A practical approach to the metabolic syndrome: review of current

concepts and management

Rajesh Tota-Maharaja,b, Andrew P. Defilippisa, Roger S. Blumenthala and
Michael J. Blahaa
a
Johns Hopkins Ciccarone Preventive Cardiology
Center, Johns Hopkins University School of Medicine,
Baltimore and bGreater Baltimore Medical Center,
Towson, Maryland, USA

Correspondence to Michael J. Blaha, MD, MPH,

Blalock 524C Division of Cardiology, 600 North Wolfe
Street, Baltimore, MD 21287, USA
Tel: +1 410 955 7376; fax: +1 410 614 9190;
e-mail: mblaha1@jhmi.edu
Current Opinion in Cardiology 2010,
25:502512

Purpose of review
Novel research over the past 2 years has necessitated an update of our ABCDE
approach to the metabolic syndrome.
Recent findings
Clinical trials investigating the role of aspirin in primary prevention have led to an
adjustment in the indication for aspirin in metabolic syndrome patients at intermediate
risk of a cardiovascular event. There has been renewed enthusiasm for the use of
niacin as second-line treatment for atherogenic dyslipidemia, with fibrates reserved for
those with severe residual dyslipidemia. In light of the noteworthy findings of the
Justification for the Use of statins in Primary Prevention: an Intervention Trial Evaluating
Rosuvastatin trial, the C category representing cholesterol has been expanded to
include the use of high-sensitivity C-reactive protein for guiding statin use and perhaps
monitoring statin therapy. Recent evidence confirms that diet and exercise continue to
be the cornerstone of any metabolic syndrome treatment strategy.
Summary
The revised ABCDE approach incorporates the most recent influential studies into a
simple yet thorough algorithm for management of the metabolic syndrome.
Keywords
ABCDE approach, diabetes mellitus, insulin resistance, metabolic syndrome
Curr Opin Cardiol 25:502512
2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0268-4705

Introduction
The term metabolic syndrome has been used to describe
the clustering of individual risk factors including atherogenic dyslipidemia, glucose intolerance, elevated blood
pressure (BP), a proinflammatory state, and a prothrombotic state that result from abdominal obesity and insulin
resistance. This article aims to update the 2008 review by
Blaha et al. [1] entitled A practical ABCDE approach to
the metabolic syndrome by examining and summarizing
important studies over the past 12 years as they relate to
definition, pathophysiology, assessment, and management
of the metabolic syndrome.

Definition
Although defining metabolic syndrome as a syndrome
remains controversial [2], the term continues to effectively alert clinicians to an important patient phenotype
[3]. Multiple clinical definitions of the metabolic syndrome have been proposed over the past 11 years [46].
The latest convergence of ideas between the American
Heart Association and the International Diabetes
0268-4705 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

Federation [7] represents an improvement over previous

definitions. In this new definition, the prerequisite of
abdominal obesity has been reconsidered. Instead, this
criterion is one of the five diagnostic parameters, as insulin
resistance and metabolic syndrome can exist in the
absence of traditional anthropomorphic measures of
obesity. Three of the following five elevated waist
circumference, elevated triglycerides, low high-density
lipoprotein (HDL), BP of at least 130/85 mmHg, or fasting
glucose of at least 100 mg/dl (5.6 mmol/l) are required for
making the diagnosis (Table 1) [7]. However, dichotomization of the components remains somewhat arbitrary,
as insulin resistance, abdominal obesity, and elevated
blood glucose are all continuous variables that reflect a
graded increase in cardiovascular disease (CVD) and
diabetes risk. Hemoglobin (Hb) A1c has not yet been
incorporated into the definition, despite its recent inclusion in the criteria for the diagnosis of diabetes mellitus
[8].
The metabolic syndrome remains underrecognized,
underdiagnosed, and undertreated perhaps owing to
confusion over its exact clinical definition. We believe
that a broad approach should be taken in identifying the
DOI:10.1097/HCO.0b013e32833cd474

Practical approach to metabolic syndrome Tota-Maharaj et al.

503

Table 1 Definition of the metabolic syndrome

Definition

Prerequisite for diagnosis

Criteria for diagnosis

WHO [4]

Insulin resistance, plus any two of the following

parameters:

NCEP ATP III [5]

At least three out of the following five:

IDF [6]

Abdominal obesity (defined by ethnicity-specific

values) plus any two of the following four:

New Consensus
definitiona [7]

At least three out of the following five:

Hypertension 140/90 mmHgb

Plasma triglycerides 150 mg/dl, low HDL, or both:
Men <35 mg/dl
Women <39 mg/dl
BMI >30 kg/m2, waisthip ratio (WHR), or both
Men >0.9 WHR
Women >0.85 WHR
Microalbuminuria
Waist circumference:
Men 102 cm (40 in.)
Women 88 cm (35 in.)
Triglycerides 150 mg/dlb
HDL-C
Men <40 mg/dl
Women <35 mg/dl
Hypertension 130/85 mmHgb
Fasting glucose 100 mg/dlb
Triglycerides  mg/dlb
HDL-Cb
Men <40 mg/dl
Women <50 mg/dl
BP 130/85 mmHgb
Fasting glucose 100 mg/dlb
Elevated waist circumference (population and ethnicity specific)
Triglycerides 150 mg/dlb
HDL-C
Men <40 mg/dl
Women <50 mg/dl
BP 130/85 mmHgb
Fasting glucose 100 mg/dlb

To convert HDL-C to mmol/l, multiply by 0.0259; to convert triglycerides to mmol/l, multiply by 0.0113; to convert glucose to mmol/l, multiply by
0.0555. HDL-C, high-density lipoprotein-cholesterol; IDF, International Diabetes Federation; NCEP ATP III, National Cholesterol Education Program
Adult Treatment Panel III.
a
Consensus: International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart
Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
b
Or taking medication or specific treatment for this risk factor.

metabolic syndrome phenotype, combining the current

unified definition with the identification of related conditions such as subclinical inflammation, family history,
fatty liver disease, polycystic ovarian syndrome, and
sleep-disordered breathing [9].

Pathophysiology: new mechanistic insights

The clinical features and cardiovascular risk associated
with the metabolic syndrome are largely related to dysregulation of adipose tissue. The adipocytokines secreted
by abdominal fat in particular are mediators of inflammation [10 21,22,23], oxidant stress [24,25,26], insulin resistance [27,28], and lipoprotein metabolism [29],
as shown in Fig. 1. These cytokines supervise a subclinical proinflammatory and oxidative state that is thought
to accelerate atherosclerosis, plaque rupture, and atherothrombosis. In addition, a growing body of evidence now
links insulin-like growth factor (IGF) to the metabolic
syndrome and worsening cardiovascular risk [30,31].
A: Assessment

The first step in effectively treating patients with the

metabolic syndrome lies in recognizing the clinical
phenotype and recording the diagnosis [7]. We endorse

the use of any of the diagnostic criteria presented in

Table 1. An established risk assessment tool should then
be used to calculate the long-term risk of adverse outcomes. However, the traditional 10-year Framingham
model for coronary heart disease (CHD) underestimates
risk in the metabolic syndrome. To account for unmeasured risk, we suggest an augmented intermediate risk
category wherein patients designated with a Framingham
risk score 620% should be considered as being at
intermediate risk [1]. As the metabolic syndrome clearly
increases the lifetime risk of CHD, the 30-year Framingham model for CHD that includes measures of obesity is
also worth calculating [32].
A: Aspirin and other antithrombotics

Patients with the metabolic syndrome have enhanced

platelet aggregation, increased fibrinogen, increased clotting factors, and decreased fibrinolysis from increased
levels of plasminogen activator inhibitor-1, all resulting in
an increased risk of atherothrombosis [33]. We previously
suggested that all patients in the augmented intermediate-risk category (calculated 10-year Framingham risk
620%) and all high-risk patients with the metabolic
syndrome should be treated with 7581 mg/day of aspirin
in the absence of contraindications [1].

504 Prevention
Figure 1 Probable pathophysiological pathways of metabolic syndrome

Adipose tissue-Abdominal fat

Genetic factors
Environmental influences-sedentary lifestyle,
excessive caloric intake

Increased adipocytokine secretion

Pro-inflammatory cytokines, subclinical inflammation-CRP [10,11,12,13], IL-6
[10], IL-18 [14], leptin [15, 16], adiponectin [17, 18], C3 [19, 20], sVCAM
1 [10], sICAM-1 [10], IMA [21], chimerin [22, 23], sCD40-L [11].
Oxidant stress-lipoprotein PLA-2 [24], serum amyloid A [25], SOD [26].
Mediators of insulin resistance and lipid metabolism-RBP-4 [27],
copeptin [28], ZAG [29].

IGF-1 [30], IGF-1/IGFBP-3 [31]

Accelerated atherosclerosis
Insulin resistance
Diabetes mellitus, hypertension, atherogenic dyslipidemia
Coronary heart disease
Obstructive sleep apnea
Non-alcoholic fatty liver disease

C3, complement 3; CRP, C-reactive protein; IGF-1, insulin-like growth factor-1; IGFBP-3, insulin-like growth factor binding protein-3; IL-18, interleukin18; IL-6, interleukin-6; IMA, ischemia-modified albumin; PLA-2, phospholipase A-2; RBP-4, retinol-binding protein-4; sCD40-L, soluble CD40 ligand;
sICAM-1, soluble intercellular adhesion molecule-1; SOD, superoxide dismutase; sVCAM-1, soluble vascular cell adhesion molecule-1; ZAG,
zinc-a2-glycoprotein.

Several recent studies [34,35,36,37,38] have increased

the uncertainty of benefit of the use of aspirin in primary
prevention. In the Prevention of Progression of Arterial
Disease and Diabetes trial [34], 1276 type 2 diabetic
patients with anklebrachial index (ABI) below 0.99
but without clinical CVD were randomized to either
aspirin (100 mg) or placebo. After a median follow-up
of 6.7 years, there was no difference in the rate of adverse
cardiovascular events [18.2 versus 18.3%, hazard ratio
0.98, 95% confidence interval (CI) 0.761.26, P 0.86].
The Japanese Primary Prevention of Atherosclerosis with
aspirin for Diabetes (JPAD) trial [35] examined the
efficacy of low-dose aspirin for primary prevention in
2539 patients with type 2 diabetes. After a median of
4.4 years, there was a nonsignificant reduction in cardiovascular events (13.6 per 1000 person-years) among those
taking aspirin versus (17.0 per 1000 person-years) in a
control population (hazard ratio 0.80, 95% CI 0.581.10,
P 0.16) after 4.4 years of follow-up. Among patients of
at least 65 years, there was a significant benefit noted with
aspirin treatment (hazard ratio 0.68, 95% CI 0.460.99).

The Aspirin for Asymptomatic Atherosclerosis trial [36]

randomized 3350 patients with an ABI of 0.95 or less to
treatment with either aspirin or placebo for a median
follow-up period of 8.2 years. The incidence of adverse
cardiovascular events did not differ between groups
(10.8% aspirin, 10.6% placebo, hazard ratio 1.03, 95%
CI 0.841.27).
De Berardis et al. [37] published a meta-analysis of the
effect of low-dose aspirin in 10 117 patients with diabetes
and no CVD. A significant benefit of aspirin in preventing
myocardial infarction (MI) was noted in men, but not in
women. Overall, there was no statistically significant
reduction in the risk of major cardiovascular events [five
studies, 9584 participants; relative risk (RR) 0.90, 95% CI
0.811.00] or cardiovascular mortality (four studies,
n 8557; RR 0.94, 95% CI 0.721.23).
The potential risk of bleeding must be weighed when
considering aspirin therapy in primary prevention. Ogawa
et al. [35] in the JPAD trial showed that the composite
of hemorrhagic stroke and significant gastrointestinal

Practical approach to metabolic syndrome Tota-Maharaj et al.

bleeding was not significantly different between aspirin

and nonaspirin groups. However, the Antithrombotic
Trialists collaboration [38] demonstrated increased
major gastrointestinal and extracranial bleeding (0.10
versus 0.07% per year, P < 0.0001) among those randomized to aspirin. Importantly, as some patients will
have contraindications or will be resistant to aspirin,
Lev et al. [39] recently demonstrated that omega-3 fatty
acids are a reasonable alternative to low-dose aspirin
among a cohort who meet a laboratory definition of
aspirin resistance.
We advise that all older patients (65 years old) and all
patients at high Framingham risk with metabolic syndrome receive low-dose aspirin. Patients in the low
intermediate-risk group (610%) will need individualized decision-making, whereas most patients in the
conventional intermediate risk category (1020%) should
receive aspirin. There is no evidence to indicate that use
of aspirin in low-risk groups (<6%) is beneficial, and the
risk of hemorrhage outweighs benefit in this category.
B: Blood pressure

Mechanisms by which hypertension occurs in patients

with the metabolic syndrome include oxidative stress
leading to altered bioavailability of nitric oxide, adipocyte-induced increased angiotensinogen production leading to increased sodium reabsorption, hyperinsulinemia
leading to increased sympathetic activity [40], and
increased sodium intake [41].
We have previously suggested angiotensin receptor
blockers (ARBs) and angiotensin-converting enzyme
inhibitors (ACEIs) as first-line treatment of high BP in
the metabolic syndrome due to their beneficial effect in
delaying the onset of diabetes mellitus [1]. Danchin et al.
[42] in a recent meta-analysis of 33 960 patients followed
for a mean of 4.4 years confirmed the long-term cardiovascular benefit of ACEIs. Conversely, we recommend
that thiazide diuretics and beta-blockers, first-line antihypertensive treatment according to Seventh Report of
the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure
guidelines [43], be relegated to second-line or third-line
agents in patients with the metabolic syndrome due to
their risk of worsening glucose intolerance. Several newer
trials have produced results worthy of discussion.

505

an amlodipineperindopril combination compared with

an atenololbendroflumethiazide combination (hazard
ratio 0.70, 95% CI 0.630.78, P < 0.0001). Although
one small study [46] in elderly patients with the metabolic syndrome showed that telmisartan attained better
24-h BP control than ramipril, the choice between ACEIs
or ARBs has been shown in the much larger ONgoing
Telmisartan Alone and in combination with Ramipril
Global Endpoint Trial [47] to be inconsequential.
The Avoiding Cardiovascular Events in Combination
Therapy in Patients Living with Systolic Hypertension
trial [48] showed that, in addition to treatment with
benazepril, amlodipine is more beneficial than a thiazide
diuretic in preventing cardiovascular events (hazard ratio
0.80, 95% CI 0.720.90, P < 0.001).
Two recent trials have evaluated the issue of optimal BP
control in hypertensive patients with and without diabetes mellitus. The Cardio-Sis trial [49] evaluated 1111
nondiabetic patients with respect to tight control
(<130 mmHg) or usual control (<140 mmHg). Electrocardiographic evidence of left ventricular hypertrophy
was reduced in the tight-control group [odds ratio (OR)
0.63, 95% CI 0.430.91, P 0.013], suggesting that, in
nondiabetic patients, systolic blood pressure (SBP) below
130 mmHg may be more beneficial.
More recently, the Action to Control CardiOvascular Risk
in Diabetes (ACCORD) study [50] suggested that, in
diabetic patients, intensive BP control (mean SBP of
119 mmHg) was not more beneficial than standard control
(mean SBP of 134 mmHg). The annual rate of the
primary composite outcome (nonfatal stroke or MI, or
cardiovascular death) was 1.87% in the intensive therapy
group and 2.09% in the standard therapy group (hazard
ratio 0.88, 95% CI 0.731.06, P 0.20). On the basis of
this evidence, we believe that a SBP goal of 125
135 mmHg is reasonable for patients with the metabolic
syndrome.
In summary, the evidence continues to support the use of
ACEIs and ARBs as first-line agents for BP lowering,
given their positive effects on glycemic control. Amlodipine appears to be a reasonable choice for combination
therapy.
C: Cholesterol, high-sensitivity C-reactive protein

The Nateglinide And Valsartan in Impaired Glucose

Tolerance Outcomes Research (NAVIGATOR) study
[44] randomized 9306 nondiabetic patients to treatment
with valsartan versus placebo, and showed that valsartan
demonstrated a 14% reduction in incident diabetes.
The Anglo-Scandinavian Cardiac Outcomes Trial-Blood
Pressure Lowering Arm study [45] demonstrated a significant reduction in the incidence of diabetes mellitus with

Low-density lipoprotein (LDL), triglycerides, and HDL

have traditionally been the primary targets in treating
atherogenic dyslipidemia [1,55,63]. However, nonHDL-cholesterol is the most effective way of quantifying
atherogenic dyslipidemia on a standard, fasting or nonfasting lipid profile [64]. Newer biomarkers including
LDL particle number and small, dense LDL (sdLDL)
[65], oxidized LDL (oxLDL) [66,67], adiponectin,

506 Prevention
Table 2 Recent studies involving metabolic syndrome, antilipid, and anti-inflammatory treatment
Reference

Medications tested

Endpoint

Results

Landmark studies on treatment of atherogenic dyslipidemia

Ridker et al. [51]
(JUPITER trial)
Ginsberg et al. [52]
(ACCORD trial)
Taylor et al. [53,54]
(ARBITER
6-HALTS trial)

17 802 patients with normal LDL

but high CRP randomized to
rosuvastatin or placebo
5518 type 2 diabetic patients
randomized to simvastatin/
fenofibrate or simvastatin/placebo
208 coronary heart disease risk
equivalent patients, on long-term
statin therapy, randomized to
niacin or ezetimibe

MI/stroke/ arterial revascularization/ Trial stopped early due to significant

unstable angina hospitalization/
reduction in primary endpoint with
cardiovascular death
rosuvastatin
Nonfatal MI/stroke or
Combination fenofibrate/simvastatin
cardiovascular death
made no difference when compared
with simvastatin alone
Change in common carotid IMT
Niacin showed greater change in
carotid IMT, trial stopped early due
to benefit in niacin arm

Studies evaluating cholesterol medications and effect on lipid profile

Robinson et al. [55]
(VYMET study)
Winkler et al. [56]

Ansquer et al. [57]

Bahadir et al. [58]

Jialal et al. [59]

Akdim et al. [60]

1128 patients with metabolic

syndrome randomized to
ezetimibe simvastatin or
atorvastatin
56 metabolic syndrome patients
randomized to fluvastatin/
fenofibrate or simvastatin/
ezetimibe

% change in LDL

Combination therapy was significantly

more effective at reducing LDL than
atorvastatin

Lipid profile and sdLDL

particle size

180 patients with metabolic

syndrome type IIb dyslipidemia
randomized to fenofibrate/ezetimibe
or ezetimibe or fenofibrate
monotherapy
40 hypercholesterolemic metabolic
syndrome patients randomized to
rosuvastatin or others
Pooled analysis of three double-blind,
placebo-controlled trials:
colesevelam versus placebo
in 1018 patients with diabetes
mellitus and hypercholesterolemia
Phase 2 trial of 74 patients being
treated with statins assigned to
different doses of mipomersen

Lipid profile, apolipoproteins,

hsCRP

Simvastatin/ezetimibe better at
reducing LDL and TC; however,
in patients with sdLDL, fluvastatin/
fenofibrate was better at reducing
triglycerides and increasing
LDL radius
Combination therapy better than either
monotherapy in reducing LDL,
non-HDL, ApoB, equal to fenofibrate
alone in reducing triglycerides and
in increasing HDL
Similar reduction in sdLDL levels
among all statins

sdLDL level
HbA1C and LDL levels

HbA1C and LDL significantly reduced

compared with placebo

ApoB and serum LDL levels

Mipomersen decreased both LDL

and ApoB levels significantly

Studies evaluating effect of cholesterol medications on inflammatory markers

Jialal et al. [59]

Rosenson [61]

Belfort et al. [62]

Pooled analysis of three double-blind,

placebo-controlled trials: colesevelam
versus placebo in 1018 patients
with diabetes mellitus and
hypercholesterolemia
Randomized placebo-controlled trial
of 55 hypercholesterolemic
metabolic syndrome patients:
fenofibrate versus placebo

hsCRP

Colesevelam significantly reduced

hsCRP compared with placebo

Adiponectin other markers

of inflammation

Fenofibrate raised adiponectin levels

in patients with metabolic syndrome
and hypertriglyceridemia, changes
in adiponectin were significantly
inversely associated with changes
in multiple inflammatory markers
Fenofibrate reduces systemic
inflammation independent of
improvement in lipid profile

25 nondiabetic insulin-resistant
Lipid profile, inflammatory
metabolic syndrome patients
markers
randomized to fenofibrate or placebo

ACCORD, Action to Control CardiOvascular Risk in Diabetes; ApoB, apolipoprotein B; ARBITER 6-HALTS, Arterial Biology for the Investigation of the
Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis; carotid IMT, carotid intimamedia thickness;
HbA1C, hemoglobin A1C; hsCRP, high-sensitivity C-reactive protein; JUPITER, Justification for the Use of statins in Primary Prevention: an Intervention
Trial Evaluating Rosuvastatin; LDL, low-density lipoprotein; MI, myocardial infarction; sdLDL, small, dense LDL; VYMET, Vytorin in metabolic syndrome.

fetuin-A [68], and apolipoprotein B are emerging as

additional ways to quantify atherogenic dyslipidemia
(Table 2 [51,52,53,54 60,61,62]).
Inflammation, characterized by high-sensitivity C-reactive protein (hsCRP), is a central feature of the metabolic
syndrome. The Justification for the Use of statins in

Primary Prevention: an Intervention Trial Evaluating

Rosuvastatin (JUPITER) trial [51] emphasized the
added benefit of targeting individuals with high CRP
levels even in the presence of normal LDL. Among
17 802 patients with LDL below 130 mg/dl (3.4 mmol/l)
and CRP at least 2 mg/l (19.1 nmol/l), rosuvastatin 20 mg
reduced the primary endpoint (MI, stroke, arterial

Practical approach to metabolic syndrome Tota-Maharaj et al.

507

Table 3 Beneficial versus detrimental nutrient categories in the metabolic syndrome

Reference

Food category

Comments

Beneficial
Coyne et al. [69]
Sluijs et al. [70]

Carotenoids

Lower serum carotenoids lead to increased risk of metabolic syndrome

Higher carotenoid intake (especially b-carotene lycopene) associated
with lower prevalence of metabolic syndrome
Protective role against metabolic syndrome in type 2 diabetic patients

Steemburgo et al. [71]



Lopez-Alvarenga et al. [72 ]

Chen et al. [73]
Detrimental
Van Dijk et al. [74]
Nettleton et al. [75]
Azadbakht et al. [76]
Radhika et al. [77]

Soluble fibers, especially

whole grains and fruits
Polyunsaturated fatty acids
Reduction in salt intake

Saturated fatty acid-rich diet

Dietary soda
Red meat
Refined grains

Negatively associated with serum triglycerides

Metabolic syndrome enhances BP response to sodium intake, reduction
in sodium intake can be especially important in reducing BP in patients
at risk of metabolic syndrome
Proinflammatory obesity-linked gene expression profile
Diet soda daily was associated with increased risk of select incident
metabolic syndrome components and type 2 diabetes mellitus
Higher risk of metabolic syndrome
Higher intake of refined grains was associated with insulin resistance and
the metabolic syndrome

BP, blood pressure.

revascularization, and hospitalization for unstable angina,

or death from cardiovascular causes) after a mean followup of 1.9 years (hazard ratio 0.56, 95% CI 0.460.69,
P < 0.00001). In subgroup analysis, the JUPITER trial
confirmed a significant benefit from the use of rosuvastatin in the 41% of patients with metabolic syndrome
(7375 patients, hazard ratio 0.7).
The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL
Treatment Strategies in Atherosclerosis trial [53,54]
compared add-on treatment with niacin versus ezetimibe
in 208 CHD risk equivalent patients receiving long-term
statin therapy. Niacin significantly decreased mean carotid intimamedia thickness (P 0.003), whereas LDL
lowering with ezetimibe was paradoxically and significantly associated with an increase in the carotid intima
media thickness in univariate analysis (R 0.31,
P < 0.001). Although this provides the impetus to treat
with niacin, patients were not on maximal statin dose and
the trial was not designed to identify differences in CVD
events. Furthermore, consideration must be given to the
side-effect profile, which includes poor tolerability and
glucose intolerance.
The recently concluded ACCORD trial lipid therapy arm
[52] assigned 5518 patients receiving simvastatin to
either fenofibrate therapy or placebo. The primary outcome (first occurrence of nonfatal MI, nonfatal stroke, or
death from cardiovascular causes) was not reduced in the
fenofibrate group (hazard ratio 0.92, 95% CI 0.791.08,
P 0.32). However, subgroup analysis of patients with
triglyceride at least 204 mg/dl (2.3 mmol/l) and HDL
34 mg/dl (0.88 mmol/l) or less revealed a nonstatistically
significant 4.95% reduction in the percentage of adverse
cardiovascular events (P 0.06). This finding of a treatment benefit in patients with high triglycerides and low
HDL correlates well with previous large fibrate studies

[7880] that demonstrate a reduction in CVD events in the

absence of statin therapy, implying that fibrates may have
some role in treating the high triglyceridelow HDL
phenotype characteristic of the metabolic syndrome.
In summary, niacin has shown promise as a second-line
agent after statins. Fenofibrate may have a diminished
role, most specifically in treating patients with both low
HDL and high triglycerides. The JUPITER trial has
highlighted hsCRP as a risk factor for identifying a
patient population that benefits from statin therapy
despite a relatively low LDL.
D: Diabetes prevention

Patients with impaired glucose tolerance have a much

higher risk of developing diabetes mellitus. The annual
incidence of type 2 diabetes mellitus in patients with
impaired glucose tolerance and the metabolic syndrome
without treatment may be as high as 18.7% [81]. A
recently concluded Japanese prospective epidemiological study [82] showed that patients with the metabolic
syndrome retained a high hazard ratio [2.37 (95% CI
1.453.88)] for developing diabetes mellitus, even after
adjustment for patients with impaired fasting glucose.
The importance of lifestyle therapy has been reiterated
in a new analysis from the Diabetes Prevention Program
[83,84]. Among 3234 patients at high risk for the development of diabetes mellitus, the intensive lifestyle modification group showed a significant regression (hazard
ratio 2.05, P < 0.01), whereas the metformin group
showed a notable yet nonsignificant trend for regression
from impaired fasting glucose to normal glucose regulation (hazard ratio 1.25, P 0.06).
The NAVIGATOR trial [44], discussed above, demonstrated a 14% reduction in incident diabetes mellitus over
5 years with valsartan therapy. Several other genres of

508 Prevention
Table 4 New changes to ABCDE approach to the metabolic syndrome
A: Assessment
A: Aspirin
B: BP control

C: Cholesterol
First target: LDL
Second target: non-HDL
Third target: HDL
Fourth target: CRP
D: Diabetes prevention/diet

E: Exercise

Calculate Framingham risk score

Make diagnosis of metabolic syndrome, using new criteria
High risk aspirin definitely beneficial
High intermediate risk (1020%) aspirin likely to be beneficial
Lowintermediate risk (610%) individualized decision-making, depending on sex and risk of bleeding
Aim for BP 125135/80 mmHg
ACEIs/ARBs first line, may reduce incident diabetes mellitus
Dihydropyridine calcium channel blockers second line
Beta-blockers and thiazides third line may have an adverse effect on impaired glucose tolerance but
outweighed by benefits of reaching BP goal if first-line and second-line agents insufficient
Statins to achieve LDL-C <100 mg/dl in high-risk, <130 mg/dl in intermediate-risk (6% 10-year risk) patients
Statin intensification, consider niacin and omega-3 fatty acids once statin maximized
Consider further reduction in LDL with statin therapy to mitigate risk of low HDL, consider niacin.
Consider fibrates, especially for those with combined hypertriglyceridemia/low HDL
Statin therapy for those with hsCRP 2 mg/dl
Intensive lifestyle modification is the most important therapy
Weight loss, reduction in salt intake
Mediterranean diet: increase omega-3 fatty acids, fruits, vegetables, fiber, nuts
Consider dietary supplementation with polyunsaturated fatty acids
Metformin is second line in delaying the onset of diabetes mellitus
Thiazolidinediones, alpha-glucosidase inhibitors, and incretin mimetics have shown benefit in smaller
studies and are therefore third line
Daily vigorous activity
Recommend use of pedometer with goal >10 000 steps/day

To convert LDL to mmol/l, multiply by 0.0259; to convert CRP to nmol/l, multiply by 9.524. ACEIs, angiotensin-converting enzyme inhibitors; ARBs,
angiotensin receptor blockers; BP, blood pressure; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDL-C, LDLcholesterol.

antidiabetic medication, including thiazolidinediones

[85], incretin mimetics [86], metformin [83,84], the
alpha-glucosidase inhibitors acarbose [87] and voglibose
[88], and omega-3 fatty acids [89], have generated
interest in the treatment of the metabolic syndrome.
Although thiazolidinediones reduce insulin resistance,
their effect on inflammatory pathways seems complex
and has not yet been fully elucidated [85]. Bhushan et al.
[86] performed a retrospective analysis of glycemic
control and cardiometabolic risk factors in 176 patients
treated with exanetide, an incretin mimetic. Exanetide
demonstrated a favorable metabolic profile by decreasing
HbA1C and also improving the lipid profile, body weight,
and abdominal girth. The alpha-glucosidase inhibitor,
acarbose, has previously been shown to be effective in
preventing diabetes mellitus in patients with impaired
glucose tolerance [87], whereas its newer sibling, voglibose [88], has also shown promise.
There are still several areas of uncertainty in this field. It is
currently unknown whether lifestyle therapy combined
with pharmacotherapy leads to greater diabetes reduction
than lifestyle therapy alone. It is also currently unknown
whether lifestyle therapy and medications need to be
continued indefinitely for prevention of diabetes, or
whether there is durable effect after drug discontinuation.
D: Diet

The importance of adopting a healthy diet cannot be

overemphasized. Several low glycemic index and highprotein diets have shown beneficial profiles in either
preventing or reducing the likelihood of the metabolic

syndrome [90,91,92,97]. The Mediterranean-style diet,

in particular, rich in whole grains, fruit, vegetables, nuts,
and omega-3 fatty acids, and low in refined grains, saturated and trans fats, has been found to offer an advantage
in preventing or treating the metabolic syndrome [93,94]
and is one of the few diets to reduce cardiovascular events
in a randomized clinical trial [95].
Studies evaluating specific dietary components have
revealed the benefit of carotenoids [69,70], soluble fiber
(whole grains and nuts) [71], polyunsaturated fatty acids
[72], and a reduction in salt intake [73] (Table 3
[69,70,71,72,73,74,75,76,77]). Conversely, saturated
fatty acid-rich diets [74], daily dietary soda [75], red
meat [76], and refined grains [77] have been noted to
be detrimental.
E: Exercise

Several large-scale studies in different populations have

highlighted the benefit of physical activity in both preventing and treating components of the metabolic syndrome [9698,99]. Three recent studies [100,101,102]
have confirmed that exercise lowers several markers of
inflammation, including hsCRP, adiponectin, and interleukin (IL)-18.
Although the optimal amount of exercise is unknown,
newer studies give more credence to the philosophy that
some is better than none. Modest benefit from workplace
activity, particularly in women who reported at least
3 h/day of workplace activity (OR 0.75, 95% CI 0.59
0.96), has been demonstrated [97]. Metzger et al. [103]

Practical approach to metabolic syndrome Tota-Maharaj et al.

demonstrated that, once a weekly minimum of exercise is

met, it does not matter whether exercise is spread out
throughout the week or accumulated into a few days of
vigorous activity. In contrast, Tjnna et al. [104] demonstrated a significant reduction of several indicators of the
metabolic syndrome with vigorous exercise (90% of highest measured heart rate) compared with moderate exercise
(70%).
We have found a pedometer goal of a minimum daily
number of steps per day to be a useful way to keep
patients motivated in achieving specific exercise targets.
On the basis of our prior recommendations [1], we continue to strongly advocate for regular, brisk exercise.
Research with respect to the effect of smoking on
the metabolic syndrome is lacking. One study [105]
investigating the combined effects of both smoking and
the metabolic syndrome on cardiovascular events
revealed a general increased risk of CHD in 2334
Chinese patients.

Conclusion
Table 4 summarizes our latest additions to the previously
described ABCDE approach to the metabolic syndrome. The diagnosis of the metabolic syndrome can
be used to guide more aggressive lifestyle changes; lower
BP goals; and initiate therapy with aspirin, LDL-C-modifying medications, and reninangiotensinaldosterone
system blockers at an earlier time point than might
otherwise be recommended. Several recent trials outlined in this review have enhanced our understanding of
management of the metabolic syndrome.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 531532).

Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic
syndrome: a joint interim statement of the International Diabetes Federation
Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood
Institute; American Heart Association; World Heart Federation; International
Atherosclerosis Society; and International Association for the Study of
Obesity. Circulation 2009; 120:16401645.
This article is of paramount importance to the diagnosis of the metabolic syndrome.
One of the major arguments against the metabolic syndrome is the lack of
uniformity of diagnostic criteria. This article details the most recent diagnostic
criteria, achieved with the collaboration of several international organizations.

Inzucchi S, Bergenstal R, Fonseca V, et al. Diagnosis and classification of

diabetes mellitus: American Diabetes Association. Diabetes Care 2010; 33
(Suppl 1):S62S69.
This article identifies the most recent diagnostic criteria for diabetes mellitus. The
most notable addition has been the utilization of HbA1C as a part of the diagnostic
criteria.

8


Tota-Maharaj R, Blumenthal RS, Blaha MJ. Update on obstructive sleep

apnea and its associated metabolic abnormalities: insulin resistance, metabolic syndrome, and type 2 diabetes mellitus. Curr Cardiovasc Risk Rep
2010; 4:165173.
This review article summarizes recent associations between the metabolic syndrome,
diabetes mellitus, and obstructive sleep apnea, in light of increasing evidence that
obstructive sleep apnea may be part of the spectrum of the metabolic syndrome.

9


Jacobs M, van Greevenbroek M, van der Kallen C, et al. Low-grade inflammation can partly explain the association between the metabolic syndrome
and either coronary artery disease or severity of peripheral arterial disease:
the CODAM study. Eur J Clin Invest 2009; 39:437444.
This study aims to explain the hypothesis that the metabolic syndrome is correlated
with CHD by virtue of subclinical inflammation. Several inflammatory markers are
measured and summated into an inflammation score.

10


Unek IT, Bayraktar F, Solmaz D, et al. Enhanced levels of soluble CD40 ligand
and C-reactive protein in a total of 312 patients with Metabolic Syndrome.
Metabolism 2010; 59:305313.
This study assesses the inflammatory burden of the metabolic syndrome by
measuring CD40CD40 ligand interactions and CRP in a population with the
metabolic syndrome. This is a new concept, as CD40CD40 ligand interactions
have been found to be closely associated with subclinical inflammation.

11


Anuurad E, Tracy RP, Pearson TA, et al. Comparison of C-reactive protein

and metabolic syndrome as cardiovascular risk factors in AfricanAmericans
and European-Americans. Am J Cardiol 2009; 103:523527.
This study is important because it compares the use of CRP to the metabolic
syndrome as prognostic factors in both an AfricanAmerican and a EuropeanAmerican population.

12


13


Kilic T, Jneid H, Ural E, et al. Impact of the metabolic syndrome on highsensitivity C reactive protein in patients with acute coronary syndrome.
Atherosclerosis 2009; 207:591596.
This study is significant because it investigates the response of CRP to acute
coronary syndromes in patients with metabolic syndrome, noting an augmented
response in these patients due to their underlying subclinical inflammation.
Troseid M, Seljeflot I, Hjerkinn EM, Arnesen H. Interleukin-18 is a strong
predictor of cardiovascular events in elderly men with the metabolic syndrome: synergistic effect of inflammation and hyperglycemia. Diabetes Care
2009; 32:486492.
The significance of this study is the utility of IL-18 as an independent prognostic
marker of CVD in the metabolic syndrome population.

14


Ntyintyane L, Panz V, Raal FJ, Gill G. Leptin, adiponectin, and high-sensitivity

C-reactive protein in relation to the metabolic syndrome in urban South
African blacks with and without coronary artery disease. Metab Syndr Relat
Disord 2009; 7:243248.
This study is important because it significantly links leptin to patients with both the
metabolic syndrome and CHD, whereas adiponectin and CRP did not show this
association.

15


Ding EL, Smit LA, Hu FB. The metabolic syndrome as a cluster of risk factors:
is the whole greater than the sum of its parts? Comment on The metabolic
syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch Intern Med 2010; 170:484485.
This invited commentary summarizes the most salient arguments for and against
the metabolic syndrome as an independent entity and predictor of diabetes
mellitus and CVD.

16


2


Blaha M, Elasy TA. Clinical use of the metabolic syndrome: why the confusion? Clin Diab 2006; 24:125131.

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
553.

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) final report. Circulation 2002; 106:3143
3421.

Alberti KG, Zimmet P Shaw J, IDF Epidemiology Task Force Consensus

Group. The metabolic syndrome: a new worldwide definition. Lancet 2005;
366:10591062.

7


Blaha MJ, Bansal S, Rouf R, et al. A practical ABCDE approach to the

metabolic syndrome. Mayo Clin Proc 2008; 83:932943.

509

Yun JE, Kimm H, Jo J, Jee SH. Serum leptin is associated with metabolic
syndrome in obese and nonobese Korean populations. Metabolism 2010;
59:424429.
This article emphasizes the association of serum leptin with the metabolic
syndrome, even in the absence of obesity. The authors further suggest that leptin
can be considered as a parameter to assess the effectiveness of treatment of the
metabolic syndrome.
Yun JE, Sull JW, Lee HY, et al. Serum adiponectin as a useful marker for
metabolic syndrome in type 2 diabetic patients. Diabetes Metab Res Rev
2009; 25:259265.
This paper assessed the clinical utility of serum adiponectin as a predictor of the
adiponectin can be used to aid in diagnosis of the metabolic syndrome in the
future.

17


510 Prevention
Pencina MJ, DAgostino RB, Larson MG, et al. Predicting the 30-year risk of
cardiovascular disease: the Framingham Heart Study. Circulation 2009;
119:30783084.
This study from Framingham is important, as it is the first effort to formulate a
30-year risk score for CHD based on known risk factors. This is important because
the metabolic syndrome increases lifetime risk of CHD.

18


Seino Y, Hirose H, Saito I, Itoh H. High-molecular-weight adiponectin

is a predictor of progression to metabolic syndrome: a population-based
6-year follow-up study in Japanese men. Metabolism 2009; 58:355
360.
This is the first study to assess high-molecular-weight adiponectin as a long-term
predictor of the metabolic syndrome, in patients without diabetes mellitus.

32


Phillips CM, Goumadi L, Bertrais S, et al. Complement component 3

polymorphisms interact with polyunsaturated fatty acids to modulate risk
of metabolic syndrome. Am J Clin Nutr 2009; 90:16651673.
This study is unique because it not only assesses the relation between several
different C3 polymorphisms and the metabolic syndrome but also determines
how polyunsaturated fatty acids modulate this interaction. This is important in
delineating genenutrient interactions in the pathophysiology of the metabolic
syndrome.

33

Devaraj S, Rosenson RS, Jialal I. Metabolic syndrome: an appraisal of the proinflammatory and procoagulant status. Endocrinol Metab Clin North Am
2004; 33:431453.

34

Belch J, MacCuish A, Campbell I, et al. The prevention of progression of

arterial disease and diabetes (POPADAD) trial: factorial randomised placebo
controlled trial of aspirin and antioxidants in patients with diabetes and
asymptomatic peripheral arterial disease. BMJ 2008; 337:a1840.

35

Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary

prevention of atherosclerotic events in patients with type 2 diabetes: a
randomized controlled trial. JAMA 2008; 300:21342141.

19


Puchau B, Zulet MA, Gonzalez de Echavarri A, et al. Selenium intake reduces

serum C3, an early marker of metabolic syndrome manifestations, in healthy
young adults. Eur J Clin Nutr 2009; 63:858864.
This study suggests that serum complement 3, an early marker of the metabolic
syndrome, can be modulated by selenium intake. This has implications for possible
treatment of the inflammatory response in the metabolic syndrome with dietary
selenium supplementation.

20


Valle Gottlieb MG, Da Cruz IB, Duarte MM, et al. Associations among
metabolic syndrome, ischemia, inflammatory, oxidatives, and lipid biomarkers.
J Clin Endocrinol Metab 2010; 95:586591.
This is the first study to assess the association of ischemia-modified albumin with
the metabolic syndrome.

21


22

Bozaoglu K, Segal D, Shields KA, et al. Chemerin is associated with

metabolic syndrome phenotypes in a MexicanAmerican population. J Clin
Endocrinol Metab 2009; 94:30853088.

Lehrke M, Becker A, Greif M, et al. Chimerin is associated with markers

of inflammation and components of the metabolic syndrome but does
not predict coronary atherosclerosis. Eur J Endocrinol 2009; 161:339
344.
Chimerin is a novel adipocytokine, but its clinical value is unknown. This study is
important because it notes an association with the metabolic syndrome, but not
with CHD.

23


Tsimikas S, Willeit J, Knoflach M, et al. Lipoprotein-associated phospholipase

A2 activity, ferritin levels, metabolic syndrome, and 10-year cardiovascular
and noncardiovascular mortality: results from the Bruneck study. Eur Heart J
2009; 30:107115.
This study is important in adding to current knowledge of the effect of oxidative
stress on the metabolic syndrome and CVD.

24


25

Kotani K, Satoh N, Kato Y, et al. A novel oxidized low-density lipoprotein

marker, serum amyloid A-LDL, is associated with obesity and the metabolic
syndrome. Atherosclerosis 2009; 204:526531.

Isogawa A, Yamakado M, Yano M, Shiba T. Serum superoxide dismutase

activity correlates with the components of metabolic syndrome or carotid
artery intima-media thickness. Diabetes Res Clin Pract 2009; 86:213
218.
This clinical trial adds to knowledge of pathophysiological mechanisms relating
oxidative stress to the metabolic syndrome and atherosclerosis.

26


Lin C, Lai M, Li T, et al. Relationship between serum retinol-binding protein 4

and visfatin and the metabolic syndrome. Diabetes Res Clin Pract 2009;
85:2429.
This study is important as it examines the association of two novel adipokines with
the metabolic syndrome.

27


Saleem U, Khaleghi M, Morgenthaler NG, et al. Plasma carboxy-terminal

provasopressin (Copeptin). A novel marker of insulin resistance and metabolic syndrome. J Clin Endocrinol Metab 2009; 94:25582564.
This study addresses a new pathophysiological concept: stress-mediated interaction of the hypothalamicpituitaryadrenal axis (by virtue of copeptin, a surrogate marker of vasopressin) with the metabolic syndrome.

28


29

De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of

cardiovascular events in people with diabetes: meta-analysis of randomized
controlled trials. BMJ 2009; 339:b4531.
Although several trials have produced conflicting results with respect to the issue
of aspirin in primary prevention, this meta-analysis is a landmark article as it
attempts to collate data from all the large randomized controlled trials to determine
the best recommendation.

37


Collins R, Peto R, Hennekens C, et al. Aspirin in the primary and secondary

prevention of vascular disease: collaborative meta-analysis of individual
participant data from randomized trials. Lancet 2009; 373:1849
1860.
This study extends the knowledge of the benefit of aspirin not only in primary
prevention but also in secondary prevention.

38


Lev EI, Solodky A, Harel N, et al. Treatment of aspirin-resistant patients with

omega-3 fatty acids versus aspirin dose escalation. J Am Coll Cardiol 2010;
55:114121.
This clinical trial is a significant one because it investigates the efficacy of two
different therapies in aspirin-resistant patients. Metabolic syndrome, by virtue of its
procoagulant state, may predispose patients to aspirin resistance, and omega-3
fatty acids are good for many other features of the syndrome.

39


40

Reaven GM. Insulin resistance/compensatory hyperinsulinemia, essential

hypertension, and cardiovascular disease. J Clin Endocrinol Metab 2003;
88:23992403.

41

Hoffmann IS, Cubeddu LX. Salt and the metabolic syndrome. Nutr Metab
Cardiovasc Dis 2009; 19:123128.

42

Danchin N, Cucherat M, Thuillez C, et al. Angiotensin-converting enzyme

inhibitors in patients with coronary artery disease and absence of heart failure
or left ventricular systolic dysfunction: an overview of long-term randomized
controlled trials. Arch Intern Med 2006; 166:787796.

43

Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure: the JNC 7 Report. JAMA 2003; 289:2560
2571.

McMurray JJ, Holman RR, Haffner SM, et al. Effect of valsartan on the
incidence of diabetes and cardiovascular events: the NAVIGATOR Study
Group. N Engl J Med 2010; 362:14771490.
This is a landmark study in the metabolic syndrome arena, as it confirms that
valsartan does not only treat hypertension but is also quite effective at preventing
diabetes mellitus in patients with impaired glucose tolerance.

44


45

Yeung DC, Lam KS, Wang Y, et al. Serum zinc-a2-glycoprotein correlates

with adiposity, triglycerides, and the key components of the metabolic
syndrome in Chinese subjects. J Clin Endocrinol Metab 2009; 94:2531
2536.

Brugts MP, van Duijn CM, Hofland LJ, et al. IGF-1 bioactivity in an elderly
population- relation to insulin sensitivity, insulin levels, and the metabolic
syndrome. Diabetes 2010; 59:505508.
There has been recent research into the interaction of IGF-1 with the metabolic
syndrome. This interaction is still obscure, and this article attempts to identify the
exact nature of the relationship between the two.

30


Sierra-Johnson J, Romero-Corral A, Somers VK, et al. IGF-I/IGFBP-3 ratio: a

mechanistic insight into the metabolic syndrome. Clin Sci 2009; 116:507
512.
This study adds to the known association between the IGF-1 pathway and the
metabolic syndrome, by investigating the clinical utility of a new ratio in identifying
the metabolic syndrome.

31


Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial
index: a randomised controlled trial. JAMA 2010; 303:841848.
This trial enrolled patients with a noninvasive surrogate marker of atherosclerosis to
determine whether aspirin is indicated and beneficial in this population.

36


Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events

with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
(ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;
366:895906.

Formosa V, Bellomo A, Iori A, et al. The treatment of hypertension with

telmisartan in the sphere of circadian rhythm in metabolic syndrome in the
elderly. Arch Gerontol Geriatr 2009; 49 Suppl 1: 95101.
This study noted an advantage of telmisartan compared with valsartan and ramipril
when comparing 24-h BP control.

46


47

Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at

high risk for vascular events. N Engl J Med 2008; 358:15471559.

48

Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or

hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med
2008; 359:24172428.

Practical approach to metabolic syndrome Tota-Maharaj et al.

Verdecchia P, Staessen JA, Angeli F, et al. Usual versus tight control of
systolic blood pressure in nondiabetic patients with hypertension (CardioSis): an open-label randomised trial. Lancet 2009; 374:525533.
The significance of this study is that it suggests that there is additional benefit in
aggressively treating SBP to less than 130 mmHg in the nondiabetic hypertensive
population.
50 Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood pressure control in type 2 diabetes mellitus: the ACCORD Study Group.
N Engl J Med 2010; 362:15751585.
The implications of this large study are that, in the diabetic population, an
adjustment of the BP goal to SBP of approximately 130 mmHg is no worse than
aggressively lowering to SBP below 120 mmHg. This study reassures us of our
BP goals for patients with the metabolic syndrome.
51 Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular
events in men and women with elevated C-reactive protein. N Engl J Med
2008; 359:21952207.
52 Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy
 in type 2 diabetes mellitus. N Engl J Med 2010; 362:15631574.
This trial contrasts with others in the comparison of combination lipid treatment
with a fibrate and a statin. It suggests that there is indeed no benefit from the
addition of fenofibrate to a statin.
53 Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe
 and carotid intimamedia thickness. N Engl J Med 2009; 361:21132122.
This was a critical surrogate endpoint trial that showed that niacin is clearly
preferable to ezetimibe for treating arterial wall thickness in metabolic syndrome
patients. The result is that niacin has regained some popularity as a second-line
option in treating dyslipidemia, despite its flushing side effects and tendency to
mildly worsen glucose tolerance.
54 Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial

Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results
and the impact of medication adherence, dose, and treatment duration. J Am
Coll Cardiol 2010; 55:27212726.
This analysis of the ARBITER-HALTS trial incorporates all patients regardless of
treatment duration, and confirms the findings of the original study.
55 Robinson JG, Ballantyne CM, Grundy SM, et al. Lipid-altering efficacy and

safety of ezetimibe/simvastatin versus atorvastatin in patients with hypercholesterolemia and the metabolic syndrome (from the VYMET study). Am J
Cardiol 2009; 103:16941702.
This study is one of the first to compare combination ezetimibesimvastatin with
atorvastatin, specifically in metabolic syndrome patients.
56 Winkler K, Schewe T, Putz G, et al. Fluvastatin/fenofibrate vs. simvastatin/

ezetimibe in patients with metabolic syndrome: different effects on LDLprofiles. Eur J Clin Invest 2009; 39:463470.
This study was unique because it compared two different combination antilipid
treatment regimes not only in terms of traditional lipid treatment parameters but
also in terms of LDL particle size.
57 Ansquer J, Bekaert I, Guy M, et al. Efficacy and safety of coadministration of

fenofibrate and ezetimibe compared with each as monotherapy in patients
with type IIb dyslipidemia and features of the metabolic syndrome: a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study. Am J Cardiovasc Drugs 2009; 9:91101.
This study is important because it evaluated the efficacy of a nonstatin combination
of drugs in treating dyslipidemia.
58 Bahadir MA, Oguz A, Uzunlulu M, Bahadir O. Effects of different statin

treatments on small dense low-density lipoprotein in patients with metabolic
syndrome. J Atheroscler Thromb 2009; 16:684690.
This study was valuable in demonstrating that the effect on LDL particle size is not
dependent on which statin is used, and can be considered a class effect.
59 Jialal I, Abby SL, Misir S, Nagendran S. Concomitant reduction in low-density

lipoprotein cholesterol and glycated hemoglobin with colesevelam hydrochloride in patients with type 2 diabetes: a pooled analysis. Metab Syndr
Relat Disord 2009; 7:255258.
Colesevelam is a relatively new antidiabetic medication that has been found to
have a significant anti-inflammatory profile. This study combines three trials to
demonstrate the robust benefits of colesevelam.
60 Akdim F, Stroes ES, Sijbrands EJ, et al. Efficacy and safety of mipomersen, an

antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects
receiving stable statin therapy. J Am Coll Cardiol 2010; 55:16111618.
This study is important, as mipomersen is a relatively new class of medication that
has shown great potential for use as an adjunct to present antilipid treatment.
61 Rosenson R. Effect of fenofibrate on adiponectin and inflammatory biomarkers in metabolic syndrome patients. Obesity 2008; 17:504509.
62 Belfort R, Berria R, Cornell J, Cusi K. Fenofibrate reduces systemic inflam
mation markers independent of its effects on lipid and glucose metabolism in
patients with the metabolic syndrome. J Clin Endocrinol Metab 2010; 95:829
836.
This study evaluates a novel mechanism of action of fenofibrate, an anti-inflammatory effect, and is significant because it proves that fenofibrate does have a
therapeutic anti-inflammatory effect, independent of its antilipid profile.
49


511

Zhao X, Krasuski RA, Baer J, et al. Effects of combination lipid therapy on

coronary stenosis progression and clinical cardiovascular events in coronary
disease patients with metabolic syndrome: a combined analysis of the
Familial Atherosclerosis Treatment Study (FATS), the HDL-Atherosclerosis
Treatment Study (HATS), and the Armed Forces Regression Study
(AFREGS). Am J Cardiol 2009; 104:14571464.
This study is noteworthy as its analysis combines three smaller trials that used
combination antilipid therapy to treat hypercholesterolemia in metabolic syndrome
patients.

63


64

Blaha MJ, Blumenthal RS, Brinton EA, Jacobson TA. The importance of nonHDL cholesterol reporting in lipid management: National Lipid Association
Taskforce on Non-HDL Cholesterol. J Clin Lipidol 2008; 2:267273.

Rizzo M, Pernice V, Frasheri A, et al. Small, dense low-density lipoproteins

(LDL) are predictors of cardio- and cerebro-vascular events in subjects with
the metabolic syndrome. Clin Endocrinol 2009; 70:870875.
This is the first study that assessed the predictive role of sdLDL beyond traditional
cardiovascular risk factors in metabolic syndrome patients.

65


Ueba T, Nomura S, Nishikawa T, et al. Circulating oxidized LDL, measured

with FOH1a/DLH3 antibody, is associated with metabolic syndrome and the
coronary heart disease risk score in healthy Japanese. Atherosclerosis 2009;
203:243248.
In this study, a new monoclonal antibody to oxLDL was used to determine the
presence and concentration of oxLDL, which was found to be an independent
predictor of metabolic syndrome.

66


Satoh N, Shimatsu A, Kotani K, et al. Highly purified eicosapentaenoic acid

reduces cardio-ankle vascular index in association with decreased serum
amyloid A-LDL in metabolic syndrome. Hypertens Res 2009; 32:1004
1008.
This study is the first to attempt to delineate a mechanistic pathway by which
eicosapentaenoic acid is beneficial in the metabolic syndrome.

67


68

Kaushik SV, Plaisance EP, Kim T, et al. Extended release niacin decreases
serum fetuin-A concentrations in individuals with metabolic syndrome. Diabetes Metab Res Rev 2009; 25:427434.

Coyne T, Ibiebele TI, Baade PD, et al. Metabolic syndrome and serum
carotenoids: findings of a cross-sectional study in Queensland, Australia.
Br J Nutr 2009; 102:16681677.
This trial is a result of increasing evidence of the benefit of antioxidant dietary
supplementation in the metabolic syndrome. Carotenoids were shown to be
beneficial.

69


Sluijs I, Beulens JW, Grobbee DE, Van der Schouw YT. Dietary carotenoid
intake is associated with lower prevalence of metabolic syndrome in middleaged and elderly men. J Nutr 2009; 139:987992.
This study adds to the evidence supporting carotenoid intake, but investigates a
variety of different carotenoids to determine which subclass is most beneficial.

70


71

Steemburgo T, DallAlba V, Almeida JC, et al. Intake of soluble fibers has a

protective role for the presence of metabolic syndrome in patients with type 2
diabetes. Eur J Clin Nutr 2009; 63:127133.

Lopez-Alvarenga JC, Ebbesson SO, Ebbesson LO, et al. Polyunsaturated

fatty acids effect on serum triglycerides concentration in the presence of
metabolic syndrome components. The AlaskaSiberia Project. Metabolism
2010; 59:8692.
This study is unique because it investigates the benefit of polyunsaturated fatty
acids in the Eskimo population, and compares the traditional diet with the
Westernized diet.

72


73

Chen J, Gu D, Huang J, et al. Metabolic syndrome and salt sensitivity of blood

pressure in nondiabetic people in China: a dietary intervention study. Lancet
2009; 373:829835.

74

Van Dijk SJ, Feskens EJ, Bos MB, et al. A saturated fatty acid-rich diet
induces an obesity-linked proinflammatory gene expression profile in adipose
tissue of subjects at risk of metabolic syndrome. Am J Clin Nutr 2009;
90:16561664.

Nettleton JA, Lutsey PL, Wang Y, et al. Diet soda intake and risk of incident
metabolic syndrome and type 2 diabetes in the Multi-Ethnic Study of
Atherosclerosis (MESA). Diabetes Care 2009; 32:688694.
This is the first study to investigate the association of dietary soda intake with
the metabolic syndrome, its components, and diabetes mellitus in a large
cohort.

75


76

Azadbakht L, Esmaillzadeh A. Red meat intake is associated with metabolic

syndrome and the plasma C-reactive protein concentration in women. J Nutr
2009; 139:335339.

77

Radhika G, Dam RB, Sudha V, et al. Refined grain consumption and the
metabolic syndrome in urban Asian Indians (Chennai Urban Rural Epidemiology Study 57). Metabolism 2009; 58:675681.

78

Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride

and LDL cholesterol and HDL cholesterol concentrations on coronary heart
disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992; 85:3745.

512 Prevention
79

Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary prevention trial
with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment,
changes in risk factors, and incidence of coronary heart disease. N Engl J
Med 1987; 317:12371245.

80

Schlesinger Z, Vered Z, Friedenson A, et al. Secondary prevention by raising

HDL cholesterol and reducing triglycerides in patients with coronary artery
disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;
102:2127.

Hanefeld M, Karasik A, Koehler C, et al. Metabolic syndrome and its single

traits as risk factors for diabetes in people with impaired glucose tolerance:
the STOP NIDDM trial. Diabetes Vasc Dis Res 2009; 6:3237.
This secondary analysis of the STOP-NIDDM trial is significant as it evaluates the
progression of the metabolic syndrome, and its component parts, as longitudinal
predictors of diabetes mellitus.

81


Mukai N, Doi Y, Ninomiya T, et al. Impact of metabolic syndrome compared

with impaired fasting glucose on the development of type 2 diabetes in a
general Japanese population: the Hisayama study. Diabetes Care 2009;
32:22882293.
This study is important as it involves an Asian cohort to evaluate the progression of
the metabolic syndrome to diabetes mellitus longitudinally.

82


83

Perreault L, Kahn SE, Christophi CA, et al. Regression from pre-diabetes to

normal glucose regulation in the diabetes prevention program. Diabetes Care
2009; 32:15831588.

84

Goldberg RB, Temprosa M, Haffner S, et al. Effect of progression from

impaired glucose tolerance to diabetes on cardiovascular risk factors and its
amelioration by lifestyle and metformin intervention. The Diabetes Prevention
Program randomized trial by the Diabetes Prevention Program Research
Group. Diabetes Care 2009; 32:726732.

Al-Sarraj T, Saadi H, Calle MC, et al. Carbohydrate restriction, as a first-line

dietary intervention, effectively reduces biomarkers of metabolic syndrome in
Emirati adults. J Nutr 2009; 139:16671676.
This trial is informative about possible dietary interventions in the metabolic syndrome, proving that carbohydrate restriction is able to reduce inflammatory markers.

91


Lee L, Lee J, Bae WK, et al. Efficacy of low-calorie, partial meal replacement diet
plans on weight and abdominal fat in obese subjects with metabolic syndrome:
a double-blind, randomised controlled trial of two diet plans one high in
protein and one nutritionally balanced. Int J Clin Pract 2009; 63:195201.
This trial was unique because it compared two distinct dietary interventions, both
of which led to comparable weight loss and abdominal fat reduction.

92


Rumawas ME, Meigs JB, Dwyer JT, et al. Mediterranean-style dietary pattern,
reduced risk of metabolic syndrome traits, and incidence in the Framingham
Offspring Cohort. Am J Clin Nutr 2009; 90:16081614.
This study adds to burgeoning evidence that the Mediterranean diet is vital to the
treatment of the metabolic syndrome.

93


94

Aizawa K, Shoemaker JK, Overend TJ, Petrella RJ. Effects of lifestyle modification on central artery stiffness in metabolic syndrome subjects with prehypertension and/or prediabetes. Diab Res Clin Pract 2009; 83:249256.

95

De Lorgeril M, Salen P, Martin J, et al. Mediterranean diet, traditional risk factors,

and the rate of cardiovascular complications after myocardial infarction: final
report of the Lyon Diet Heart Study. Circulation 1999; 99:779785.

96

Cho ER, Shin A, Kim J, et al. Leisure-time physical activity is associated with a
reduced risk for metabolic syndrome. Ann Epidemiol 2009; 19:784792.

97

Mendez-Hernandez P, Flores Y, Siani C, et al. Physical activity and risk of

metabolic syndrome in an urban Mexican cohort. BMC Public Health 2009;
9:276.

98

Vaughan C, Schoo A, Janus ED, et al. The association of levels of physical

activity with metabolic syndrome in rural Australian adults. BMC Public
Health 2009; 9:273.

Halvorsen B, Heggen E, Ueland T, et al. Treatment with the PPAR-gamma

agonist rosiglitazone downregulates interleukin-1 receptor antagonist in
individuals with metabolic syndrome. Eur J Endocrinol 2010; 162:267
273.
This study is significant because it proves that the thiazolidinediones do not only
prevent progression from impaired glucose tolerance to diabetes mellitus but also
have some pleiotropic effects on inflammation.

99


Bhushan R, Elkind-Hirsch KE, Bhushan M, et al. Improved glycemic control

and reduction of cardiometabolic risk factors in subjects with type 2 diabetes
and metabolic syndrome treated with exanetide in a clinical practice setting.
Diab Technol Ther 2009; 11:353359.
This study adds to the list of antidiabetic drug classes that have been shown to be
beneficial in preventing the progression from impaired glucose tolerance to
diabetes mellitus.

100 Trseid M, Lappegard KT, Mollnes TE, et al. The effect of exercise on serum

levels of interleukin-18 and components of the metabolic syndrome. Metab
Syndr Relat Disord 2009; 7:579584.
This study elaborates on the protective effect of exercise in the metabolic
syndrome by virtue of its effect on subclinical inflammation.

85


86


87

Chiasson JL, Josse RG, Gomis R, et al., for the STOP-NIDDM Trial Research
Group. Acarbose for prevention of type 2 diabetes mellitus: the STOPNIDDM randomised trial. Lancet 2002; 359:20722077.

Kawamori R, Tajima N, Iwamoto Y, et al., for the Voglibose Ph-3 Study Group.
Voglibose for prevention of type 2 diabetes mellitus: a randomised, doubleblind trial in Japanese individuals with impaired glucose tolerance. Lancet
2009; 373:16071614.
Voglibose is a newer alpha-glucosidase inhibitor with a similar spectrum of
coverage to acarbose, including its ability to prevent or slow the progression
from impaired glucose tolerance to diabetes mellitus.

88


Nigam A, Frasure-Smith N, Lesperance F, Julien P. Relationship between n-3

and n-6 plasma fatty acids and insulin resistance in coronary patients with
and without metabolic syndrome. Nutr Metab Cardiovasc Dis 2009;
19:264270.
n-3 fatty acids have been shown in this study to have a protective role against
insulin resistance, whereas n-6 fatty acids have not.

89


90

Leite ML, Nicolosi A. Dietary patterns and metabolic syndrome factors in a

nondiabetic Italian population. Public Health Nutr 2009; 12:14941503.

Wijndaele K, Duvigneaud N, Matton L, et al. Sedentary behaviour, physical

activity and a continuous metabolic syndrome risk score in adults. Eur J Clin
Nutr 2009; 63:421429.
Most studies examining the effect of exercise on the metabolic syndrome determine the risk based on the extent of physical activity, whereas this trial aims to
compute the level of sedentary activity.

101 Yu Z, Ye X, Wang J, et al. Associations of physical activity with inflammatory


factors, adipocytokines, and metabolic syndrome in middle-aged and older
Chinese people. Circulation 2009; 119:29692977.
This trial adds to the evidence supporting exercise as a definite treatment option of
patients with the metabolic syndrome, presumably because reductions in abdominal fat lead to decreased production of adipocytokines and less inflammation.
102 Cicero AF, Derosa G, Bove M, et al. Effect of a sequential training programme
on inflammatory, prothrombotic and vascular remodelling biomarkers in
hypertensive overweight patients with or without metabolic syndrome. Eur
J Cardiovasc Prev Rehabil 2009; 16:698704.
103 Metzger JS, Catellier DJ, Evenson KR, et al. Associations between patterns of
objectively measured physical activity and risk factors for the metabolic
syndrome. Am J Health Promot 2010; 24:161169.
104 Tjnna AE, Lee SJ, Rognmo O, et al. Aerobic interval training versus
continuous moderate exercise as a treatment for the metabolic syndrome.
A pilot study. Circulation 2008; 118:346354.
105 He Y, Lam TH, Jiang B, et al. Combined effects of tobacco smoke exposure
and metabolic syndrome on cardiovascular risk in older residents of China.
J Am Coll Cardiol 2009; 53:363371.