TR E N D S I N C A R D I O V A S C U L A R M E D I C I N E 26 (2016) 364–373

Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

Metabolic syndrome update

Scott M. Grundy, MD, PhDa,b,n
a
Department of Internal Medicine and Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX
b
Veterans Affairs Medical Center, Dallas, TX

abstract

The metabolic syndrome is a multiplex risk factor for atherosclerotic cardiovascular disease and type 2 diabetes. It is composed
of atherogenic dyslipidemia, elevated blood pressure, insulin resistance and elevated glucose, a pro-thrombotic state, and a
pro-inflammatory state. Excess energy intake and concomitant obesity are the major drivers of the syndrome. Lifestyle
intervention can reverse metabolic risk factors, but at times, drug therapies or bariatric surgery may be required to control more overt
risk factors.

Key words: Metabolic syndrome, Diabetes, Dyslipidemia, Hypertension, Nutrition, Obesity.

Published by Elsevier Inc.

The metabolic syndrome is a multiplex risk factor for athero-
sclerotic cardiovascular disease (ASCVD) and type 2 diabetes
[1]. It doubles risk for ASCVD and, in patients without
diabetes, increases risk for type 2 diabetes fivefold [2]. The
metabolic syndrome occurs commonly throughout the world,
ranging in prevalence from 10% to 40% [3]. The syndrome
occurs most often in populations characterized by excessive
nutrient intake and physical inactivity [4], but underlying
metabolic and genetic susceptibilities are critical factors
as well.
Definition of metabolic syndrome
The metabolic syndrome consists of five factors for ASCVD:
atherogenic dyslipidemia, elevated blood pressure, dysglyce-
mia, a pro-thrombotic state, and a pro-inflammatory state [5]
(Fig. 1). They occur most commonly in obese persons.
Atherogenic dyslipidemia comprises elevations in plasma
triglycerides and apolipoprotein B (apo B), and reductions in
high-density lipoproteins (HDL). Elevated blood pressure
includes both overt and borderline hypertension. Dysglyce-
mia consists of either prediabetes or diabetes. Abnormalities
in coagulation factors and blood platelets make up a pro-
thrombotic state. A pro-inflammatory state results from
inflammatory mediators acting on a variety of tissues. The
contribution of each of these components to cardiovascular
risk undoubtedly varies among individuals but, in combina-
tion, they double the risk for ASCVD.
Several attempts have been made to craft a clinical defi-
nition of the syndrome. The most commonly accepted is a
recent consensus definition [4] (Table). It includes abdominal
obesity as a key (but not necessary) component, elevations in
serum triglyceride and glucose, increased blood pressure, and
reduced levels of HDL cholesterol (HDL-C). The presence of
three or more of these constitutes a clinical diagnosis.
Pathogenesis
An early hypothesis was that insulin resistance is the cause
of metabolic syndrome [6,7]. Without question, insulin

This work was financially supported by the Center for Human Nutrition, UT Southwestern Medical Center, United States.
The author has indicated that there are no conflicts of interest.
n
Correspondence to: Department of Internal Medicine and Center for Human Nutrition, UT Southwestern Medical Center, 5323 Harry
Hines Bvd., Dallas, TX 75390-9052. Tel.: þ1 214 648 2890; fax: þ1 214 648 4837.
E-mail address: scott.grundy@utsouthwestern.edu (S.M. Grundy).

http://dx.doi.org/10.1016/j.tcm.2015.10.004
1050-1738/Published by Elsevier Inc.
 T R E N D S I N C A R D I O V A S C U L A R ME
Fig. 1 – Relationships between energy excess/obesity and
risk factors of the metabolic syndrome. Available evidence
indicates that excess energy intake and concomitant obesity
are major causes of all the metabolic risk factors.
resistance contributes to hyperglycemia. Its role in causing
other metabolic risk factors is uncertain.
Another view sees obesity (or energy imbalance) as the
main cause. Since obesity strongly associates with all meta-
bolic risk factors, its role is plausible. A related view contends
that positive caloric balance underlies the metabolic syn-
drome (Fig. 1). Obesity is a useful clinical indicator of a state
of overnutrition but this does not necessarily mean that an
excess of adipose tissue is the true cause. For example, caloric
restriction, even in the presence of continuing obesity,
reverses most metabolic risk factors [8]. This suggests that a
positive energy imbalance (overnutrition) takes precedence
over excess adipose tissue as the primary cause of the
syndrome [9].
Components of metabolic syndrome
Upper-body obesity
Most persons with the metabolic syndrome are categorically
obese (BMI Z 30 kg/m2) [10]. Among them, individuals with
Table – Criteria for clinical diagnosis of the metabolic syndrome.
Measure
Elevated waist circumferencea
Elevated triglycerides (drug treatment for elevated triglycerides is an alternate indicatorb)
Reduced HDL-C (drug treatment for reduced HDL-C is an alternate indicatorb)
Elevated blood pressure (anti-hypertensive drug treatment in a patient with a history of hypertension
is an alternate indicator)
Elevated fasting glucosec (drug treatment of elevated glucose is an alternate indicator)
HDL-C indicates high-density lipoprotein cholesterol.
a
Waist circumference cut points used in the USA. Cut points for other populations are listed in the parent document [4].
b
The most commonly used drugs for elevated triglycerides and reduced HDL-C are fibrates and nicotinic acid. A patient taking one of these
drugs can be presumed to have high triglycerides and low HDL-C. High-dose n-3 fatty acids presume high triglycerides.
c
Most patients with type 2 diabetes mellitus will have the metabolic syndrome by the current criteria [4].
D I C I N E 26 (2016) 364–373 365
predominant upper-body obesity are most prone to metabolic
syndrome. Fat in the upper body can be either intraperitoneal
(visceral) or subcutaneous. Excess visceral fat associates
strongly with the metabolic syndrome [11,12]. But in addition,
excessive amounts of upper-body subcutaneous fat are
accompanied by greater risk for metabolic syndrome [13–16].
In persons with upper-body obesity, the amount of subcuta-
neous fat typically exceeds that of visceral fat by twofold or
threefold [17].
It is commonly believed that obesity supplies excess fat to
various organs or tissues, especially muscle and liver. Fat
overload in tissues is referred to as ectopic fat [18]. A
mediator between adipose-tissue fat and ectopic fat appears
to be a high plasma level of non-esterified fatty acids (NEFA)
[19]. Ectopic fat in muscle associates strongly with insulin
resistance [18]. In the liver, excess fatty acids can be burned
completely or partially degraded to ketone bodies. The
remaining fatty acids are re-esterified into triglycerides,
which are incorporated into very-low-density lipoproteins
(VLDL); the latter are secreted into the circulation.
In another form of obesity, adipose tissue locates predom-
inately in the lower body. This is called lower-body obesity or
gluteofemoral obesity. This pattern is more common in
women, but can be found in men. It accompanies a lower
prevalence of metabolic syndrome than occurs with upper-
body obesity [16]. A reason for this difference may be that
individuals with lower-body obesity have a lower rate of
release of NEFA into the circulation. Some articles suggest
that lower-body adipose tissue actually protects against
metabolic syndrome [16,20]; if so, the mechanism is not
entirely clear.
It is widely believed that the excess body weight in obese
persons consists largely of adipose-tissue triglyceride; how-
ever, in fact, excess weight divides almost equally between
fat mass and lean body mass [21]. The burning of a portion of
excess energy by lean mass may protect against the adverse
effects of overnutrition. In some individuals, overnutrition is
well tolerated without development of risk factors, whereas
in others, metabolic risk factors appear [22].
Recent studies reveal that adipose tissue contributes a
host of bio-active peptides (adipokines) that may influence
Categorical cut points
Z102 cm in males
Z88 cm in females
Z150 mg/dL (1.7 mmol/L)
o40 mg/dL (1.0 mmol/L) in males
o50 mg/dL (1.3 mmol/L) in
females
Systolic Z130 and/or diastolic
Z85 mmHg
Z100 mg/dL
366 T R E N D S I N C A R D I O V A S C U L A R
metabolic risk factors [23]. Among these are adiponectin,
interleukin-6, tumor necrosis factor-alpha (TNF-alpha), resis-
tin, leptin, angiotensinogen, and plasminogen activator
inhibitor-1 (PAI-1) [24]. Adiponectin is an adipocyte-secre-
tory protein; plasma levels are decreased in obese and
diabetic states. Its levels are inversely associated with insulin
resistance, and it is postulated to have anti-atherogenic
properties. Interleukin-6 and TNF-alpha are pro-inflamm-
atory cytokines that may contribute both to insulin resistance
and systemic inflammation. Resistin is a putative inflamma-
tory biomarker and potential mediator of obesity-associated
metabolic diseases. Leptin is known to be an appetite-
suppressing hormone, but a considerable body of data sug-
gests that leptin also has systemic metabolic actions.
Adipose-tissue secretion of angiotensinogen may contribute
to a systemic hypertension. Finally, secretion of PAI-1 may
promote a pro-thrombotic state. Thus available literature
suggests that these products can influence the development
of metabolic risk factors [24]. Such actions are plausible but
remain to be confirmed with certainty.
Obesity results from a greater nutrient intake than required
for normal metabolism. Certainly, most obese, sedentary
individuals consume more nutrient energy than do non-
obese persons [25]. Of course, energy expenditure through
exercise must be taken into account when defining over-
nutrition. In a word, overnutrition, in metabolic terms,
represents a state of energy imbalance leading to ectopic fat
accumulation. A reasonable hypothesis is that detrimental
consequences associated with obesity result directly or indi-
rectly from the metabolic stress of overnutrition. Support for
this concept comes from the rapid reduction of metabolic risk
factors that occurs when caloric intake is curtailed [26,27].
These risk factors usually disappear even in the presence of
persistent obesity.
Atherogenic dyslipidemia
Most persons with metabolic syndrome exhibit atherogenic
dyslipidemia [28]. The major component of atherogenic
dyslipidemia is elevation of apo B-containing lipoproteins.
These include low-density lipoprotein (LDL) and VLDL. Other
components include elevated triglycerides and reduced high-
density lipoprotein cholesterol (HDL-C).
High levels of apo B-containing lipoproteins are considered
by many to be the primary cause of ASCVD [5]. Their
postulated role is shown in Fig. 2. Without some elevation
of these lipoproteins, atherosclerosis rarely develops, even in
the presence of other risk factors [29]. Circulating lipoproteins
filter into the arterial wall, where they are trapped, modified
in various ways, and incorporated into macrophages to form
lipid-laden foam cells [30]. These cells dominate in the first
stage of atherosclerosis—the fatty streak. As foam cells
degrade they stimulate a connective tissue reaction, resulting
in a fibrous plaque. This plaque usually covers a cholesterol-
rich core. In regions where the fibrous covering of this core is
thin and enriched with macrophages, the plaque becomes
unstable: rupture can occur, precipitating a thrombosis [31].
Other risk factors of the metabolic syndrome accelerate this
process. When plaque rupture occurs, the patient frequently
ME D I C I N E 26 (2016) 364–373
Fig. 2 – Role of cardiovascular risk factors in development of
atherosclerosis and its complications. Atherogenic
lipoproteins initiate atherosclerosis and play an important
role at each stage of its development. Intervention to reduce
these lipoproteins will decrease the risk for atherosclerotic
disease at any stage of development. Other risk factors
accelerate atherosclerosis at various stages of
atherogenesis.
suffers an acute cardiovascular event, e.g., myocardial infarc-
tion or stroke.
Many clinical trials conclusively prove that intensive low-
ering of apo B-containing lipoproteins reduces the risk for
major cardiovascular events [32]. In particular, several RCTs
show that statins reduce risk for ASCVD in patients with
metabolic syndrome [33–35].
The apo B-containing lipoproteins are clinically identified
by their cholesterol (C) content, i.e., LDL-C and VLDL-C. The
sum of these two lipoprotein factions is called non-HDL-C.
Both lipoproteins have similar atherogenic potential; hence,
non-HDL-C is more predictive than LDL-C alone [36–38].
Of course, VLDL is also rich in triglycerides; when this
fraction is elevated, a patient is said to have hypertriglycer-
idemia. Elevations in VLDL-triglycerides are common in those
with the metabolic syndrome (Table). Moreover, both total
apo B and non-HDL-C are characteristically increased in
patients with metabolic syndrome [39–41]. Because of a high
correlation between total apo B and non-HDL-C, the latter can
be used as a surrogate for the former.
Another component of atherogenic dyslipidemia is a low
level of HDL-C. In epidemiologic studies, this abnormality
associates strongly with a higher risk for ASCVD [42]. To date,
RCTs with HDL-raising therapies have not documented risk
reduction for ASCVD but at the very least, a low HDL-C is a
marker for increased risk. Whether it is a causative factor
remains to be proven through clinical trials.
Elevated blood pressure
A second component of the metabolic syndrome is an
elevation in blood pressure [4,5] (Table). Several mechanisms
have been proposed to explain the relationship between
elevated blood pressure and obesity (and caloric excess).
Among these are enhanced renal reabsorption of sodium
(possibly resulting from insulin resistance), expansion of
 T R E N D S I N C A R D I O V A S C U L A R
intravascular volume, activations of the reninangiotensin
aldosterone system and sympathetic nervous system, release
of angiotensinogen from adipose tissue, and insulin resist-
ance [43,44]. The current consensus is that these factors act in
conjunction to raise the blood pressure.
Metabolic syndrome and stroke
The metabolic syndrome doubles risk for stroke [45,46].
Metabolic syndrome associates with both carotid atheroscle-
rosis [47,48] and intracranial arteriosclerosis [49,50]. Presum-
ably the mechanisms for cerebral vascular disease are similar
to those for CHD.
Hyperglycemia
Prediabetes and diabetes
Most persons with the metabolic syndrome have some
elevation of plasma glucose [51]. This elevation can be in
the range of either prediabetes or diabetes. Two patterns of
higher glucose define prediabetes: a fasting glucose in the
range of 100125 mg/dL or a 2-h postprandial level of 140–
199 mg/dL. Categorical diabetes is defined as a fasting glucose
Z126 mg/dL or a postprandial level Z200 mg/dL. The primary
cause of hyperglycemia in patients with metabolic syndrome
is insulin resistance. However, otherwise normal persons
who are insulin resistant can avoid an elevated glucose by
compensatory hyperinsulinemia. Only when pancreatic beta-
cell function begins to decline do glucose levels start to rise.
Thus, hyperglycemia typically is not the first indication of
metabolic syndrome, but develops as a later sequelae. In the
consensus definition for metabolic syndrome (Table), both
prediabetes and diabetes count as metabolic risk factors.
Microvascular disease
The primary clinical outcome of hyperglycemia is micro-
vascular disease, i.e., chronic kidney disease and diabetic
retinopathy. In fact, type 2 diabetes is the foremost cause of
chronic kidney disease. However, patients with diabetes
commonly have hypertension as well, which may accelerate
the decline in kidney function. Microvascular disease may
have widespread consequences beyond its effects on kidneys
and eyes. It is likely that diabetic neuropathy is due in part to
microvascular disease [52]. Microvascular disease may fur-
ther accelerate development of congestive heart failure [53]
and contribute to atherogenesis [54].
Macrovascular disease
The contribution of hyperglycemia to atherogenesis is uncer-
tain. Certainly patients with diabetes are at increased risk for
ASCVD. Whether this excess risk can be explained by a direct
effect of hyperglycemia or concomitant metabolic risk factors
remains to be determined.
Pro-inflammatory state
A link between inflammation and metabolic diseases has
been increasingly recognized. Obesity may underlie a low-
grade, systemic inflammation [55,56]. Macrophages invade
excess adipose tissue, resulting in the release of cytokines.
They may trigger systemic inflammation [57]. Associated
ME D I C I N E 26 (2016) 364–373 367
with obesity is an increase in acute-phase reactants, such
as C-reactive protein [58]. Although an excess of adipose
tissue per se may be responsible for low-grade inflammation,
overnutrition independent of obesity may also engender
inflammatory responses [59,60]. Cytokines released from
adipose tissue may induce insulin resistance in skeletal
muscle [61], alter the pituitaryadrenal axis [62], and may
accelerate loss of pancreatic beta cells [63]. Finally, low-grade
inflammation within atherosclerotic lesions may increase the
likelihood of plaque rupture, causing acute cardiovascular
events [64].
Pro-thrombotic state
Individuals with obesity and metabolic syndrome appear to
have multiple abnormalities in the hemostatic system that
may well predispose to ASCVD. Among these are endothelial
dysfunction, enhanced coagulation, impaired fibrinolysis, and
platelet dysfunction [65,66]. Specific abnormalities include ele-
vated levels of inhibitor of plasminogen activator type 1 [66,67],
tissue factor [68,69], fibrinogen [67], and factor VIII activity [70].
Persons with metabolic syndrome have increased baseline
platelet reactivity and a lower antiplatelet response to aspirin
[71]. Finally, it seems likely that patients with this syndrome are
at higher risk for venous thrombosis.
Management of metabolic syndrome
Lifestyle intervention
Most persons with metabolic syndrome are obese and sed-
entary. Urbanization and access to inexpensive foods are
creating a metabolic syndrome pandemic [3]. Thus, primary
intervention should be lifestyle change, i.e., caloric restric-
tion, improved health quality of foods, and increased physical
activity.
Caloric restriction
The most efficacious intervention is caloric restriction [9].
This can be achieved in several ways. Previously, very-low-
calorie diets (e.g., approximately 1000 cal per day) were tried.
This approach was largely unsuccessful. Very rapid weight
loss is invariably followed by weight regain. The reason is a
lack of behavioral change. A better way is behavioral mod-
ification combined with a low-calorie diet [5]. A team
approach is more effective, especially including a medical
nutrition therapist [72]. Of course, behavioral modification
requires a lifetime commitment to dietary modification. For
many patients, this is a major challenge. Consequently, many
social and environmental changes are necessary for success-
ful weight loss. A reasonable first goal for the obese patient is
to reduce weight by approximately 10%. Further gradual
weight loss provides more benefit.
The composition of food intake must also be considered. A
low-fat/high-carbohydrate diet has been commonly recom-
mended, but a somewhat higher intake of unsaturated fat at
the expense of carbohydrate may be more beneficial [73–75].
Too much carbohydrate in the diet can worsen metabolic risk
factors [76,77]. Most importantly, saturated fats should be
368 T R E N D S I N C A R D I O V A S C U L A R
largely avoided; they will increase serum cholesterol levels
and consequently will raise risk for ASCVD.
If greater caloric restriction is needed, bariatric surgery can
be considered. Obese patients with multiple risk factors (e.g.,
metabolic syndrome) are potential candidates for bariatric sur-
gery, especially if their body mass index is greater than 35 kg/m2
[78]. Weight losses of 20% or more can be achieved. These losses
have a favorable impact on all metabolic risk factors [26]. Of
course, clinical judgment is required to decide whether bariatric
surgery is appropriate for particular individuals.
Regular physical activity
Physical activity has several beneficial effects on metabolic
syndrome [79]. It favorably affects caloric balance; it reduces
insulin resistance; and it increases physical fitness, which
appears to independently reduce risk for cardiovascular
disease [80,81]. Thus the introduction of a program of regular
physical activity should be considered an integral part of
clinical management of metabolic syndrome.
Treatment of atherogenic dyslipidemia
Apo B-containing lipoproteins (both LDL and VLDL) are the
primary target of dyslipidemia therapy. An acceptable meas-
ure of these lipoproteins is non-HDL-C [82,83]. Available
ASCVD-outcome trials support the concept of “the lower,
the better” for reduction of atherogenic lipoproteins [84], but
for practical consideration, the following “goals” have been
proposed for non-HDL-C [85]. In secondary prevention, it is
reasonable to reduce non-HDL-C to o100 mg/dL; in primary
prevention, a reasonable goal is o130 mg/dL [85]. They
correspond to LDL-C reductions of o70 mg/dL and
o 100 mg/dL, respectively. Ample clinical trial evidence exists
in patients with metabolic syndrome to justify these target
values [33–35]. Finally, in particularly high-risk patients with-
out ASCVD, reducing non-HDL-C to less than 100 mg/dL may
be prudent.
First-line treatment for non-HDL-C in metabolic syndrome
is statin therapy. Persons with this syndrome have a high-
lifetime-risk trajectory for ASCVD. For secondary prevention,
a non-HDL-C of o70 mg/dL is best achieved with high-
intensity statins (e.g., atorvastatin 80 mg or rosuvastatin
20–40 mg). However, some patients may not be able to
tolerate high-intensity statins. If not, it is reasonable to add
ezetimibe to moderate-intensity statin (e.g., atorvastatin
10 mg, rosuvastatin 5 mg, simvastatin 20 mg, or another
similar potency statin). These combinations produce the
same non-HDL-C lowering as do maximum-intensity statins.
A recent secondary-prevention trial showed added risk
reduction when ezetimibe was combined with a high-
intensity statin [86]. This trial supports the “the lower, the
better” concept for atherogenic lipoproteins [84]. A new
approach to reducing atherogenic lipoproteins is to use a
monogenic antibody against PCSK9; the latter is a protein
that facilitates the degradation of LDL receptors. Use of PCSK9
inhibitors induces a marked reduction in non-HDL-C. Pre-
liminary evidence strongly suggests that they also reduce risk
for ASCVD [87,88]. Therefore, new alternatives are needed for
patients who are intolerant to statins or who are at very
high risk.
ME D I C I N E 26 (2016) 364–373
Since the majority of persons with metabolic syndrome
have elevated plasma triglycerides, a persistent question has
been whether triglyceride-lowering drugs might be beneficial
in this condition. Two such drugs have been employed: niacin
and fibrates. In a large multicenter trial of secondary pre-
vention, niacin therapy decreased the occurrence of 6-year MI
and 15-year total mortality similarly among patients with or
without the metabolic syndrome [89]. Multiple RCTs, which
were enriched in patients with metabolic syndrome, show
benefit from fibrate monotherapy in both primary and sec-
ondary prevention [90–93]. Risk reductions, however, usually
are less than seen with statin therapy. Whether adding
triglyceride-lowering drugs to statins provides incremental
benefit is uncertain. In two studies [94,95], addition of niacin
to maximal dose statins failed to show further risk reduction.
In another RCT in patients with diabetes, adding fenofibrate
to statin therapy found no benefit [96]; but in a subgroup with
hypertriglyceridemia, a nearly significant decrease in risk (p ¼
0.06) was noted [97]. Thus, at present it is reasonable to add
fenofibrate to statin therapy in high-risk patients with meta-
bolic syndrome; nonetheless, RCT evidence of benefit is
limited. Finally, in patients with type 2 diabetes, fenofibrate
appears to have a favorable effect on microvascular disease
[98,99]; the mechanism for this benefit is not known. The
same drugs that lower triglyceride also raise HDL-C. The
evidence of benefit from niacin and fibrates has been attrib-
uted by some to raising HDL, but by others to lowering VLDL.
RCTs are currently underway to test other HDL-raising drugs
[100]; however, to date, the results of these trials have not
been reported. Regardless, a low HDL-C is a common finding
in patients with metabolic syndrome and their levels can be
raised through lifestyle intervention. We must keep in mind
that one of the benefits of maximum lifestyle intervention
could result from an increase in HDL-C.
Control of blood pressure
The key therapy for hypertension in patients with metabolic
syndrome is caloric restriction. It has long been known that
reducing caloric intake will decrease blood pressure [101,102].
Bariatric surgery is a particularly effective means of reducing
blood pressure [103–105]. In addition to caloric restriction,
modifying diet composition can facilitate blood pressure
lowering. The so-called DASH diet was constructed for hyper-
tensive patients [106]; this diet contains a favorable electro-
lyte intake, caloric restriction, and reduction in saturated fat.
A recent modification of the DASH diet, resembling the
Mediterranean diet, may be a more acceptable eating pattern
for the United States [107]. This diet allows more total fat
intake, provided the fat is unsaturated.
A persistent question is whether certain anti-hypertensive
drugs are preferable for patients with obesity or metabolic
syndrome. For example, some investigators [108,109] believe
that ACE inhibitors or ARBs should be first-line therapy.
These agents do not induce insulin resistance or other
metabolic risk factors. In contrast, beta-1 receptor blockers
(e.g., atenolol and metoprolol) enhance insulin resistance and
potentially worsen the metabolic syndrome [110]. Conversely,
non-selective beta/alpha-1 receptor blockers (e.g., carvediol)
do not have these adverse metabolic effects, and when
 T R E N D S I N C A R D I O V A S C U L A R
indicated, appear to be preferable for patients with metabolic
syndrome [111]. In addition, thiazide diuretics are known to
enhance insulin resistance [112]. Overall, both beta-blockers
and thiazides reduce ASCVD, so clinical judgment is needed
whether to use one or both of these agents in patients with
the metabolic syndrome. Finally, calcium channel blockers
appear to be metabolically neutral, or cause a slight improve-
ment of insulin resistance, and thus are acceptable drugs for
those with metabolic syndrome [113,114].
An anti-hypertensive agent of biological interest is telmi-
sartin, an angiotensin II receptor antagonist. This agent also
acts as a selective modulator of peroxisome proliferator-
activated receptor gamma (PPAR-γ), a regulator of insulin
and glucose metabolism [115]. Because of the latter action,
this agent might be useful in treatment of the metabolic
syndrome [116]. On the other hand, to date, telmisartin has
failed to show unique cardioprotection [117].
Management of hyperglycemia
Patients with metabolic syndrome commonly have predia-
betes, which consists of impaired fasting glucose, glucose
intolerance, or hemoglobin A1C 5.7–6.4%. An important goal
in these patients is to prevent the conversion to diabetes.
There is a general consensus that the first goals of treatment
are weight loss of 10% of body weight and increasing physical
activity to at least 150 min/week of moderate activity [118].
Lifestyle modification of this type will cut the rate of con-
version of prediabetes to diabetes in half [119]. Metformin
therapy likewise will slow conversion of prediabetes to
diabetes, but it is less effective than lifestyle therapy [119].
Although metformin has been advocated for prediabetes,
generally its use is restricted to higher-risk patients. For
example, consideration can be given to use of metformin in
very obese persons who are o60 years [119].
For those patients with categorical hyperglycemia (type 2
diabetes), an effort must be made to keep the hemoglobin A1c
level in a relatively low range (e.g., o7%). There is a concern,
however, that overtreatment of hyperglycemia can induce
hypoglycemia. The latter is potentially life threatening and
must be avoided [120]. Clinical trials show that reduction of
hyperglycemia will reduce the risk for microvascular disease
in patients with diabetes [121]. Whether improved glucose
control in type 2 diabetes will reduce macrovascular disease
is probable but less certain than for microvascular disease [121].
A host of hypoglycemic agents are currently available. The
American Diabetes Association and European Association for
Study of Diabetes have made reasonable suggestions for their
use in patients with type 2 diabetes [122]. An alternative to drug
therapy of hyperglycemia is bariatric surgery [123]. It is highly
effective in controlling hyperglycemia.
Possible interventions on the pro-thrombotic state
Patients with the metabolic syndrome exhibit many of the
features of a pro-inflammatory state. Ridker and Lüscher [124]
have recently identified a host of potential targets for
anti-inflammatory therapies. Included in this list are interleu-
kin-1-beta, interleukin-18, interleukin-6, tumor necrosis fac-
tor-alpha, matrix metalloproteinase-9, lipoprotein-associated
ME D I C I N E 26 (2016) 364–373 369
phospholipase A2, secretory phospholipase A2, intercellular
adhesion molecule type 1, vascular cellular adhesion mole-
cule, plasminogen activator inhibitor type 1, serum amyloid A,
C-reactive protein, 5-lipoxygenase, sirtuin-1, and chemokine
receptor types 2 and 5. These investigators further speculated
on potential agents that could impair inflammation acting on
one or more of these targets. Examples include low-dose
methotrexate, various monoclonal antibodies, inhibitors of
adhesion molecules, and colchicine. A limited number of RCTs
are either underway or being considered [125–127]. Although it
is too early to know whether these approaches will reduce risk
for ASCVD, they have a theoretical basis for risk reduction in
patients with metabolic syndrome.
Reduction of pro-thrombotic state
Caloric restriction and weight loss are accompanied by
reduction in coagulation activation factors [128]. At present
there are no specific drug therapies for a pro-thrombotic state
in patients with the metabolic syndrome other than aspirin.
Aspirin can be recommended for patients with metabolic
syndrome who have ASCVD. The best recommendation for
use of aspirin therapy in primary prevention is to follow
current guidelines, which attempt to balance risk versus
benefit [129–131]. Generally, these guidelines favor use of
aspirin for patients whose estimated 10-year risk for ASCVD
is 410% provided there are no contraindications.
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