 1. General study characteristics are
given in Table 1. Sample size varied between 161 and
161,808 with a follow-up time ranging from 3.7 to
30 years. The total number of subjects in the included
studies was 841,211.
According to the different clinical outcomes, overall risk
of all-cause mortality was evaluated in seventeen cohorts,
cardiovascular mortality in fourteen cohorts, combined
cardiovascular events in twenty-eight cohort studies,
coronary heart disease in fifteen cohorts, and stroke in eleven
Random effects model data (as summarized in Table 2)
revealed that top versus bottom third combined MUFA,
olive oil, oleic acid, and MUFA:SFA ratio was significantly
associated with a reduced risk of: all-cause mortality
(relative risk, RR: 0.89, 95% confidence interval 0.83 to 0.96;
p = 0.001, I2 = 64%) (Figure 1), cardiovascular mortality
(RR: 0.88, 95% CI 0.80 to 0.96, p = 0.004, I2 = 50%)
(Figure 2), combined cardiovascular events (RR: 0.91, 95%
CI 0.86 to 0.96, p = 0.001, I2 = 58%) (Figure 3), and stroke
(RR: 0.83, 95% CI 0.71 to 0.97, p = 0.02, I2 = 70%). In
contrast, no significant changes could be observed for
coronary heart disease (RR: 0.96, 95% CI 0.90 to 1.01,
p = 0.13, I2 = 41%).
Following subgroup analyses, olive oil most likely turned
out to be crucial for the results of the primary analysis,
since significant associations could only be found between
higher intakes of olive oil and reduced risk of all-cause
mortality (RR: 0.77, 95% CI 0.71 to 0.84, p < 0.00001,
I2 = 0%), cardiovascular events (RR: 0.72, 95% CI 0.57 to
0.91, p = 0.007, I2 = 77%), and stroke (RR: 0.60, 95% CI
0.47 to 0.77, p < 0.0001, I2 = 0%), respectively. Subgroup
analysis for MUFA (of mixed animal and plant origin) did
not reveal any significant risk reduction for all-cause
mortality (RR: 1.00, 95% CI 0.93 to 1.08, p = 0.93, I2 = 23%),
cardiovascular mortality (RR: 0.95, 95% CI 0.89 to 1.02,
p = 0.14, I2 = 52%), cardiovascular events (RR: 0.96, 95%
CI 0.89 to 1.04, p = 0.36, I2 = 7%), coronary heart disease
(RR: 0.99, 95% CI 0.93 to 1.06, p = 0.76, I2 = 29%), and
stroke (RR: 0.85, 95% CI 0.72 to 1.01, p = 0.07, I2 = 65%).
To investigate statistical heterogeneity, sensitivity analyses
were performed with the metaan command in STATA.
Heterogeneity of the main analysis could be confirmed in
the sensitivity analyses. Differentiating between studies
performed in Europe vs. non-European investigations
resulted in significant differences as compared to the main
analysis. Pooling European based cohorts resulted in a
significant risk reduction for all-cause mortality (RR: 0.87,
95% CI 0.79 to 0.95) as well as for cardiovascular mortality
(RR: 0.76, 95% CI 0.64 to 0.91) and cardiovascular events
(RR: 0.86, 95% CI 0.78, 0.95). In contrast, no significant
reduction in all-cause mortality risk (RR: 0.97, 95% CI
0.91 to 1.04) could be observed for non-European cohorts
(the respective data for cardiovascular mortality being
RR: 0.94, 95% CI 0.89 to 0.99 and for cardiovascular
events being RR: 0.93, 95% CI 0.87 to 0.98). With respect
to study length, studies with a follow-up ≥ 10 years
resulted in similar results as compared to short-term studies
(<10 years follow up). Likewise, high quality studies could
confirm the results of the primary analysis.
The Egger’s linear regression tests provided evidence for
a potential publication bias for combined cardiovascular
events (p = 0.018), all-cause mortality (p = 0.041), and
cardiovascular mortality (p = 0.12) following comparison
of the top versus bottom third combined MUFA, olive
oil, oleic acid, and MUFA:SFA ratio. No evidence of
publication bias could be detected for risk of CHD (p = 0.28)
and stroke (p = 0.28). All funnel plots indicate little to
moderate asymmetry, suggesting that publication bias
cannot be completely excluded as a factor of influence on
the present meta-analysis (Additional file 1: Figures S1,
Study USA CHD CHD mortality
Wakai et al.
Cohort Study JAP
BMI Body Mass Index, CHD coronary heart disease, CVD cardiovascular disease, DEN Denmark, EDI Elderly Diet Index, EU European Union, FRA France, GBR Great Britain, HDI Healthy Diet Index, ISR Israel, ITA Italy, JAP
Japan, MET metabolic equivalent of task, MUFA monounsaturated fatty acids, NED The Netherlands, PA physical activity, SFA saturated fatty acids, SPA Spain, SWE Sweden, WHI Women’s Health Initiative, USA United
States of America.
All MUFA combined
Combined cardiovascular events
All MUFA combined
aI2 inconsistency, percentage of variation across studies due to heterogeneity.
MUFA monounsaturated fatty acids, n.a. not applicable, SFA saturated fatty acids.
S2, S3, S4 and S5). It remains possible that small studies
with inconclusive results have not been published or failed
to do so.
In the present meta-analysis, comparison of the top
versus the bottom third of combined MUFA subgroups
(MUFA, olive oil, oleic acid, and MUFA:SFA) was
associated with reduced risk of all-cause mortality (11%),
cardiovascular mortality (12%), combined cardiovascular
events (9%), and stroke (17%). In the ensuing subgroup
analyses, this significant correlation could only be
observed between higher intakes of olive oil and reduced
risk of all-cause mortality, cardiovascular events, and
stroke, respectively. In contrast, monounsaturated fatty
acids of mixed animal and plant origin did not result in
any significant effects with respect to these outcome
parameters. Thus, it seems possible that olive oil
represents the crucial factor of influence for the protective
health effects observed in the primary analysis. However,
one has to keep in mind the limitations of the present
systematic review and meta-analysis summarized at the
end of this section, especially the fact that the specific
sources of MUFA have not been indicated in every
In order to properly evaluate the potential beneficial
or detrimental effects of MUFA with respect to
cardiovascular diseases, it seems of importance to consider the
source of food providing these fatty acids. In the Nurses’
Health Study, MUFA intake was highly correlated with
SFA intake (correlation coefficient of 0.81) but only
moderately correlated with intakes of PUFA (correlation
coefficient of 0.30), suggesting that fat was primarily of animal
]. In the different EPIC cohorts, MUFA intakes
ranged between approximately 10% of daily total energy
consumption (TEC) in The Netherlands and ~ 20% of
TEC in Greece. In general, intake of MUFA was higher in
southern European countries as compared central or
northern cohorts. However, another distinguishing feature
seems to be the predominant source of MUFA in the
respective cohorts. In Greece, Spain, and Italy, fat of plant
origin (mainly olive oil) provided up to 64% of MUFA
intake, whereas in most other EPIC centers, the main
contributors to total MUFA intake were meat and meat
products, added fats, and dairy products [
]. This might also
provide an explanation for the somewhat mixed results
provided by systematic reviews and meta-analyses in the
past. Thus, a diet rich in MUFA was found to have
beneficial effects on a broad range of CVD risk factors, not only
in the primary prevention of CVD [
]. On the other
hand, no association between total and individual MUFA
and CHD was reported in a meta-analysis of studies
assessing both dietary intake and circulating fatty acid
composition,  while a meta-analysis of observational
studies suggested that replacing SFAs with PUFAs might
have a greater benefit than replacement of SFAs by MUFA
]. There is some evidence drawn from prospective
studies of an adverse association between MUFA and
coronary events, but this correlation might be influenced by
high amounts of MUFA of animal origin [
A number of in-vivo and in-vitro studies examined the
health effects of extra virgin olive oil, the potential
“Unique Selling Proposition” of a genuine Mediterranean
diet. Thus, the study demonstrated that
individuals who consumed olive oil had a significantly lower
risk of developing obesity, impaired glucose metabolism,
hypertriglyceridemia, and lower HDL cholesterol levels
as compared to a group consuming sunflower oil [
In addition, results from experimental studies provide
evidence that olive oil consumption improves several
CHD risk factors [
]. The PREDIMED dietary
intervention trial aimed a intake of 50 g/d or more of extra
virgin olive oil observed a significant risk reduction of
both combined cardiovascular events as well as primary
stroke, but not of CHD, indicating a consistency with
the results of the present meta-analyses of cohort studies
. In a long-term intervention trial by Esposito et al., a
higher regression in as well as a lower rate of
progression of the intima–media thickness of the carotid artery
was found in the group adopting a Mediterranean diet
as compared to a low-fat diet reference arm [
Apart from oleic acid, olive oil contains a number of
bioactive compounds such as polyphenols which are
especially prominent in virgin and extra-virgin olive oil,
but not in refined olive oil [
]. A key olive oil
polyphenol is oleuropein (a compound that generates tyrosol
and hydroxytyrosol), which accounts for approximately
80% of olive oil phenolic content and is a potent
scavenger of superoxide radicals and inhibits LDL oxidation
]. There is a causal link between oxidative stress,
inflammation, endothelial dysfunction, and CVD/CHD
]. A meta-analysis of intervention trials provide
evidence that an MD decreases inflammation and improves
endothelial function [
]. When focusing on virgin olive
oil consumption, the inverse correlation between olive
oil and CHD risk found in the present meta-analysis is
consistent with the fact that olive oil is not just a
supplier of MUFA but of other biologically active
components as well.
Several limitations should be taken into account when
interpreting the results of the present meta-analysis.
MUFA coexist with SFA in several food sources. In
addition, cis- and trans-isomers of MUFAs were
sometimes categorized together in cohort studies. Furthermore,
moderate to substantial heterogeneity could be observed
in the present meta-analysis. Potential sources of
heterogeneity include combining MUFA/olive oil/oleic acid/
MUFA:SFA ratio in the same analysis, heterogeneous risk
estimates, heterogeneous populations/ages/gender, sample
sizes as well as follow-up periods of the included studies.
No unpublished data were considered for the present
meta-analysis, and it cannot be excluded that these results
may influence the effect size estimates. Examination
of funnel plots showed little to moderate asymmetry
suggesting that publication bias cannot be completely
excluded as a confounder of the present meta-analysis (e.g.
it remains possible that small studies yielding inconclusive
data have not been published). In addition, the specific
food sources of MUFA could not always identified,
limiting the validity of any general recommendation towards
MUFAs of plant origin (it is most likely olive oil, but it
might be other types of food as well, e.g. nuts, canola oil
or a specific variety of sunflower oil). Conversely, it might
be that results from studies using mixed sources of
MUFA might be biased by non-identified olive oil,
making MUFA appear to be beneficial in general when
some sources are not. Furthermore, observational
studies including cohort studies assessing outcome events
affected by nutrition should be interpreted with caution,
since reliance on nutritional assessment methods with
validity and reliability is lower when compared to
randomized controlled trials.
However, the present study has some complementary
strengths as well. Compared to cohort studies, dietary
intervention trials are often limited by lack of double
blinding, non-compliance, cross-over, and high drop-out
rates. Therefore, well-designed analyses in prospective
cohort studies could also provide important evidence
with respect to long-term clinical outcomes. Another
strength of this work is the inclusion of an overall
population >800,000 subjects. To the best of our knowledge,
this represents the most comprehensive summary of the
evidence on MUFA, olive oil, MUFA:SFA on hard
clinical outcome parameters.
The results of the present meta-analysis indicate an overall
risk reduction of all-cause mortality (11%), cardiovascular
mortality (12%), cardiovascular events (9%), and stroke
(17%) when comparing the top vs. bottom thirds of a
combination of MUFA, olive oil, oleic acid, and MUFA:
SFA ratio. Monounsaturated fat of mixed animal and
vegetable sources per se did not yield any significant
effects on these outcome parameters. Subgroup analysis
indicated that only olive oil (the primary monounsaturated
fat source in south European countries) is was associated
with a significant risk reduction for several outcomes.
These data provide evidence that the source and origin of
MUFA within a specific diet should be taken into account
in order to evaluate the potential benefits of this type of
fatty acids. Further studies are required evaluating specific
food sources of MUFA and risk of all-cause mortality and
Additional file 1: Detailed search strategy; Figure S1-S5: Funnel
Both authors declare that they have no competing interest.
LS and GH conducted the data analysis, interpretation of results, manuscript drafting, and finalizing manuscript. Both authors read and approved the final manuscript.
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