A Comprehensive Review On Metabolic Syndrome

3/3/2020 A Comprehensive Review on Metabolic Syndrome
Cardiol Res Pract. 2014; 2014: 943162. PMCID: PMC3966331

Published online 2014 Mar 11. doi: 10.1155/2014/943162 PMID: 24711954
This article has been retracted.

Retraction in: Cardiol Res Pract. 2019; 2019: 4301528 See also: PMC Retraction Policy
A Comprehensive Review on Metabolic Syndrome

Jaspinder Kaur*
Ex-Servicemen Contributory Health Scheme (ECHS) Polyclinic, Sultanpur Lodhi, Kapurthala District 144626,
India
*Jaspinder Kaur: mailtojaspinder@yahoo.in
Academic Editor: Paul Holvoet
Received 2013 Nov 20; Accepted 2014 Jan 19.
Copyright © 2014 Jaspinder Kaur.
This is an open access article distributed under the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical,
clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes
mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia,
endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and
chronic stress are the several factors which constitute the syndrome. Chronic inflammation is known to
be associated with visceral obesity and insulin resistance which is characterized by production of
abnormal adipocytokines such as tumor necrosis factor α, interleukin-1 (IL-1), IL-6, leptin, and
adiponectin. The interaction between components of the clinical phenotype of the syndrome with its
biological phenotype (insulin resistance, dyslipidemia, etc.) contributes to the development of a
proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and
results in atherosclerotic processes. Lifestyle modification remains the initial intervention of choice for
such population. Modern lifestyle modification therapy combines specific recommendations on diet
and exercise with behavioural strategies. Pharmacological treatment should be considered for those
whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of
literature related to the syndrome's definition, epidemiology, underlying pathogenesis, and treatment
approaches of each of the risk factors comprising metabolic syndrome.
1. Introduction
The metabolic syndrome (MetS) is a major and escalating public-health and clinical challenge
worldwide in the wake of urbanization, surplus energy intake, increasing obesity, and sedentary life
habits. MetS confers a 5-fold increase in the risk of type 2 diabetes mellitus (T2DM) and 2-fold the risk
of developing cardiovascular disease (CVD) over the next 5 to 10 years [1]. Further, patients with the
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MetS are at 2- to 4-fold increased risk of stroke, a 3- to 4-fold increased risk of myocardial infarction
(MI), and 2-fold the risk of dying from such an event compared with those without the syndrome [2]
regardless of a previous history of cardiovascular events [3]. A version of MetS has a WHO
International Classification of Disease (ICD-9) code (277.7) which permits healthcare reimbursement.
This shows that the term “metabolic syndrome” is institutionalized and a part of the medical
vocabulary. MetS is considered as a first order risk factor for atherothrombotic complications. Its
presence or absence should therefore be considered an indicator of long-term risk. On the other hand,
the short-term (5–10 years) risk is better calculated using the classical algorithms (Framingham,
REGICOR {Registre GIroní del COR}), as they include age, sex, total cholesterol or LDL, and
smoking [4].
2. Background
MetS started as a concept rather than a diagnosis [11]. The metabolic syndrome has its origins in 1920
when Kylin, a Swedish physician, demonstrated the association of high blood pressure (hypertension),
high blood glucose (hyperglycemia), and gout [12]. Later in 1947, Vague described that the visceral
obesity was commonly associated with the metabolic abnormalities found in CVD and T2DM [13].
Following this, in 1965, an abstract was presented at the European Association for the Study of
Diabetes annual meeting by Avogaro and Crepaldi [14] which again described a syndrome which
comprised hypertension, hyperglycemia, and obesity. The field moved forward significantly following
the 1988 Banting Lecture given by Reaven [15]. He described “a cluster of risk factors for diabetes and
cardiovascular disease” and named it “Syndrome X”. His main contribution was an introduction of the
concept of the insulin resistance. However, he surprisingly missed obesity or visceral obesity from the
definition which was later added as a crucial abnormality. In 1989, Kaplan [16] renamed the syndrome
“The Deadly Quartet” for the combination of upper body obesity, glucose intolerance,
hypertriglyceridemia, and hypertension and however, in 1992, it was again renamed “The Insulin
Resistance Syndrome” [17]. Several groups have attempted to develop diagnostic criteria for the
diagnosis of the MetS [18]. The first attempt was made by a World Health Organization (WHO)
diabetes group in 1998 to provide a definition of the MetS [5]. In response, the European Group for the
study of Insulin Resistance (EGIR) countered with a modification of the WHO definition in 1999 [6].
In 2001, the National Cholesterol Education Program Adult Treatment Panel (NCEP/ATP) released its
definition [7]. Subsequently, the American Association of Clinical Endocrinologists (AACE) in 2003
offered its views regarding the definition of the syndrome [8]. The proliferation of definitions
suggested that a single unifying definition was desirable [19]. In the hope of accomplishing this, the
International Diabetes Federation (IDF) proposed a new definition of the MetS in April 2005 [9].
3. Definition
MetS is defined by a constellation of an interconnected physiological, biochemical, clinical, and
metabolic factors that directly increases the risk of atherosclerotic cardiovascular disease (ASCVD),
(T2DM), and all cause mortality [20, 21]. This collection of unhealthy body measurements and
abnormal laboratory test results include atherogenic dyslipidemia, hypertension, glucose intolerance,
proinflammatory state, and a prothrombotic state. There have been several definitions of MetS, but the
most commonly used criteria for definition at present are from the World Health Organization (WHO)
[5], the European Group for the study of Insulin Resistance (EGIR) [6], the National Cholesterol
Education Programme Adult Treatment Panel III (NCEP ATP III) [7], American Association of
Clinical Endocrinologists (AACE) [8], and the International Diabetes Federation (IDF) [9] (Table 1).
Table 1
Diagnostic criteria proposed for the clinical diagnosis of the MetS.
Clinical WHO (1998) [5] EGIR ATPIII AACE (2003) [8] IDF (2005) [9]
measures (1999) [6] (2001) [7]
Insulin IGT, IFG, T2DM, or Plasma None, but IGT or IFG None
resistance lowered insulin insulin any 3 of the plus any of
a
Sensitivity >75th following 5 thefollowing
plus any 2 of the percentile features based on the
following plus any 2 clinical judgment
of the
following
2
Body Men: waist-to-hip ratio WC ≥94 cm WC ≥102 BMI ≥ 25 kg/m Increased WC
weight >0.90; in men or cm in men (population
women: waist-to-hip ratio ≥80 cm in or ≥88 cm in specific)
>0.85 and/or BMI > 30 women women plus any 2 of the
2
kg/m following
Lipids TGs ≥150 mg/dL and/or TGs ≥150 TGs ≥150 TGs ≥150 mg/dL TGs ≥150 mg/dL
HDL-C mg/dL mg/dL and HDL-C <40 or on TGs Rx.
<35 mg/dL in men or <39 and/or HDL-C <40 mg/dL in men or HDL-C <40
mg/dL in women HDL-C mg/dL in <50 mg/dL in mg/dL in men or
<39 mg/dL men or <50 women <50 mg/dL in
in men or mg/dL in women or on
women women HDL-C Rx
Blood ≥140/90 mm Hg ≥140/90 ≥130/85 ≥130/85 mm Hg ≥130 mm Hg

pressure mm Hg or mm Hg systolic or ≥85
on mm Hg diastolic
hypertension or on
Rx hypertension Rx
Glucose IGT, IFG, or T2DM IGT or IFG >110 mg/dL IGT or IFG (but ≥100 mg/dL
(but not (includes not diabetes) (includes
b
diabetes) diabetes) diabetes)
Other Microalbuminuria: Other features of
Open in a separate window
aInsulin sensitivity measured under hyperinsulinemic euglycemic conditions, glucose uptake below lowest
quartile for background population under investigation.
b
In 2003, the American Diabetes Association (ADA) changed the criteria for IFG tolerance from >110 mg/dl to
>100 mg/dl [10].
c
Includes family history of type 2 diabetes mellitus, polycystic ovary syndrome, sedentary lifestyle, advancing
age, and ethnic groups susceptible to type 2 diabetes mellitus.
BMI: body mass index; HDL-C: high density lipoprotein cholesterol; IFG: impaired fasting glucose; IGT:
impaired glucose tolerance; Rx: receiving treatment; TGs: triglycerides; T2DM: type 2 diabetes mellitus; WC:
waist circumference.
Although each definition possesses common features, there are several parameters that differ which
results in difficulty in terms of applicability, uniformity, and positive predictive value with all these
definitions. The AACE, WHO, and EGIR definitions are all largely focused on insulin resistance,
which is determined by an oral glucose tolerance test and hyperinsulinemic-euglycemic clamp.
However, this labour intensive method is primarily used in a research environment [22]. In contrast, the
ATPIII definitions were developed which use measurements and laboratory results that are readily
available to physicians, facilitating their clinical and epidemiological application and therefore have
remained a backbone for subsequent classifications such as the IDF diagnostic criterion [22]. However,
a major problem with the WHO and NCEP ATP III definitions has been their applicability to the
different ethnic groups, especially when trying to define obesity cut-offs. This is particularly evident
for the risk of T2DM, which is apparent at much lower levels of obesity in Asians compared to
Europeans. The IDF, having recognized the difficulties in identifying unified criteria for MetS that
were applicable across all the ethnicities, has proposed a new set of criteria with ethnic/racial specific
cut-offs [1] (Table 2). This accounts for the fact that the different populations, ethnicities, and
nationalities have the different distributions of norms for body weight and waist circumference. It also
recognizes that the relationship between these values and the risk of T2DM or CVD differs in different
populations.
Table 2
Gender and age-specific waist circumference cut-offs [1].
Country/ethnic group Waist circumference cut-off

Male (cm) Female (cm)
Europids ≥94 ≥80
In USA, the ATPIII values (102 cm males; 88 cm females) are
likely to continue to be used for clinical purposes.
South Asians ≥90 ≥80
Based on a Chinese, Malay, and Asian-Indian population.
Chinese ≥90 ≥80
Japanese ≥90 ≥80
Ethnic South and Central Americans Use South Asians recommendations until
more specific data are available.
Sub-Saharan Africans Use European data until more specific data
are available.
Eastern Mediterranean and Middle East (Arabs) population Use European data until more specific data
are available.
4. Epidemiology
Worldwide prevalence of MetS ranges from <10% to as much as 84%, depending on the region, urban
or rural environment, composition (sex, age, race, and ethnicity) of the population studied, and the
definition of the syndrome used [23, 24]. In general, the IDF estimates that one-quarter of the world's
adult population has the MetS [9]. Higher socioeconomic status, sedentary lifestyle, and high body
mass index (BMI) were significantly associated with MetS. Cameron et al. have concluded that the
differences in genetic background, diet, levels of physical activity, smoking, family history of diabetes,
and education all influence the prevalence of the MetS and its components [25]. The observed
prevalence of the MetS in National Health and Nutrition Examination Survey (NHANES) was 5%
among the subjects of normal weight, 22% among the overweight, and 60% among the obese [26]. It
further increases with age (10% in individuals aged 20–29, 20% in individuals aged 40–49, and 45% in
individuals aged 60–69) [27]. The prevalence of MetS (based on NCEP-ATP III criteria, 2001) varied
from 8% to 43% in men and from 7% to 56% in women around the world [25]. Park et al. [26] noticed
that there is an increase in the prevalence of MetS from 20 years old through the sixth and seventh
decade of life for males and females, respectively. Ponholzer et al. reported that there is high
prevalence of MetS among postmenopausal women, which varies from 32.6% to 41.5% [28]. A
Framingham Heart Study report indicated that a weight increase of ≥2.25 kg over a period of 16 yr was
associated with an up to 45% increased risk of developing the MetS [29], and it has been shown by
Palaniappan et al. that each 11 cm increase in waist circumference (WC) is associated with an adjusted
80% increased risk of developing the syndrome within 5 years [30]. The metabolic alterations occur
simultaneously more frequently than would be expected by chance and the concurrence of several
factors increases cardiovascular risk over and above the risk associated with the individual factors
alone [31]. The risk increases with the number of MetS components present [32].
5. Pathophysiology
MetS is a state of chronic low grade inflammation as a consequence of complex interplay between
genetic and environmental factors. Insulin resistance, visceral adiposity, atherogenic dyslipidemia,
chronic stress are the several factors which constitute the syndrome (Figure 1).

Figure 1
Schematic presentation of MetS. (FFA: free fatty acid, ATII: angiotensin II, PAI-1: plasminogen activator
inhibitor-1, RAAS: renin angiotensin aldosterone system, SNS: sympathetic nervous system.)
5.1. Abdominal Obesity

The “obesity epidemic” is principally driven by an increased consumption of cheap, calorie-dense food
and reduced physical activity. Adipose tissue is a heterogeneous mix of adipocytes, stromal
preadipocytes, immune cells, and endothelium, and it can respond rapidly and dynamically to
alterations in nutrient excess through adipocytes hypertrophy and hyperplasia [33]. With obesity and
progressive adipocytes enlargement, the blood supply to adipocytes may be reduced with consequent
hypoxia [34]. Hypoxia has been proposed to be an inciting etiology of necrosis and macrophage
infiltration into adipose tissue that leads to an overproduction of biologically active metabolites known
as adipocytokines which includes glycerol, free fatty acids (FFA), proinflammatory mediators (tumor
necrosis factor alpha (TNFα) and interleukin-6 (IL-6)), plasminogen activator inhibitor-1 (PAI-1), and
C-reactive protein (CRP) [35]. This results in a localized inflammation in adipose tissue that propagates
an overall systemic inflammation associated with the development of obesity related comorbidities
[36]. Adipocytokines integrate the endocrine, autocrine, and paracrine signals to mediate the multiple
processes including insulin sensitivity [37], oxidant stress [38], energy metabolism, blood coagulation,
and inflammatory responses [39] which are thought to accelerate atherosclerosis, plaque rupture, and
atherothrombosis. This shows that the adipose tissue is not only specialized in the storageand
mobilization of lipids but it is also a remarkable endocrine organ releasing the numerous cytokines.
5.1.1. FFA Upper body subcutaneous adipocytes generate a majority of circulating FFA while an intra-
abdominal fat content has been positively correlated with the splanchnic FFA levels which may
contribute to the liver fat accumulation commonly found in abdominal obesity [40]. Further, an acute
exposure of skeletal muscle to the elevated levels of FFA induces insulin resistance by inhibiting the
insulin-mediated glucose uptake, while, a chronic exposure of the pancreas to the elevated FFA impairs
a pancreatic β-cell function [41]. FFAs increase fibrinogen and PAI-1 production [42].
5.1.2. TNFα It is a paracrine mediator in adipocytes and appears to act locally to reduce the insulin
sensitivity of adipocytes [35]. Evidence suggests that TNF-α induces adipocytes apoptosis [43] and
promotes insulin resistance by the inhibition of the insulin receptor substrate 1 signalling pathway [44].
The paracrine action would further tend to exacerbate the FFA release, inducing an atherogenic
dyslipidemia [45]. Plasma TNFα is positively associated with the body weight, WC, and triglycerides
(TGs), while, a negative association exists between the plasma TNFα and High density lipoprotein–
cholesterol (HDL-C) [43].
5.1.3. CRP Elevated levels of CRP are associated with an increased WC [46], insulin resistance [47],
BMI [48], and hyperglycemia [46] and are increased with the number of the MetS components. It is
more likely to be elevated in obese insulin-resistant, but, not in obese insulin-sensitive subjects [49]. In
addition, it has been demonstrated that regardless of the presence or degree of the MetS in an
individual, CRP levels independently predicted the occurrence of future CVD events [50]. Because the
MetS has been linked with a greater chance of future CVD events [51], CRP levels may be an
important independent predictor of unfavourable outcomes in the MetS.
5.1.4. IL-6 It is released by both adipose tissue and skeletal muscle in humans [52]. It has both an
inflammatory and an anti-inflammatory action. IL-6 receptor is also expressed in the several regions of
the brain, such as the hypothalamus, in which it controls an appetite and energy intake [53]. It is a
systemic adipokine, which not only impairs insulin sensitivity but is also a major determinant of the
hepatic production of CRP [54]. IL-6 is capable of suppressing lipoprotein lipase activity. It has been
shown to be positively associated with BMI, fasting insulin, and the development of T2DM [55] and
negatively associated with HDL-C [56].
5.1.5. PAI-1 A serine protease inhibitor is secreted from intra-abdominal adipocytes, platelets, and the
vascular endothelium [35]. It exerts its effects by inhibiting the tissue plasminogen activator (tPA) [57]
and thus is considered as a marker of an impaired fibrinolysis and atherothrombosis. Plasma PAI-1
levels are increased in abdominally obese subjects [58] and inflammatory states [59], thus, increasing
the risk of an intravascular thrombus and adverse cardiovascular outcomes [60].
5.1.6. Adiponectin
It regulates the lipid and glucose metabolism, increases insulin sensitivity, regulates food intake and
body weight, and protects against a chronic inflammation [61]. It inhibits hepatic gluconeogenic
enzymes and the rate of an endogenous glucose production in the liver. It increases glucose transport in
muscles and enhances fatty acid oxidation [18]. It has a multifactorial antiatherogenic action which
includes an inhibition of endothelial activation, a reduced conversion of macrophages to foam cells,
and inhibition of the smooth muscle proliferation and arterial remodelling that characterizes the
development of the mature atherosclerotic plaque [62]. Adiponectin is inversely associated with CVD
risk factors such as blood pressure, low density lipoprotein cholesterol (LDL-C), and TGs [63].
Moreover, Pischon et al. have shown adiponectin to be a strong inverse independent risk factor for
CVD [64]. Further, Fumeron et al. concluded that hypoadiponectinemia is associated with insulin
resistance, hyperinsulinemia, and the possibility of developing T2DM, independent of fat mass [65].
The anti-inflammatory molecule, adiponectin, is negatively associated with the body weight, WC, TGs,
fasting insulin, insulin resistance (HOMA-Homeostasis Model Assessment) [43], BMI, and blood
pressure, whereas a positive association exists between adiponectin and HDL-C [43, 66]. Its
expressions and secretions are reduced by TNFα [67], possibly through a stimulated production of IL-
6, which also inhibits adiponectin secretion [68]. Adiponectin is seen to be “protective,” not only in its
inverse relationship with the features of MetS [69] but also through its antagonism of TNFα action
[70].
5.1.7. Leptin It is an adipokine involved in the regulation of satiety and energy intake [35]. Levels of
leptin in the plasma increase during the development of obesity and decline during the weight loss.
Leptin receptors are located mostly in the hypothalamus and the brain stem and signals through these
receptors controls satiety, energy expenditure, and neuroendocrine function. Most overweight and
obese individuals have an elevated level of leptin that do not suppress appetite, or in other words, leptin
resistance. Leptin resistance is thought to be a fundamental pathology in obesity [71]. Besides its effect
on appetite and metabolism, leptin acts in the hypothalamus to increase the blood pressure through
activation of the sympathetic nervous system (SNS) [72]. High circulating levels of leptin are reported
to explain much of the increase in the renal sympathetic tone observed in obese human subjects [73].
Leptin-induced increase in renal sympathetic activity and blood pressure is mediated by the
ventromedial and dorsomedial hypothalamus [74]. Leptin is an nitric oxide (NO) dependent vasodilator
but also increases the peripheral vascular resistance and the sympathetic nerve activity [75]. The
concentration of plasma leptin is correlated with adiposity, and hyperleptinemia is indeed considered an
independent cardiovascular disease risk factor [76].
5.2. Insulin Resistance

Characteristics of the insulin-sensitive phenotype include a normal body weight [77] without
abdominal or visceral obesity [78], being moderately active [79], and consuming a diet low in saturated
fats [80]. Alternatively, insulin-resistant individuals demonstrate an impaired glucose metabolism or
tolerance by an abnormal response to a glucose challenge, an elevated fasting glucose levels and/or
overt hyperglycemia, or a reduction in insulin action after intravenous administration of insulin
(euglycemic clamp technique) with decreased insulin-mediated glucose clearance and/or reductions in
the suppression of endogenous glucose production. It is defined as a pathophysiological condition in
which a normal insulin concentration does not adequately produce a normal insulin response in the
peripheral target tissues such as adipose, muscle, and liver. Under this condition, pancreatic beta cell
secretes more insulin (i.e., hyperinsulinemia) to overcome the hyperglycemia among insulin-resistant
individuals. Although hyperinsulinemia may compensate for insulin resistance to some biological
actions of insulin, that is, maintenance of normoglycemia, however, it may cause an overexpression of
insulin activity in some normally sensitive tissues. This accentuation of some insulin actions coupled
with a resistance to other actions of insulin results in the clinical manifestations of MetS [81]. An
inability of the pancreatic beta cells over time to produce a sufficient insulin to correct the worsening
tissue insulin resistance leads to hyperglycemia and overt T2DM [82]. Physiological insulin signalling
occurs following the binding of insulin to the insulin receptor, a ligand-activated tyrosine kinase.
Binding of insulin results in a tyrosine phosphorylation of downstream substrates and activation of two
parallel pathways: the phosphoinositide 3-kinase (PI3K) pathway and the mitogen activated protein
(MAP) kinase pathway. The PI3K-Akt pathway is affected, while, the MAP kinase pathway functions
normally in insulin resistance. This leads to a change in the balance between these two parallel
pathways. Inhibition of the PI3K-Akt pathway leads to a reduction in endothelial NO production,
resulting in an endothelial dysfunction, and a reduction in GLUT4 translocation, leading to a decreased
skeletal muscle and fat glucose uptake. By contrast, the MAP kinase pathway is unaffected, so there is
a continued endothelin-1 (ET-1) production, an expression of vascular cell adhesion molecules, and a
mitogenic stimulus to vascular smooth muscle cells. In these ways, an insulin resistance leads to the
vascular abnormalities that predispose to atherosclerosis. Although insulin-resistant individuals need
not be clinically obese, they nevertheless commonly have an abnormal fat distribution that is
characterized by a predominant upper body fat. Regardless of the relative contributions of visceral fat
and abdominal subcutaneous fat to insulin resistance, a pattern of abdominal (or upper body) obesity
correlates more strongly with the insulin resistance and the MetS than does lower body obesity [83].
5.3. Dyslipidemia
This dyslipidemia is characterised by a spectrum of qualitative lipid abnormalities reflecting
perturbations in the structure, metabolism, and biological activities of both atherogenic lipoproteins and
antiatherogenic HDL-C which includes an elevation of lipoproteins containing apolipoprotein B
(apoB), elevated TGs, increased levels of small particles of LDL, and low levels of HDL-C. Insulin
resistance leads to an atherogenic dyslipidemia in several ways. First, insulin normally suppresses
lipolysis in adipocytes, so an impaired insulin signalling increases lipolysis, resulting in increased FFA
levels. In the liver, FFAs serve as a substrate for the synthesis of TGs. FFAs also stabilize the
production of apoB, the major lipoprotein of very low density lipoprotein (VLDL) particles, resulting
in a more VLDL production. Second, insulin normally degrades apoB through PI3K-dependent
pathways, so an insulin resistance directly increases VLDL production. Third, insulin regulates the
activity of lipoprotein lipase, the rate-limiting and major mediator of VLDL clearance. Thus,
hypertriglyceridemia in insulin resistance is the result of both an increase in VLDL production and a
decrease in VLDL clearance. VLDL is metabolized to remnant lipoproteins and small dense LDL, both
of which can promote an atheroma formation. The TGs in VLDL are transferred to HDL by the
cholesterol ester transport protein (CETP) in exchange for cholesteryl esters, resulting in the TG-
enriched HDL and cholesteryl ester-enriched VLDL particles. Further, the TG-enriched HDL is a better
substrate for hepatic lipase, so it is cleared rapidly from the circulation, leaving a fewer HDL particles
to participate in a reverse cholesterol transport from the vasculature. Thus, in the liver of insulin-
resistant patients, FFA flux is high, TGs synthesis and storage are increased, and excess TG is secreted
as VLDL [84]. For the most part, it is believed that the dyslipidemia associated with insulin resistance
is a direct consequence of increased VLDL secretion by the liver [85]. These anomalies are closely
associated with an increased oxidative stress and an endothelial dysfunction, thereby reinforcing the
proinflammatory nature of macrovascular atherosclerotic disease.
5.4. Hypertension
Essential hypertension is frequently associated with the several metabolic abnormalities, of which
obesity, glucose intolerance, and dyslipidemia are the most common [86]. Studies suggest that both
hyperglycemia and hyperinsulinemia activate the Renin angiotensin system (RAS) by increasing the
expression of angiotensinogen, Angiotensin II (AT II), and the AT1 receptor, which, in concert, may
contribute to the development of hypertension in patients with insulin resistance [87]. There is also
evidence that insulin resistance and hyperinsulinemia lead to SNS activation, and, as a result, the
kidneys increase sodium reabsorption, the heart increases cardiac output, and arteries respond with
vasoconstriction resulting in hypertension [88]. It has been recently discovered that adipocytes also
produce aldosterone in response to ATII [89]. In this regard, the adipocyte may be considered a
miniature renin-angiotensin-aldosterone system.
5.5. Genetics
The great variations in the susceptibility and age of onset in individuals with a very similar risk profile
suggest a major interaction between genetic and environmental factors [90]. It is recognized that some
people who are not obese by traditional measures nevertheless are insulin-resistant and have abnormal
levels of metabolic risk factors. Examples are seen in individuals with 2 diabetic parents or 1 parent
and a first- or second-degree relative [91]; the same is true for many individuals of South Asian
ethnicity [92]. Considerable individuals and ethnic variations also exist in the clinical pattern of
metabolic risk factors in obese/insulin-resistant subjects [93]. It is likely that the expression of each
metabolic risk factor falls partially under its own genetic control, which influences the response to
different environmental exposures. For example, a variety of polymorphisms in genes affecting
lipoprotein metabolism are associated with the worsening of dyslipidemia among obese people [94].
Similarly, a genetic predisposition to the defective insulin secretion when combined with insulin
resistance can raise the plasma glucose to abnormal levels [95]. According to the thrifty genotype
hypothesis proposed by Neel in 1962 [96], individuals living in a harsh environment with an unstable
food supply would maximize their probability of survival if they could maximize a storage of surplus
energy. Genetic selection would thus favour the energy-conserving genotypes in such environments.
However, the selected genetic variations that were favoured during malnutrition would become
unfavourable when nutrition improved. This hypothesis assumes that the common genetic variants of
thrifty genes predispose to MetS. Another thrifty phenotype hypothesis was introduced by Hales and
Barker in 1992 [97]. According to this hypothesis, babies who experienced an intrauterine malnutrition
may have adapted to a poor nutrition by reducing energy expenditure and becoming “thrifty.” These
metabolic adaptations are beneficial when individuals are poorly nourished during childhood and adult
life; however, with an increased food intake, these adaptations are no longer beneficial and would lead
to an increased risk of MetS in a later life. Support for this hypothesis comes from the observed
associations of low birth weight with later development of insulin resistance and T2DM in several
populations [98].
5.6. Endothelial Function

It is characterized by an impaired endothelium-dependent vasodilatation, a reduced arterial compliance,
and an accelerated process of atherosclerosis [107]. Various factors like oxidative stress,
hyperglycemia, advanced glycation products, FFAs, inflammatory cytokines, or adipokines cause an
inability of endothelium to serve its normal physiological and protective mechanisms. Hansson has
shown that immune cells play an important role in all the stages of the atherosclerotic process [108]; in
addition, a reduction in NO, a key regulator of endothelial homeostasis, and an increase in reactive
oxygen species result in an endothelial dysfunction and a proatherogenic vascular bed [109].
5.7. Hypercoagulable State

A proinflammatory state is characterized by elevated circulating cytokines and acute-phase reactants
(e.g., CRP). Further, a prothrombotic state signifies anomalies in the procoagulant factors, that is, an
increase in fibrinogen, factor VII and factor VIII as well as the antifibrinolytic factor (PAI-1), platelet
abrasions, and endothelial dysfunctions. Grundy [110] has shown that a fibrinogen, an acute-phase
reactant protein like CRP, rises in response to a high-cytokine state. This shows that the prothrombotic
and proinflammatory states may be metabolically interconnected.
5.8. Diet
A study by Aljada et al. has shown that a high dietary fat intake is associated with an oxidative stress
and an activation of the proinflammatory transcription factor, that is, nuclear factor kappa-beta (NFκB)
[111]. In contrast, a diet rich in fruits and fibres has no inflammation-inducing capacity compared with
a high-fat diet even if it has the same calories content [112].
5.9. Chronic Stress and Glucocorticoid (GC) Action

Chronic hypersecretion of stress mediators, such as cortisol, in individuals with a genetic predisposition
exposed to a permissive environment, may lead to the visceral fat accumulation as a result of chronic
hypercortisolism, low growth hormone secretion, and hypogonadism [113]. GCs increase the activities
of enzymes involved in fatty acid synthesis and promote the secretion of lipoproteins [114]; induce the
hepatic gluconeogenic pathway [115]; promote the differentiation of preadipocytes to adipocytes,
which could lead to an increased body fat mass [116]; inhibit an insulin-stimulated amino acid uptake
by adipocytes [117]; and increase lipolysis or lipid oxidation which leads to the peripheral insulin
resistance [118]. A good correlation was observed between plasma cortisol levels, total urinary GC
metabolites, and the number of features of the MetS among these patients. Both the secretion rate and
the peripheral clearance of cortisol in these patients were positively correlated with the systolic blood
pressure, and fasting glucose and insulin [119]. These hormonal alterations may lead to a reactive
insulin hypersecretion, an increasing visceral obesity, and sarcopenia, resulting in dyslipidemia,
hypertension, and T2DM [120].
6. Treatment
MetS is a state of chronic low grade inflammation with the profound systemic effects (Table 3).
Clinical identification and management of patients with the MetS are important to begin efforts to
adequately implement the treatments to reduce their risk of subsequent diseases [121]. Effective
preventive approaches include lifestyle changes, primarily weight loss, diet, and exercise, and the
treatment comprises the appropriate use of pharmacological agents to reduce the specific risk factors.
Pharmacological treatment should be considered for those whose risk factors are not adequately
reduced with the preventive measures and lifestyle changes [122]. The clinical management of MetS is
difficult because there is no recognized method to prevent or improve the whole syndrome, the
background of which is essentially insulin resistance [15]. Thus, most physicians treat each component
of MetS separately, laying a particular emphasis on those components that are easily amenable to the
drug treatment. In fact, it is easier to prescribe a drug to lower blood pressure, blood glucose, or
triglycerides rather than initiating a long-term strategy to change people's lifestyle (exercise more and
eat better) in the hope that they will ultimately lose weight and tend to have a lower blood pressure,
blood glucose, and triglycerides. For the treatment of risk factors of MetS, the physician should follow
the current treatment guidelines of the National Cholesterol Education Programme (NCEP) [123], the
seventh Joint National Commission (JNC-VII) for blood pressure treatment [124], the American
Diabetes Association (ADA) [125], the American Heart Association (AHA) [20], and the National
Institute of Health Obesity Initiative [126].
Table 3
Systemic effects of MetS.
Renal Microalbuminuria, hypofiltration, hyperfiltration, glomerulomegaly, focal segmental

glomerulosclerosis, and chronic kidney disease [99].
Hepatic Increased serum transaminase, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver
disease (NAFLD), hepatic fibrosis, and cirrhosis [100].
Skin Acanthosis nigricans, lichen planus, systemic lupus erythematosus, burn-induced insulin
resistance, psoriasis, androgenetic alopecia, skin tags, skin cancer, and acne inversa [101].
Ocular Nondiabetic retinopathy, age related cataract-nuclear, cortical, posterior subcapsular; central
retinal artery occlusion, primary open angle glaucoma, oculomotor nerve palsy, and lower lid
entropion [102].
Sleep Obstructive sleep apnea (OSA) [103].
Reproductive Hypogonadism, polycystic ovarian syndrome (PCOS), and erectile dysfunction [104].
system
Cardiovascular Coronary heart disease (CHD), myocardial infarction (MI), and stroke [105].
system
Cancers Breast, pancreas, and prostrate [106].
6.1. Risk Assessment

The goals of therapy are to reduce both a short-term and lifetime risk. The presence of the MetS per se
indicates a higher lifetime risk. A practical approach to estimate absolute, short-term CHD/CVD risk in
patients with the MetS without ASCVD or diabetes is to use the standard Framingham algorithm to
estimate a 10-year risk of the coronary heart disease (CHD) [123]. The standard Framingham risk
equations, which include cigarette smoking, blood pressure, total cholesterol, HDL-C, and age, capture
most of the risk of CVD in patients with the syndrome. This equation triages patients into 3 risk
categories based on a 10-year risk of CHD: high risk (10-year risk ≥20%), moderately high risk (10-
year risk 10% to 20%), or lower to moderate risk (10-year risk ≤10%), while affected patients with
ASCVD or diabetes are already in a high-risk category without the need for Framingham risk scoring.
6.2. Lifestyle Modification

Lifestyle modification treatment should be delivered by a multidisciplinary approach (Table 4) and a
team composed of physicians and nonphysician health professionals, such as dieticians or professionals
with a master degree in exercise physiology, behavioural psychology, or health education [127].
Although lifestyle therapy may not modify any given risk factor as much as will a particular drug, its
benefit lies in the fact that it produces a moderate reduction in all the metabolic risk factors [128].
Table 4
Multidisciplinary approach to the MetS.
A: assessment Calculate Framingham risk score: high risk (10-year risk ≥20%), moderately high risk (10-
year risk 10% to 20%), or lower to moderate risk (10-year risk ≤10%).
Make diagnosis of MetS using the diagnostic criteria.
A: aspirin High risk: aspirin definitely beneficial.

High-intermediate risk (10–20%): aspirin likely to be beneficial.
Low-intermediate risk (6–10%): “individual clinical judgment”, depending on sex and risk
of bleeding.
Low risk (<6%): Risk of haemorrhage outweighs the benefits.
B: BP control Initiate treatment: categorical hypertension (BP ≥ 140/≥90 mm Hg).

Patients with established diabetes (≥130/≥80 mm Hg).
ACEIs/ARBs first line agent may reduce incident diabetes mellitus.
Beta-blockers and thiazides may have an adverse effect on impaired glucose tolerance but
outweighed by the benefits of reaching BP goal and lowering the risk of CVD events.
C: cholesterol Statin to achieve LDL-C <100 mg/dL in high-risk, <130 mg/dL in intermediate-risk, and

First target: <160 mg/dL in low risk patients.
LDL Statin intensification, consider niacin and/or fibrates once statin maximized. Consider
Second target: fibrates, especially for those with combined hypertriglyceridemia/low HDL-C.
non-HDL Consider further reduction in LDL-C with statin therapy to mitigate a risk of low HDL-C,
Third target: consider niacin.
HDL Statin therapy for those with high sensitivity CRP (hsCRP) ≥3 mg/dL.
Fourth target:
CRP
D: diabetes Intensive lifestyle modification is the most important therapy.

prevention/diet Weight reduction of 5–10% of preintervention weight over a period of four to six months.
Sodium intake of <65–100 mmol/day with a goal of 90–120 mmol of potassium per day.
Mediterranean diet: high consumption of fruits, vegetables, legumes, and grains, moderate
alcohol intake, a moderate-to-low consumption of dairy products and meats/meat products,
and a high monounsaturated- to-saturated fat ratio.
DASH diet: rich in fruits, vegetables, and low-fat dairy products, and low in saturated and
total fat intake.
Consider low glycemic index food, complex unrefined carbohydrates, viscous soluble
6.3. Weight Reduction
Four therapies can be used for weight reduction: calorie restriction (e.g., 500 kcal/d deficit), increased
physical activity, behavioural modification, and, in appropriate patients, FDA-approved weight-
reducing drugs [128]. Several authors [20] recommend a weight loss goal of 10% reduction in body
weight in the first six months to a year and continued weight loss thereafter until BMI is less than 25.
While many patients find weight loss difficult to achieve, exercise and dietary changes that can lower
blood pressure and improve lipid levels will further improve insulin resistance, even in the absence of
weight loss [129]. A weight loss of as small as 5–10% of body weight can significantly reduce TGs and
increases HDL-C [130]. Furthermore, both hypertensive individuals and individuals at risk of
developing hypertension can see a significant reduction in the blood pressure with a modest weight loss
[131]. Fasting blood glucose, insulin, and haemoglobin A1c can also be decreased with a modest
weight loss [132]. During weight maintenance (i.e., energy balance), a regular exercise appears to play
an important role in abdominal fat loss [133] and the prevention of weight regain in those who have
successfully lost weight [134]. Persons who combine calorie restriction and exercise with behavioural
modifications should expect to lose 5–10% of preintervention weight over a period of four to six
months. This weight loss appears small to the patient but results in an improvement of many obesity
related conditions including various abnormal components of the MetS and development of diabetes
[135]. Both the Finnish Diabetes Prevention Study [136] and the US Diabetes Prevention Program
(DPP) [137] showed that diet and exercise had a significant effect on reducing the progression from
IGT to T2DM.
6.4. Diet
The effective and healthful methods for the long-term weight loss are reduced-energy diets, consisting
of a modest 500 to 1000 calories/day reduction. Sustained dietary changes may require a referral to a
registered dietician to help implement the suggestions and ensure an adequate micronutrient intake
(e.g., calcium, iron, and folate) while reducing calories. In the SUN (Seguimiento University of
Navarra) prospective cohort study [138], a Mediterranean-style diet was inversely associated with the
cumulative incidence of MetS. Adherence to the Mediterranean diet improves the physical and mental
domains of health related quality of life (physical function, vitality, general physical health, emotional
role, and self-perception of health) [139] and lowers the odds of LDL-C, postchallenge glucose values
[140], TGs, and low HDL-C levels [141]. In the PREMIER study [142], the Dietary Approaches to
Stop Hypertension (DASH) diet plus lifestyle interventions improved the metabolic parameters,
particularly blood pressure. ATP III [123] recommended that the diet should contain 25% to 35% of
calories as total fat for the individuals entering cholesterol management. If the fat content exceeds 35%,
it is difficult to sustain the low intakes of saturated fat required to maintain a low LDL-C. On the other
hand, if the fat content falls below 25%, TGs can rise and decline in HDL-C levels can be seen [143];
thus, a very low-fat diet may exacerbate an atherogenic dyslipidemia. A protein intake of 10–35% of
total calorie intake is recommended by the Institute Of Medicine (IOM) for the general population with
an exception of individuals with chronic kidney disease (CKD) who have markedly reduced glomerular
filtration rate, where, an excess protein enhances phosphorus load, which can cause acidosis and
worsen the insulin resistance [144]. Adherence may be enhanced by increasing the diet structure and
limiting food choices, thereby reducing a temptation and the potential mistakes on calculating an
energy intake [145]. A strategy to increase the diet structure is to provide patients with the meal plans,
grocery lists, menus, and recipes. Support for this strategy is derived from a study showing that the
provision of both low-calorie foods (free of charge or subsidized) and structured meal plans resulted in
significantly greater weight loss than a diet with no additional structure [146]. Another effective
strategy to increase dietary adherence is the meal replacements [147] which help to overcome some
problems that occur while consuming the conventional food diets (i.e., underestimation of calorie
intake, difficulties in estimating portion sizes, macronutrient composition, calorie content, and in
recalling the consumed food). A clear positive association has been shown between sodium intake and
blood pressure, with excessive sodium intake associated with hypertension [148]. Furthermore, a
sodium restriction has also been associated with reduced CVD events [149] and congestive heart
failure [150]. Guidelines therefore recommend that a daily sodium intake should be restricted to no
more than 65–100 mmol [151]. In addition to sodium restriction, an increased potassium intake has
also been shown to improve blood pressure, especially in the setting of high sodium intake [152].
Guidelines have recommended the intake of foods enriched with potassium, such as fruits and
vegetables, with a goal of 90–120 mmol of potassium per day [151]. Incorporation of monounsaturated
fatty acid (fat from plant source like olive oil, soybean oil, canola oil, safflower oil, peanut oil, peanuts,
peanut butter, almond, and cashew nut) may be beneficial as it improves the atherogenic dyslipidemia.
Similarly, n-3 polyunsaturated fatty acids (mainly from fish) have cardioprotective effect and it should
constitute approximately 10% of total energy intake. Viscous (soluble) fibres (mainly in oat products,
psyllium, and pectin) intake of 10–25 g/day also improves an atherogenic dyslipidemia [153]. Low
glycemic index foods (i.e., those that are minimally processed) have been shown to improve the
components of the MetS including hyperlipidemia and hyperglycemia [154], whereas, a higher
glycemic index has been shown to be positively associated with the insulin resistance and MetS
prevalence [155]. Therefore, a diet high in complex, unrefined carbohydrates with an emphasis on
fibres (14 g/1000 calories consumed daily) and low in added sugars (≤25% of calorie intake) is
recommended for individuals with or at risk of the MetS.
6.5. Physical Activity

Current physical activity guidelines [156] recommend practical, regular, and moderate regimens for
exercise. The standard exercise recommendation is a daily minimum of 30 minutes of moderate-
intensity physical activity. However, a preference is given to 60 minutes of moderate-intensity brisk
walking to be supplemented by other activities [157]. The latter includes multiple short (10 to 15
minutes) bouts of activity (walking breaks at work, gardening, or household work), using simple
exercise equipment (e.g., treadmills), jogging, swimming, biking, golfing, team sports, and engaging in
resistance training [158]; avoiding common sedentary activities in a leisure time (television watching
and computer games) is also advised. Current AHA guidelines [156] call for a clinical assessment of
the risk of the future ASCVD events before initiating a new exercise regimen. For high-risk patients
(e.g., those with recent acute coronary syndromes or recent revascularization), physical activity should
be carried out under the medical supervision. Clinicians should evaluate which type of activity is
feasible for the patient, considering the barriers (e.g., arthritis and time constraints) that can prevent a
successful increase in the physical activity. Accordingly, they should assist patients in developing a
physical activity plan based on the initial assessment. However, any type of physical activity should be
encouraged. Lifestyle activity should be increased slowly in intensity and duration (by 5
min/session/week), starting from a low-intensity exercise (<3 metabolic equivalent) in sedentary
subjects, to avoid excessive fatigue, muscle pain, strains, or injuries [159]. Patients should be
encouraged to register their baseline physical activity or to check their baseline number of steps by a
pedometer. Whenever the brisk walking is chosen as the preferred activity, they should be instructed to
add 500 steps at 3-day intervals to a target value of 10,000–12,000 steps/day [126]. Prescribing
multiple short bouts (10 min each) rather than one long session may help the patients to accumulate
more minutes of exercise. This 30 minutes of physical activity achieved in three 10-minute sessions is
equivalent to the energy expenditure of 1500 kcal a week. The impact of exercise on insulin sensitivity
is evident for 24 to 48 hours and disappears within three to five days. Thus, an individual would need
to follow the AHA and American College of Sports Medicine recommendation to exercise at least 30
min/d most days of the week [160] for a continued benefit of exercise on insulin action. Physical
training has been shown to reduce the skeletal muscle lipid levels and insulin resistance, regardless of
BMI [161]. A combination of resistance and aerobic exercise is the best, but any activity is better than
none, and patients who have been sedentary need to start with walking and gradually increase duration
and intensity [162]. According to the Centre for Disease Control and Prevention (CDC) and the
American College of Sports Medicine, physically inactive or sedentary subjects were defined as those
who did not engage in at least 150 minutes of physical activities per week [163]. The odds of having
the MetS were almost doubled in adults reporting no moderate or vigorous physical activity compared
with those who engage in at least 150 min/wk [164]. Furthermore, Koplan and Dietz have shown that a
regular exercise improves insulin sensitivity, decreases plasma TGs levels, and reduces cardiovascular
morbidity and mortality [165].
6.6. Behaviour Therapy

It has been designed to provide the patients with a set of principles and techniques to modify their
eating and activity habits [145]. The emphasis in behavioural change should include the benefit of
social support, stress management, the value of a regular exercise regimen, and an improvement in
eating habits (e.g., setting goals, planning meals, reading labels, eating regular meals, reducing portion
sizes, self-monitoring, and avoiding eating binges). Originally, the treatment was exclusively based on
the learning theory (behaviourism). The theory postulates that the behaviours causing obesity (excess
eating and low exercising) are largely learnt and therefore could be modified or relearnt. The theory
further postulated that the positive changes in eating and exercising can be achieved by modifying the
environmental cues (antecedents) and the reinforcements of these behaviours [166]. The intervention
was later integrated with the cognitive strategies (e.g., problem solving and cognitive restructuring) and
with the specific recommendations on diet and exercise [167]. Exercise promotion to decrease the
chronic disease risk is also important in adults and the middle-aged since it can slow down the
functional decline associated with ageing [168].
6.7. Pharmacological Approach

The National Institutes of Health guidelines for the treatment of obesity recommend a consideration of
pharmaceutical therapy for weight loss for the individuals with a BMI of at least 30 kg/m2 or for those
with a BMI of at least 27 kg/m2 and comorbidities associated with their excess weight.
Pharmacological approaches to weight loss include two main classes: appetite suppressants and
inhibitors of nutrient absorption. A single agent is generally recommended and an average weight loss
ranges greatly from 5% to 10% of initial weight [169]. Appetite suppressants include phentermine
derivatives and sibutramine. These agents are usually taken in the late morning and reduce appetite in
the late afternoon and evening. Krejs reported that sibutramine-induced weight loss and weight
maintenance lead to clinically relevant reductions in the risk factors associated with the syndrome
[170]. Treatment with the drug decreases visceral fat, improves lipid levels, and decreases glycosylated
haemoglobin and uric acid concentrations. Orlistat (an inhibitor of gastrointestinal lipase) is the only
nutrient absorption inhibitor currently available. It prevents absorption of up to 30% of the fat
consumed and must be taken at the time of consumption. Undesirable side effects such as flatulence
and oil leakage in the stool often occur early in the course of treatment with this medication. In
randomized clinical trials, orlistat in obese persons with T2DM at baseline led to an improved glycemic
control and a weight reduction of 6% over 1 year versus 4% weight loss with placebo [171]. A recently
published meta-analysis concerning the efficacy of pharmacological agents for obesity reported that an
average weight loss was approximately four kilograms more than for placebo users and that no drug or
class of drugs was clearly superior [172]. However, the major problem with these currently available
antiobesity drugs is a relatively high rate of adverse side effects leading to a poor tolerance and
compliance for the long-term use.
6.8. Bariatric Surgery

Surgery is recommended for the individuals who do not respond to weight loss diet or medications, are
extremely obese (BMI > 40 kg/m2), or if they have a BMI > 35 to 40 kg/m2 and one or more comorbid
conditions [169]. Improvements in the metabolic profile have been documented presumably due to the
redistribution of adiposity [174]. Bariatric surgery techniques using laparoscopic adjustable banding of
stomach along with Roux-en-Y and other forms of gastric bypass are now favoured for the severe and
morbid obesity [18]. It results in a weight loss of 25–30% and rapid normalization of glucose handling
and blood pressure in patients with diabetes and hypertension [175] with 95% of patients being free of
the syndrome one year after a surgery [18]. It has been found to be associated with the improvement
and resolution of multiple comorbidities associated with obesity, including hypertension, T2DM,
NAFLD, OSA, cardiopulmonary failure, CVD, arthritis, PCOS, dyslipidemia (exclusive of
hypercholesterolemia), hyperuricemia, and infertility [175]. However, the long-term results are not
available and recent reports of substantial mortality and morbidity of this procedure, especially in the
elderly, have raised important safety issues for this procedure [176].
6.9. Dyslipidemia
The guidelines recommend that the LDL-C goals (Table 5) should be set at less than 130 mg/dL with
the option of targeting less than 100 mg/dL in the moderately high-risk individuals. Target goals should
be set at an LDL-C less than 100 mg/dL in the high-risk patients with the option of aiming for less than
70 mg/dL in the “very high-risk” patient [173]. The goal for the non-HDL-C is 30 mg/dL greater than
LDL-C. In patients with an atherogenic dyslipidemia in whom the serum TGs levels are ≥200 mg/dL,
non-HDL-C becomes the next target of treatment after the LDL-C goal is reached. If the TGs level is
higher than 500 mg per dL, then lowering the TGs level to 500 mg per dL or less takes primacy over
LDL-C lowering to prevent the development of acute pancreatitis. After LDL-C and non-HDL-C goals
are achieved, a tertiary target is raising the HDL-C level. No goals for raising HDL-C levels are
specified but HDL-C should be raised to the possible extent after attaining the goals for LDL-C and
non-HDL-C [123].
Table 5
Goals for lowering LDL-C [173].
Risk category LDL-C goals Recommendations

Lower risk <160 mg/dL Lifestyle modifications
0-1 major risk Consider pharmacotherapy if LDL-C ≥190 mg/dL after lifestyle
factor modifications
10-yr risk <10%
Moderate risk <130 mg/dL Lifestyle modifications

≥2 major risk Consider pharmacotherapy if LDL-C ≥160 mg/dL after lifestyle
factors modifications
10-yr risk <10%
Moderately high risk <130 mg/dL Lifestyle modifications

≥2 major risk Optional Consider pharmacotherapy if LDL-C ≥130 mg/dL or optionally ≥100
factors <100 mg/dL mg/dL after lifestyle modifications
10-yr risk 10–20%
High risk <100 mg/dL Lifestyle modifications

CHD or CHD risk Optional <70 Consider pharmacotherapy if LDL-C ≥100 mg/dL or optionally ≥70
equivalents mg/dL mg/dL after lifestyle modifications
Statins are considered to be the most effective class of drugs for reducing the LDL-C concentrations
due to their minimal drug-drug interactions and side effects [123]. Depending on the dose and the
specific type of statin used, LDL-C reductions of 15 to 60 mg/dL are observed [177]. Statins increase
HDL-C by 5–10%, with greater increases seen in individuals with lower HDL-C and elevated TGs, and
reduce TGs concentrations by 7–30% primarily with moderate to high doses [178] and further decrease
very low density lipoprotein (VLDL) levels by 39% [157]. Non-lipid-lowering or pleiotropic effects of
statins have also been implicated in their beneficial effects on inflammation, endothelial function, and
CVD events [179] and may therefore be beneficial for individuals with the MetS [180]. Statins also
lower the incidence of MI or stroke by more than 33% in patients with coronary artery disease. Statins
can also be safely combined with a fibrate, especially fenofibrate, and niacin to achieve the target levels
of non-HDL-C, TGs, and HDL-C [7]. All statins had favourable effects on atherogenic dyslipidemia,
with rosuvastatin generally having the greatest effect [181].
Niacin has favourable effects on essentially all of the abnormalities of the metabolic dyslipidemia. It is
considered the most effective agent for raising HDL-C (15 to 35%) and increasing HDL particle size
[182]. Niacin significantly lowers TGs (20 to 50%) and LDL-C (5–25%) [123]. Niacin also causes
beneficial changes in the lipoprotein subclasses because it has been shown to reduce the proportion of
small, dense LDL-C particles while increasing large, more buoyant LDL-C particles and larger HDL-C
particles [183]. Combination therapy of a niacin and statin produces greater effects on the lipid levels
than does an either agent given alone [184]. The primary limitations for the use of niacin include
flushing (most often associated with immediate-release niacin) and hyperglycemia [185]. Therefore, if
nicotinic acid is used in patients with impaired fasting glucose (IFG), impaired glucose tolerance
(IGT), or diabetes, its dose should be kept relatively low (e.g., 1 to 2 g per day) and deserves careful
monitoring for the worsening of hyperglycemia [186]. Niacin has the greatest effect on increasing
HDL-C levels (15%–35%), with fibrates (6%–15%) and statins (3%–15%) having a more moderate
effect [123].
The two fibrates currently used clinically are gemfibrozil and fenofibrate, both of which can lower TGs
by 25% to 30% with the greater reductions in individuals that are hypertriglyceridemic. Fibrates further
increases HDL-C by 5–15% and reduces LDL-C by 0–30% [187]. Although fibrates reduce the plasma
TGs and increase the HDL-C extent when used in patients with diabetes mellitus, there have been no
studies specifically examining the effect of fibrates treatment in patients with the MetS [188]. The
advantage of gemfibrozil is that it is lower in cost, but fenofibrate has a fewer drug interactions,
especially when prescribed along with a statin. Several studies have reported an isolated severe
myopathy occurring from the combination of a statin with gemfibrozil due to pharmacological
interaction of statin glucuronidation and increase in the level of statins when used in conjunction [157].
ATP III has recommended the combination of fenofibrate and statin due to a very low risk of associated
myopathy [7]. Although the treatment with statin/fibrate and statin/niacin has been reported to increase
the risk of drug induced myopathy and rhabdomyolysis, such combination therapies are considered safe
[189]. Low or intermediate doses of statins (10–40 mg/day) with fenofibrate (200 mg/day) or
bezafibrate (400 mg/day) are considered effective and safe for the treatment of an atherogenic
dyslipidemia [190]. Risk factors that predispose patients to myopathy caused by the above
combinations include increased age, female sex, renal or liver disease, diabetes, hypothyroidism,
debilitated status, surgery, trauma, excessive alcohol intake, heavy exercise, uncontrolled dose of niacin
or fibrate, and use of additional medications (cyclosporine, protease inhibitors, or drugs metabolised
through cytochrome P450) [191].
Bile acid sequestrants (BAS) and cholesterol absorption inhibitors (CAI) lower the LDL-C by
decreasing the absorption of intestinal bile acids and cholesterol, respectively. BAS results in 15 to
30% reductions in LDL-C [192]. The only clinically available CAI, ezetimibe, has been shown to result
in 15–25% reductions in LDL-C [193]. Although BAS and CAI are both effective as monotherapy, the
greater benefits are obtained when used in combination with statins, an effect that may be due to their
complementary mechanism of actions [194]. The study trial has shown that BAS and ezetimibe reduce
the potential risk of major coronary events in patients with the MetS [195].
6.10. Hypertension
Categorical hypertension (BP ≥ 140/≥ 90 mm Hg) should be treated according to the USA JNC VII
guidelines on the prevention, detection, evaluation, and treatment of the high blood pressure
recommendations [124]. Antihypertensive drugs should be introduced at even lower blood pressures
(≥130/≥80 mm Hg) in the patients with established diabetes. Mild elevations of blood pressure often
can be effectively controlled with the lifestyle therapies. A simple 5% weight reduction in obese
women lowered the systolic blood pressure by 7 mmHg and was associated with the decreased levels of
angiotensinogen (−27%), renin (−43%), angiotensin-converting enzyme (−12%), aldosterone (−31%),
and angiotensinogen expression in adipocytes (−20%) [196]. It is estimated that 5 mmHg reduction of
systolic blood pressure across the general population would result in overall reductions of 14% in
stroke mortality, 9% in CHD mortality, and 7% in all cause mortality [197]. However, if hypertension
cannot be adequately controlled by lifestyle therapies, antihypertensive drugs usually are necessary to
prevent the long-term adverse effects, for example, MI, stroke, and CKD [124]. It has been proposed
that angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should
be the first-line classes of agents in the MetS, especially in the setting of diabetes or CKD [198]. ARBs
may be used in those who cannot tolerate ACE inhibitors or as an alternative to ACE inhibitors in
people who have a left ventricular dysfunction [199]. Certainly these classes of agents have been
shown to be effective in reducing the incidence of albuminuria or progression of nephropathy in
patients with diabetes [200]. Although a number of trials have shown that ACE inhibitors and ARBs
may reduce the risk of diabetes [201], a more recent study designed to examine this issue directly
found that the ACE inhibitor ramipril did not prevent the progression of diabetes in persons with IFG
or IGT [202]. In general, treatment with these classes of drugs reduces the rate of new-onset diabetes as
compared with the use of diuretic and/or β-blockers [203] but the long-term safety and efficacy of β-
blockers and diuretics has been effectively demonstrated in many clinical trials, including the
Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) that included
>40,000 patients [204]. The ALLHAT showed that the treatment with a thiazide-type diuretic in
patients with the MetS results in superior CVD outcomes compared to the treatment with calcium
channel blockers, β-blockers, or ACE inhibitors despite the less favourable metabolic profile associated
with the thiazide diuretics [205]. The ALLHAT and the United Kingdom Prospective Diabetes Study
(UKPDS) have shown that agents such as thiazide diuretics and β-blockers lower the risk of CVD
events even in the patients with diabetes [206]. These agents, however, have also been associated with
an increased risk for diabetes [205, 206]. Certainly the majority of patients who need an
antihypertensive therapy will likely need more than one agent for the proper blood pressure control
[207].
6.11. Insulin Resistance and Hyperglycemia

In MetS, patients with IFG (or IGT if assessed), weight reduction, increased physical activity, or both
will delay (or prevent) the onset of T2DM [137]. In addition, metformin [137], thiazolidinediones
[208], and acarbose [209] will lower the risk of T2DM in people with IFG or IGT. Metformin, which
has a primary mechanism of action of reducing hepatic glucose production, has been shown to reduce
the progression of diabetes from IGT by approximately 31% in the DPP, of which 53% had the MetS
[137]. Incidence of the MetS was also reduced by 17% in the metformin-treated group of the DPP,
which was driven primarily by improvements in WC and fasting glucose, whereas, intensive
therapeutic lifestyle changes reduced this risk by 58% compared to placebo [210]. Other cardiac risk
factors, however, did not improve with metformin to the same degree as with the intensive lifestyle
intervention [211]. The study trial has suggested that metformin is in fact treating IGT and not
necessarily “preventing” progression to T2DM in the long-term follow-up [212]. In the Study to
Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM) trial, acarbose, a drug that affects
carbohydrate absorption and is approved for the treatment of T2DM, was also shown to reduce the
progression to T2DM in individuals with IGT [209]. This trial also showed that acarbose treatment was
in fact associated with reduced CVD and hypertension [213]. The main limitation of the use of this
agent is its poor patient tolerability. Pioglitazone has been shown to reduce the multiple components of
MetS such as high blood pressure, high blood glucose, and TGs in addition to a decrease in urinary
albumin/creatinine ratio [214]. It was concluded that pioglitazone may be useful in the prevention of
cardiovascular events in high risk patients with T2DM although the usefulness of this approach in
MetS or IGT subjects is not clear. However, no clinical trial evidence is yet available to document that
the oral hypoglycemic agents will lessen the risk for cardiovascular events in MetS, IGT, or IFG except
for a preliminary trial with acarbose [213].
6.12. Hypercoagulable State

Measurement of CRP is the most practical way to assess the presence of an inflammatory state. An
elevated CRP (≥3 mg/L) is an emerging risk factor for CVD [123]. The AHA and CDC [215] recently
issued guidelines for the measurement of CRP in the clinical practice. They suggested that such
measurements can be made at the physician's discretion, but testing should be limited to the individuals
assessed to be at an intermediate risk by Framingham scoring, that is, those whose 10-year risk for
CHD is in the range of 10% to 20%. Several drugs used to treat the other metabolic risk factors have
been reported to reduce the CRP levels (e.g., statins, nicotinic acid, fibrates, ACE inhibitors, and
thiazolidinediones) [216]. However, these drugs cannot be recommended specifically to reduce a
proinflammatory state independent of their indications for the other risk factors. Furthermore, The
Justification for the Use of statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin
(JUPITER) trial [217] has emphasized an added benefit of statin in targeting the individuals with high
CRP levels even in the presence of normal LDL. Low-dose aspirin is frequently recommended to the
patients with MetS [218]; however, the use of aspirin in the primary prevention of CVD should remain
as an “individual clinical judgment” [219]. Further, there is no evidence to indicate that the use of
aspirin in low-risk groups (<6%) is beneficial, and the risk of haemorrhage outweighs the benefit in
this category. Patients in the low intermediate risk group (6–10%) will need an individualized decision-
making, whereas most patients in the conventional intermediate risk category (10–20%) should receive
aspirin. Blaha et al. have advised that all older patients (≥65 years old) and patients at high
Framingham risk with MetS should receive a low-dose aspirin in the absence of contraindications
[220]. A recently published meta-analysis shows that aspirin significantly reduces the risk of first MI
by a third, stroke by approximately one-third, and CVD by approximately one sixth [221].
7. Conclusion
MetS is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic
factors that directly increases the risk of atherosclerotic cardiovascular disease, type 2 diabetes
mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia,
chronic stress are the several factors which constitute the metabolic syndrome. Lifestyle modification
remains the initial intervention of choice for this population. Modern lifestyle modification therapy
combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological
treatment should be considered for those whose risk factors are not adequately reduced with lifestyle
changes.
A realistic goal for overweight/obese persons is to reduce the body weight by >7% to 10% over a
period of 6 to 12 months. Weight reduction should be combined with a daily minimum of 30 minutes of
moderate-intensity physical activity. Nutritional therapy calls for a low intake of saturated and total fat
intake; reduced consumption of simple sugars and high glycemic index foods; and increased intakes of
fruits, vegetables, legumes, and whole grains. Statins can be combined with fibrates and niacin to
achieve the target levels of LDL-C, triglycerides, and HDL-C. Further, the majority of patients who
need an antihypertensive therapy will likely need more than one agent for the proper blood pressure
control with ACEI/ARBs and beta blockers/Thiazides/CCBs as the first and second line agents,
respectively. Metformin, thiazolidinediones, and acarbose will lower the risk for type 2 diabetes
mellitus in people with IFG or IGT.
Acknowledgment
The author is grateful to all his patients who realized and encouraged him to write a review on
metabolic syndrome.
Conflict of Interests
The author declares that there is no conflict of interests regarding the publication of this paper.
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3/3/2020 A Comprehensive Review on Metabolic Syndrome

Cardiol Res Pract. 2014; 2014: 943162. PMCID: PMC3966331

This article has been retracted.

A Comprehensive Review on Metabolic Syndrome

Received 2013 Nov 20; Accepted 2014 Jan 19.

Copyright © 2014 Jaspinder Kaur.

Blood ≥140/90 mm Hg ≥140/90 ≥130/85 ≥130/85 mm Hg ≥130 mm Hg

Other Microalbuminuria: Other features of

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Country/ethnic group Waist circumference cut-off

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5.1. Abdominal Obesity

5.2. Insulin Resistance

5.6. Endothelial Function

5.7. Hypercoagulable State

5.9. Chronic Stress and Glucocorticoid (GC) Action

Renal Microalbuminuria, hypofiltration, hyperfiltration, glomerulomegaly, focal segmental

6.1. Risk Assessment

6.2. Lifestyle Modification

A: aspirin High risk: aspirin definitely beneficial.

B: BP control Initiate treatment: categorical hypertension (BP ≥ 140/≥90 mm Hg).

C: cholesterol Statin to achieve LDL-C <100 mg/dL in high-risk, <130 mg/dL in intermediate-risk, and

D: diabetes Intensive lifestyle modification is the most important therapy.

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6.3. Weight Reduction

6.5. Physical Activity

6.6. Behaviour Therapy

6.7. Pharmacological Approach

6.8. Bariatric Surgery

Risk category LDL-C goals Recommendations

Moderate risk <130 mg/dL Lifestyle modifications

Moderately high risk <130 mg/dL Lifestyle modifications

High risk <100 mg/dL Lifestyle modifications

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6.11. Insulin Resistance and Hyperglycemia

6.12. Hypercoagulable State

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206. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme

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