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]. Metabolic Syndrome and Its Implications Essay. 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.

5.2. 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.Metabolic Syndrome and Its Implications Essay.  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. Metabolic Syndrome and Its Implications Essay. 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.Metabolic Syndrome and Its Implications Essay.  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.Metabolic Syndrome and Its Implications Essay.

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].

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].

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]. Metabolic Syndrome and Its Implications Essay. 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]. Metabolic Syndrome and Its Implications Essay. 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. Metabolic Syndrome and Its Implications Essay.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]. Metabolic Syndrome and Its Implications Essay.

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].

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].Metabolic Syndrome and Its Implications Essay.  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]. Metabolic Syndrome and Its Implications Essay.

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].

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