Context The metabolic syndrome has been identified as a target for dietary therapies
to reduce risk of cardiovascular disease; however, the role of diet in the
etiology of the metabolic syndrome is poorly understood.
Objective To assess the effect of a Mediterranean-style diet on endothelial function
and vascular inflammatory markers in patients with the metabolic syndrome.
Design, Setting, and Patients Randomized, single-blind trial conducted from June 2001 to January 2004
at a university hospital in Italy among 180 patients (99 men and 81 women)
with the metabolic syndrome, as defined by the Adult Treatment Panel III.
Interventions Patients in the intervention group (n = 90) were instructed to follow
a Mediterranean-style diet and received detailed advice about how to increase
daily consumption of whole grains, fruits, vegetables, nuts, and olive oil;
patients in the control group (n = 90) followed a prudent diet (carbohydrates,
50%-60%; proteins, 15%-20%; total fat, <30%).
Main Outcome Measures Nutrient intake; endothelial function score as a measure of blood pressure
and platelet aggregation response to L-arginine; lipid and
glucose parameters; insulin sensitivity; and circulating levels of high-sensitivity
C-reactive protein (hs-CRP) and interleukins 6 (IL-6), 7 (IL-7), and 18 (IL-18).
Results After 2 years, patients following the Mediterranean-style diet consumed
more foods rich in monounsaturated fat, polyunsaturated fat, and fiber and
had a lower ratio of omega-6 to omega-3 fatty acids. Total fruit, vegetable,
and nuts intake (274 g/d), whole grain intake (103 g/d), and olive oil consumption
(8 g/d) were also significantly higher in the intervention group (P<.001). The level of physical activity increased in both groups
by approximately 60%, without difference between groups (P = .22). Mean (SD) body weight decreased more in patients in the intervention
group (−4.0 [1.1] kg) than in those in the control group (−1.2
[0.6] kg) (P<.001). Compared with patients consuming
the control diet, patients consuming the intervention diet had significantly
reduced serum concentrations of hs-CRP (P = .01),
IL-6 (P = .04), IL-7 (P =
0.4), and IL-18 (P = 0.3), as well as decreased insulin
resistance (P<.001). Endothelial function score
improved in the intervention group (mean [SD] change, +1.9 [0.6]; P<.001) but remained stable in the control group (+0.2 [0.2]; P = .33). At 2 years of follow-up, 40 patients in the intervention
group still had features of the metabolic syndrome, compared with 78 patients
in the control group (P<.001).
Conclusion A Mediterranean-style diet might be effective in reducing the prevalence
of the metabolic syndrome and its associated cardiovascular risk.
The metabolic syndrome consists of a constellation of factors that increase
the risk of cardiovascular disease and type 2 diabetes. Recent estimates indicate
that the metabolic syndrome is highly prevalent in the United States, with
an estimated 24% of the adult population affected.1 Its
clinical identification is based on measures of abdominal obesity, atherogenic
dyslipidemia, elevated blood pressure, and glucose intolerance.2 The
etiology of this syndrome is largely unknown but presumably represents a complex
interaction between genetic, metabolic, and environmental factors including
diet.3,4 Several recent studies
also suggest that a proinflammatory state is one component of the metabolic
syndrome.5-8 Moreover,
evidence has accumulated indicating that low-grade inflammation is associated
with endothelial dysfunction.9,10
Although aspects of diet have been linked to individual features of
the metabolic syndrome,11 the role of diet
in the etiology of the syndrome is poorly understood and limited to only a
few observational studies.12,13 The
Adult Treatment Panel III recommendations for patients with the metabolic
syndrome are consistent with general dietary recommendations.14 Recently,
the scientific advisory committee of the American Heart Association has stated
that a Mediterranean-style diet has impressive effects on the progression
of cardiovascular disease.15
The aim of this study was to assess the effect of a Mediterranean-style
diet on endothelial function and vascular inflammation in patients with the
metabolic syndrome. We studied endothelial function by assessing the vascular
responses to L-arginine, the natural precursor of nitric oxide.
Moreover, we characterized the low-grade inflammatory state of patients with
the metabolic syndrome by measuring circulating levels of high-sensitivity
C-reactive protein (hs-CRP) as well as of interleukins 6 (IL-6), 7 (IL-7),
and 18 (IL-18). These proinflammatory ILs have been prospectively associated
with thrombotic cardiovascular events16,17 or
have been suggested to be involved in plaque destabilization.18 We
then performed a randomized controlled trial of a Mediterranean-style diet
designed to increase consumption of foods rich in phytochemicals, antioxidants, α-linolenic
acid, and fiber.
Men and women were recruited from June 2001 to January 2004 among those
attending the outpatient department of the Division of Metabolic Diseases
at the Second University of Naples, Naples, Italy. The study participants
were sedentary (engaging in less than 1 hour per week of physical activity)
and within the previous 6 months had no evidence of participation in weight
reduction programs and had maintained a stable weight (±1 kg). None
of the study participants had previously participated in dietary studies.
Each patient was asked to complete a personal health and medical history questionnaire
that served as a screening tool.
To be enrolled in the study, patients had to have 3 or more of the following
criteria to meet the diagnosis of the metabolic syndrome, as defined by the
Adult Treatment Panel III2: (1) abdominal adiposity
(defined as waist circumference >102 cm [men] or >88 cm [women]); (2) low
levels of serum high-density lipoprotein cholesterol (<40 mg/dL [men] or
<50 mg/dL [women]); (3) hypertriglyceridemia (triglycerides level of 150
mg/dL or greater); (4) elevated blood pressure (130/85 mm Hg or greater);
and (5) impaired glucose homeostasis (fasting plasma glucose concentration
of 110 mg/dL or greater). Patients were excluded if they had cardiovascular
disease, psychiatric problems, a history of alcohol abuse (alcohol consumption
≥500 g/wk in the last year), if they smoked, or if they took any medication.
The study was approved by the institutional committee of ethical practice
of the Second University of Naples, and all of the study patients gave written
informed consent.
Patients were randomly assigned to either the intervention or the control
diet using a computer-generated random number sequence (Figure 1). Allocation was concealed in sealed study folders that
were held in a central, secured location until after informed consent was
obtained. The nurses who scheduled the study visits did not have access to
the randomization list. However, the staff members involved in the intervention
had to be aware of the group assignment; thus, the study was only partly blinded.
Laboratory staff did not know the patients' group assignments.
Patients consuming the intervention diet were given detailed advice
about the usefulness of the experimental diet. Through a series of monthly
small-group sessions, intervention patients received education in reducing
dietary calories (if needed), personal goal-setting, and self-monitoring using
food diaries. Behavioral and psychological counseling was also offered. The
dietary advice was tailored to each patient on the basis of 3-day food records.
The recommended composition of the dietary regimen was as follows: carbohydrates,
50% to 60%; proteins, 15% to 20%; total fat, less than 30%; saturated fat,
less than 10%; and cholesterol consumption, less than 300 mg per day. Moreover,
patients were advised to consume at least 250 to 300 g of fruits, 125 to 150
g of vegetables, and 25 to 50 g of walnuts per day; in addition, they were
also encouraged to consume 400 g of whole grains (legumes, rice, maize, and
wheat) daily and to increase their consumption of olive oil. Patients were
in the program for 24 months and had monthly sessions with the nutritionist
for the first year and bimonthly sessions for the second year. Compliance
with the program was assessed by attendance at the meetings and completion
of the diet diaries.
Patients consuming the control diet were given general oral and written
information about healthy food choices at baseline and at subsequent visits
but were offered no specific individualized program. However, the general
recommendation for macronutrient composition of the diet was similar to that
for the intervention group (carbohydrates, 50%-60%; proteins, 15%-20%; and
total fat, <30%). Moreover, patients in the control group also had bimonthly
sessions with study personnel during the 2-year study. All patients in both
groups also received guidance on increasing their level of physical activity,
mainly by walking for a minimum of 30 minutes per day but also by swimming
or playing aerobic ball games (eg, soccer).
Height and weight were recorded with participants wearing lightweight
clothing and no shoes using a Seca 200 scale with attached stadiometer (Seca,
Hamburg, Germany). Twenty-four–hour nutrient intakes were calculated
with food-composition tables and patients' weekly diet diaries. To assess
dietary adherence and exercise activity, all patients were asked to complete
a 3-day food record and to record occupational, household, and leisure-time
physical activity. Foods were measured using standard measuring cups and spoons
and weight-approximation diagrams.
Endothelial function was assessed with the L-arginine
test, as previously described.19,20 Briefly,
after applying a device for automatic measurements of blood pressure and heart
rate (Omheda 2300; Finapres, Englewood, Calif), an intravenous bolus of 3
g of L-arginine (10 mL of a 30% solution of L-arginine
monochloride), the natural precursor of nitric oxide, was injected intravenously
within 60 seconds. Blood pressure and platelet aggregation response to 1.25
µM adenosine diphosphate were measured before L-arginine
injection and after 10 minutes.
We developed a score in which both responses were summed. For blood
pressure, 1 point was attributed for a mean blood pressure response less than
2 mm Hg, 2 points for a response between 2 and 3 mm Hg, 3 points for a response
between 3 and 4 mm Hg, 4 points for a response between 4 and 5 mm Hg, and
5 points for a response greater than 5 mm Hg. For platelet aggregation, 1
point was attributed for a response less than 2.5%, 2 points for a response
between 2.5% and 5%, 3 points for a response between 5% and 7.5%, 4 points
for a response between 7.5% and 10%, and 5 points for a response greater than
10%. In our laboratory, the mean (SD) blood pressure and platelet aggregation
decreases following the L-arginine bolus (difference between
basal and 10-minute values) in a matched control group of healthy men and
women (n = 50 for each) were −6.5 (1.5) mm Hg and −13% (3%), respectively,
which correspond to the maximal score of 10.
Estimation of insulin sensitivity in the fasting state was assessed
with homeostasis model assessment (HOMA) and calculated with the formula:
fasting plasma glucose (mmol/L) × fasting serum insulin (µU/mL)
divided by 25, as described by Matthews et al.21 With
such a method, high HOMA scores denote low insulin sensitivity (insulin resistance).
Assays for serum levels of total cholesterol and high-density lipoprotein
cholesterol, triglycerides, and glucose were performed in the hospital's chemistry
laboratory. Plasma insulin levels were assayed by radioimmunoassay (Ares,
Serono, Italy).
Serum samples for cytokine and hs-CRP levels were stored at –80°C
until assay. Serum concentrations of IL-6, IL-7, and IL-18 were determined
in duplicate using a high-sensitivity, quantitative sandwich enzyme assay
(Quantikine HS, R&D Systems, Minneapolis, Minn). High-sensitivity CRP
was assayed by immunonephelometry using a Behring Nephelometer 2 (Dade Behring,
Marburg, Germany). In our laboratory, the median (interquartile range) for
these values in a group of 100 healthy participants of both sexes (n = 50
for each) were as follows: hs-CRP, 0.7 mg/L (0.2-3.2 mg/L); IL-6, 2.1 pg/mL
(0.3-5.2 pg/mL); IL-7, 1.8 pg/mL (0.5-5.2 pg/mL); and IL-18, 129 pg/mL (50-275
pg/mL).
Data are presented as mean (SD) unless stated otherwise. Data were analyzed
by intention-to-treat. We compared baseline data using a t test for continuous variables and a Wilcoxon test for hs-CRP, IL-6,
IL-7, and IL-18. We classified all study patients as having 3, 4, or 5 components
of the metabolic syndrome and assessed for evidence of a relation of median
hs-CRP level and mean HOMA and endothelial function scores across these groups
using the Jonckheere-Terpstra test. We compared risk factors and nutrient
intakes after 2 years using a test based on the values at the end of follow-up
and a t test based on differences from baseline.
Results of the analysis omitting patients lost in the follow-up did not differ
from that including their last available records; data are therefore shown
for the analysis that includes all participants as randomized. Spearman rank
correlation coefficients were used to quantify the relations between metabolic
variables and cytokine levels. The effects of treatment on HOMA and endothelial
function scores, cytokine levels, and each of the components of the metabolic
syndrome were tested by means of paired t tests and
a Wilcoxon matched test, after adjustment for changes in body weight. The χ2 test was used for comparing proportions of participants in the 2 groups
with the metabolic syndrome after treatment. P<.05
was considered statistically significant. All analysis were conducted using
SPSS version 9.0 (SPSS Inc, Chicago, Ill).
One hundred eighty patients were randomly assigned to the intervention
(n = 90) or control (n = 90) group (Figure
1). Both groups were comparable, including the number of components
of the metabolic syndrome (Table 1).
There was an increase in hs-CRP levels and HOMA scores as the number of components
of the metabolic syndrome increased; by contrast, there was an inverse relation
between the number of components of the metabolic syndrome and the endothelial
function score (P<.001 for trend for all) (Figure 2). Spearman rank correlation coefficients
showed that endothelial function score was negatively associated with waist
circumference (r = −0.30, P = .01), hs-CRP level (r = −0.33, P = .01), HOMA score (r = −0.24, P = .02), and IL-6 level (r =
−0.21, P = .02).
After 2 years of follow-up, 8 participants in the intervention group
and 8 in the control group dropped out of the study; all dropouts occurred
after 24 weeks of follow-up. Patients who dropped out from the intervention
group showed a decrease in body weight after 24 weeks of follow-up, suggesting
that they were adhering to the lifestyle changes.
Baseline data showed no important difference in the nutrient intake
between the 2 groups (Table 2).
After 2 years, patients following the intervention diet consumed a greater
percentage of calories from complex carbohydrates and from polyunsaturated
and monounsaturated fat; had a greater intake of fiber; had a lower ratio
of omega-6 to omega-3 fatty acids; and had lower energy, levels of saturated
fat, and levels of cholesterol than did controls. Total fruit, vegetable,
nuts, and whole grain intakes and olive oil consumption were also significantly
higher in the intervention group (Table
2). The level of physical activity increased in both groups (intervention
group: from 48 [SD, 10] min/wk to 84 [SD, 36] min/wk, P<.001; control group: from 51 [SD, 9] min/wk to 81 [SD, 38] min/wk, P<.001) without any difference between them (P = .22).
After 2 years, patients in the intervention group had significant decreases
in body weight; body mass index; waist circumference; HOMA score; blood pressure;
and levels of glucose, insulin, total cholesterol, and triglycerides and a
significant increase in levels of high-density lipoprotein cholesterol, all
of which were greater than those recorded in the control group (Table 3). There was no difference for sex. Serum concentrations
of IL-6, IL-7, IL-18, and hs-CRP were significantly reduced in patients in
the intervention group compared with those in the control group. Endothelial
function score improved in the intervention group but remained stable in the
control group. There was an inverse relation between changes in endothelial
function score and changes in hs-CRP levels (r =
−0.36, P = .01) and HOMA scores (r = −31, P = .01).
At 2 years of follow-up, 60 participants in the intervention group had
experienced reductions in the number of components of the metabolic syndrome
(Table 3), so that only 40 patients
could still be classified as having the metabolic syndrome. This was significantly
different from the control group, in which 78 patients were still classified
as having the metabolic syndrome (P<.001). The
data unadjusted for changes in body weight showed a greater reduction in the
number of components of the metabolic syndrome, such that at 2 years of follow-up,
30 patients in the intervention group and 73 patients in the control group
were classified as having the metabolic syndrome (P<.001).
In this study, consumption of a Mediterranean-style diet by patients
with the metabolic syndrome was associated with improvement of endothelial
function and a significant reduction of markers of systemic vascular inflammation.
Moreover, participants who followed the intervention diet showed a reduction
in the number of the components of the syndrome such that the overall prevalence
of the metabolic syndrome was reduced by approximately one half. Because data
were adjusted for changes in body weight, the overall reduction in the prevalence
of the metabolic syndrome after the intervention is likely to represent a
conservative measure. Taken together, these findings suggest that a Mediterranean-style
diet is a safe strategy for treatment of the metabolic syndrome and for helping
to reduce the associated cardiovascular risk.
Current guidelines on the management of the individual components of
the metabolic syndrome emphasize that lifestyle modification (weight loss
and physical activity) is a first-line therapy, whereas drug therapy is considered
secondary, unless otherwise indicated by current cardiovascular disease prevention
guidelines.22 In our study, the effect of the
intervention diet was associated with modest changes in body weight, which
has been shown to have no effect on CRP levels,23 as
well as an increment in physical activity not different from the control group.
Because the results were adjusted for body weight changes, our findings suggest
that, largely independent of concomitant changes in body weight, a Mediterranean-style
diet might play a role in reducing the inflammatory state and endothelial
dysfunction associated with the metabolic syndrome.
The mechanism by which a Mediterranean-style diet can reduce the low-grade
inflammatory state associated with the metabolic syndrome is unclear. Macronutrient
intake produces oxidative stress that leads to a proinflammatory state.24 This intriguing evidence is also supported by the
ability of antioxidant vitamins25,26 or
food antioxidants20 to improve the transient
endothelial dysfunction seen in healthy individuals after consumption of a
single high-fat meal. Moreover, modulation of the fiber content of the meal
may influence the cytokine milieu: increasing the fiber content (from 4.5
g to 16.8 g) of a high-carbohydrate meal was associated with significant reduction
of circulating IL-18 levels in both healthy persons and in patients with type
2 diabetes.27 Because dietary fiber may have
anti-inflammatory roles, at least in intestinal functions,28 it
can be speculated that the fiber content of the intervention diet, eventually
magnified by some other components with antioxidant capability, may influence
the transient oxidative stress that occurs after macronutrient ingestion.
An anti-inflammatory effect for omega-3 fatty acids also has been suggested,29 although most of this effect was seen with supplement
use.
Our results show a linear increment in hs-CRP levels and a linear impairment
of endothelial function score associated with increase in the number of components
of the metabolic syndrome. This leads to the speculation that CRP, which is
produced by the liver under the influence of IL-6,9 may
be one link between the altered cytokine milieu and endothelial dysfunction
associated with the metabolic syndrome. In addition to being a powerful risk
marker, recent evidence suggests that CRP may directly participate in lesion
formation through leukocyte activation and endothelial dysfunction.30,31 Moreover, it has been suggested that
increased inflammatory responses could lead to insulin resistance and compensatory
hyperinsulinemia attributable in large part to the important role of inflammatory
cytokines released from adipocytes.9 Alternatively,
insulin resistance may be responsible for the higher production of cytokines
as a consequence of reduced anti-inflammatory effect of insulin in insulin-resistant
states.32 Regardless of the mechanisms, the
proinflammatory state that accompanies the metabolic syndrome is associated
with both insulin resistance and endothelial dysfunction, providing a connection
between inflammation and metabolic processes that are highly deleterious for
vascular function.
One limitation of our study is the inability to determine whether individual
components of the diet can account for the changes observed or whether the
changes in metabolic risk factors are a result of the sum of all the dietary
changes. Although multiple dietary interventions, as in the study herein,
render difficult the assessment of the effect of each intervention separately,
the clinical usefulness of a whole-diet approach in the prevention of cardiovascular
disease has been emphasized.33 The Lyon Heart
Study34 has shown that diet can help reduce
the risk of fatal and nonfatal cardiovascular events in individuals with cardiovascular
disease. Singh et al35 tested an Indo-Mediterranean
diet in 1000 patients with existing coronary disease or at high risk for coronary
disease. As compared with the control diet, the intervention diet reduced
the rate of fatal myocardial infarction by one third and the rate of sudden
death from cardiac causes by two thirds. In a population-based study involving
22 043 apparently healthy adults in Greece, adherence to a traditional
Mediterranean diet was associated with significantly lower total mortality,
mortality from coronary heart disease, and mortality from cancer.36 Despite a robust inverse association between the
overall Mediterranean-diet score and mortality, no appreciable associations
were seen for most of the individual dietary components, which would suggest
that the cumulative effects (synergistic or interactive) of multiple dietary
components may be substantial. In other words, the effect appears to be more
than the sum of its parts.
The results of this study represent the first demonstration, to our
knowledge, that a Mediterranean-style diet rich in whole grains, fruits, vegetables,
legumes, walnuts, and olive oil might be effective in reducing both the prevalence
of the metabolic syndrome and its associated cardiovascular risk. One of the
mechanisms responsible for the cardioprotective effect of such a diet may
be through reduction of the low-grade inflammatory state associated with the
metabolic syndrome. Although weight reduction remains a cornerstone of therapy
for the metabolic syndrome, from a public health perspective adoption of a
diet similar to that investigated herein may provide further benefit on cardiovascular
risk, especially in patients who do not lose weight.
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