ABSTRACT

The metabolic syndrome (MetS) is a compilation of risk factors that predispose individuals to the development of type 2 diabetes (T2DM) and cardiovascular disease (CVD) first described in 1988 by Reaven. Since then multiple definitions of the syndrome have been proposed, the most recent being the Harmonized Definition where 3 of the 5 risk factors are present: enlarged waist circumference with population-specific and country-specific criteria; triglycerides ≥ 150 mg/dL, HDL-c < 40 mg/dL in men and < 50 mg/dL in women, systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg and fasting glucose > 100 mg/dL, with the inclusion of patients taking medication to manage hypertriglyceridemia, low HDL-c, hypertension and hyperglycemia. In the years since its definition, there have been mixed results from studies examining MetS’ comparative ability in predicting CVD and T2DM over traditional risk models. Despite this, it continues to be used both in clinical practice as well as the research arena. Insulin resistance is thought to play a paramount role in connecting the different components of MetS and adding to the syndrome's development. Insulin resistance has been demonstrated to alter glucose and lipid metabolism. In addition, elevated free fatty acids, a pro-inflammatory state, increased oxidative stress, and alterations in adipokine profile have all been described in animal models as well as patients with MetS. T2DM, dyslipidemia, non-acoholic fatty liver disease, polycystic ovarian syndrome, obstructive sleep apnea, sexual dysfunction, and cancer are among the disease states associated with MetS. The association is not surprising given commonalities pathophysiologic pathways thought to be essential in their genesis. Ultimately, as a clinical tool, MetS should heighten attention and focus treatment on its components in an effort to reduce risk of CVD and other sequelae of MetS. Lifestyle modifications including increased physical activity and dietary changes are considered a paramount component of treatment for with strong evidence in its efficacy of treating individual components. Beyond lifestyle modifications, further treatment lies in treatment specifically for obesity, dyslipidemia, hypertension and impaired glucose tolerance in which there have been advances. For in depth review of all related aspects of endocrinology, visit www.endotext.org.

BACKGROUND

The metabolic syndrome (MetS) is a compilation of risk factors that predispose individuals to the development of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Reaven (1) first described MetS in his 1988 Banting lecture as “Syndrome X. ” Reaven suggested that insulin resistance clustered together with glucose intolerance, dyslipidemia and hypertension to increase the risk of cardiovascular disease. The initial definition of metabolic syndrome included impaired glucose tolerance (IGT), hyperinsulinemia, elevated triglycerides (TG) and reduced high-density lipoprotein cholesterol (HDL-c). Hyperuricemia, microvascular angina and elevated plasminogen activator inhibitor 1 (PAI-1) were later proposed as possible additional components of the same syndrome (1,2). Obesity was not included as part of Syndrome X as Reaven believed that insulin resistance, not obesity, was the common denominator. Reaven noted that all of the elements of Syndrome X could occur in non-obese individuals, and while he acknowledged that obesity could lead to a decrease in insulin mediated glucose uptake, he stressed that obesity was only one of the environmental factors that affect insulin sensitivity (3,4).

The World Health Organization (WHO) produced the first formalized definition of the MetS in 1998. The working definition included impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or diabetes mellitus and/or insulin resistance (as measured using a hyperinsulinemic euglycemic clamp study) together with two or more additional components. Additional components included hypertension (defined as a blood pressure ≥160/90 mm Hg), raised plasma triglycerides (≥150 mg/dl) and/or low HDL-cholesterol (<35 mg/dl for men and <39 mg/dl for women), central obesity (defined either as body mass index (BMI) > 30 kg/m² or waist to hip ratio>0.90 for males and >0.85 for females) and microalbuminuria (5). Critics questioned the practicality of this definition given the need for a hyperinsulinemic clamp study. Others argued that measuring waist circumference was superior in terms of convenience to the waist to hip ratio with similar correlations to obesity. Additionally, there was a question about the value of including microalbuminuria in the definition as there was insufficient evidence of a connection with insulin resistance (5).

These critiques led to the first revision of the definition of the syndrome in 1999 by the European Group for the Study of Insulin Resistance (EGIR). They renamed the syndrome the “insulin resistance syndrome” (IRS) as it included non-metabolic features. They excluded patients with diabetes because of the difficulty of measuring insulin resistance in these individuals. The need for hyperinsulinemic clamp studies was obviated by defining insulin resistance as a fasting insulin level above the 75^th percentile for the population. Additional criteria (elements associated with increased risk of coronary artery disease by the Second Joint Task Force of European and other Societies on Coronary Prevention) were also included, namely obesity (defined as waist circumference ≥ 94 cm (37 inches) for men and ≥ 80 cm (32 inches) for women), hypertension (now defined as a blood pressure ≥140/90 mm Hg) and dyslipidemia (with triglycerides ≥ 180 mg/dl or HDL-c ≤ 39). Additionally, microalbuminuria was omitted from the definition (6).

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) recognized that these multiple metabolic elements were cardiovascular risk factors and renamed the constellation of these metabolic risk factors as “The Metabolic Syndrome” (7). The criteria included any three of the following: obesity (defined as waist circumference ≥ 102 cm (40 inches) in males and ≥ 88 cm (35 inches) in females (based on the 1998 National Institutes of Health (NIH) obesity clinical guidelines), hypertension (defined as blood pressure ≥ 130/85 mm Hg based on the Joint National Committee guidelines), fasting glucose > 110 mg/dL, triglycerides ≥ 150 mg/dL and HDL-c < 40 mg/dL. Additionally, in this report MetS was recognized as a secondary target of risk reduction therapy after the primary target of LDL cholesterol (7).

In 2003, the American Association of Clinical Endocrinologists (AACE) modified the ATP III criteria and restored the condition to the name “Insulin Resistance Syndrome,” again highlighting the central role of insulin resistance in the pathogenesis of the syndrome (8). This definition did not rely on strict diagnostic criteria. The components of the syndrome included some degree of glucose intolerance (but not overt diabetes), abnormal uric acid metabolism, dyslipidemia, hemodynamic changes (including hypertension), prothrombotic factors, markers of inflammation and endothelial dysfunction. The AACE position statement also identified factors that increased the likelihood of developing the insulin resistance syndrome, including a diagnosis of CVD, hypertension, polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD) or acanthosis nigricans, a family history of T2DM, hypertension or CVD, a personal history of gestational diabetes (GDM) or glucose intolerance, non-Caucasian ethnicity, a sedentary lifestyle, overweight/obesity (defined as BMI > 25 kg/m² or waist circumference > 40 inches in men and > 35 inches in women) and age > 40 years (8).

The International Diabetes Federation (IDF) aimed to create a straightforward, clinically useful definition to identify individuals in any country worldwide at high risk of CVD and diabetes and to allow for comparative epidemiologic studies. This resulted in the IDF consensus definition of MetS in 2005 (9). Central obesity, as defined as BMI> 30 kg/m² or if ≤ 30 kg/m² by ethnic specific waist circumference measurements) was a requisite for the syndrome. Additionally, the definition required the presence of two of the following four elements: triglycerides ≥ 150 mg/dL, HDL-c < 40 mg/dL in men or < 50 mg/dL in women, systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg, fasting glucose > 100 mg/dL ( based on the 2003 ADA definition of IFG) (10) including diabetes and those with a prior diagnosis of or treatment of any of these conditions (9).

In 2005, the American Heart Association (AHA)/ National Heart, Lung and Blood Institute (NHLBI) also suggested criteria for diagnosis of the metabolic syndrome. Their revised definition of the metabolic syndrome was based on the ATP III criteria and required three of any of the five following criteria: elevated waist circumference ( ≥ 102 cm (40 inches) in males and ≥ 88 cm (35 inches) in females) , triglycerides ≥ 150 mg/dL and HDL-c < 40 mg/dL in men and < 50 mg/dL in women, elevated blood pressure ≥ 130/85 mm Hg and elevated fasting glucose > 100 mg/dL (11). As suggested by the IDF, ethnic-specific waist circumferences were taken into account when using this definition. Additionally, impaired fasting glucose was defined as >100, which was also consistent with the IDF guidelines.

Despite the efforts by the IDF and AHA/NHBLI to provide a more unified definition for practitioners and researchers alike, all of these conflicting definitions led to confusion on how to identify patients with MetS and inconsistencies that proved difficult when trying to compare different epidemiologic research studies.

DEFINITION

In an effort to provide more consistency in both clinical care and research of patients with MetS, the IDF, NHBLI, AHA, World Heart Federation and the International Association for the Study of Obesity published a joint statement in 2009 that provided a “harmonized” definition of MetS (12). According to this joint statement, a diagnosis of the MetS is made when any 3 of the 5 following risk factors are present (Table 1): enlarged waist circumference with population-specific and country-specific criteria; elevated triglycerides, defined as ≥ 150 mg/dL, decreased HDL-c, defined as < 40 mg/dL in men and < 50 mg/dL in women, elevated blood pressure, defined as systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg and elevated fasting glucose, defined as blood glucose > 100 mg/dL, with the inclusion of patients taking medication to manage hypertriglyceridemia, low HDL-c, hypertension and hyperglycemia. This definition is frequently referred to as the current Harmonization definition.

*Drug treatment for elevated triglycerides, low HDL-c, elevated blood pressure or elevated glucose are alternate indicators

It is important to note that in the current Harmonization definition, obesity is diagnosed using waist circumference and not BMI as waist circumference has been shown to better correlate with visceral adiposity and insulin resistance as well as the development of T2DM and CVD than does BMI (9,13,14). Contrary to earlier findings, a recent meta-analysis has demonstrated the superiority of waist to height ratio as compared to both waist circumference and BMI (15). It is not clear if other studies will confirm this or if the definition of MetS will be revised over time to reflect these new findings. Additionally, in the current Harmonization definition, ethnic-specific waist circumference cut-off values are used, as it has been shown that (16) certain ethnic groups, especially South Asian populations, have higher degrees of visceral adiposity for given waist circumference measurements compared to Europeans (9,12,17).

The clinical utility of a diagnosis of MetS has been studied extensively. A meta-analysis using earlier definitions of MetS found that a diagnosis of MetS was associated with an increased relative risk of developing T2DM of 2.99 (1.96-4.57) and an increased relative risk of cardiovascular disease of 1.65 (1.38-1.99) (18). A more recent systematic review and meta-analysis pooled 87 studies including 951,083 patients, using 2001 NCEP and 2004 rNCEP MetS definitions, and found a similar increase in the risk of cardiovascular outcomes as well as an increase in all-cause mortality (RR 2.35 and RR 1.54 respectively) (19). A study by Pajunen and colleages comparing the predictive ability of various definitions of MetS, namely the WHO, ATP III, IDF and new Harmonization definitions, found that all these definitions of MetS were significant predictors for incident CVD and T2DM. Additionally, the new Harmonization definition was found to be a better predictor of CVD endpoint than the sum of its components, but this was not the case for T2DM (20).

Substantial controversy continues to center on MetS, in terms of its existence, its definitions and its clinical significance. Critics question if the diagnosis of MetS adds to the Framingham risk factors for predicting the development of CVD or to the fasting glucose in predicting T2DM. In 2004, Stern and colleagues compared the predictive ability of the diagnosis of MetS (ATP III criteria) with the Framingham Risk Score for CVD and the Diabetes Predicting Model and found MetS inferior to both of these established predictive models (21). Wannamethee et al. also compared the predictive value of MetS (ATP III criteria) with the Framingham Risk Score as predictors of CVD, stroke, and T2DM in middle-aged men. They found that the Framingham Risk Score was a better predictor of CVD and stroke than MetS but MetS was more predictive of T2DM (22). Patients with metabolic syndrome, according to the ATP III definition, were found to have a greater prevalence, severity, and prognosis of CAD, as assessed by coronary CT angiography, compared to patients with 1 but not 2 components of metabolic syndrome (16). It is important to note that these studies were conducted using the ATP III criteria, and that the outcomes of these studies may have been different if the new Harmonized definition was used. In fact, Pajunen and colleagues reported that the new Harmonization definition of MetS was a better predictor of CVD than the Framingham Risk Score (20). In a cohort of elderly Chinese, MetS, according to the Harmonized definition, was found to be predictive of all-cause and CVD mortality in men but not women after adjustment for age, gender, LDL-C, smoking and drinking history(23).

Others argue that making the diagnosis of MetS does not change the clinical management of these patients, as treatment of patients with MetS starts with diet and exercise and most physicians would offer the same recommendations to a patient with any of the individual elements of MetS (24,25). However, several studies have described the existence of obese individuals who are metabolically normal and are not necessarily at an increased risk of developing CVD or T2DM, despite their weight (26,27). On the other hand, the National Health and Nutrition Examination Survey reported that obesity in the absence of metabolic derangements is a rare occurrence. Additionally, it found that obese, metabolically normal patients have an increased all-cause mortality similar to that of obese, metabolically abnormal individuals (28).

In an attempt to settle some of the controversy, a WHO Expert Consultation was undertaken in November 2008. The panel concluded that MetS has limited practical utility as a diagnostic or management tool. They determined that MetS should not be applied as a clinical diagnosis, but rather should be considered a pre-morbid condition and people with established diabetes or known cardiovascular disease should be excluded (29). They also stated that further attempts to redefine it are inappropriate in light of current knowledge and understanding (30). Despite the conclusions of the panel, the diagnosis of MetS is still commonly encountered in clinical practice as well as in the research arena.

PREVALENCE

The prevalence of MetS depends on the definitions used as well as the population being studied (31). Prevalence rates vary greatly depending on criteria used to define MetS, the age, gender, ethnicity and environment of the population being studied and obesity prevalence of the background population. Regardless of which criteria are used, however, the prevalence of MetS is high and is on the rise in many western societies(32).

The National Health and Nutrition Examination Survey (NHANES) reported the age-adjusted prevalence of MetS between 2009 and 2010 at 22.9%, a decrease from 25.5% between 1999 and 2000, in the United States population ≥ 20 years (29). Prevalence of MetS increased with age (a finding that has been seen in other studies worldwide (31,33,34). Among males, Mexican Americans have the highest prevalence at 34.76%. The prevalence is lower in African American men (18.99%) than in White American men (22.91%). Among women, White Americans had the lowest prevalence (20.28%) compared to African American (24.51%) and Mexican American (28.50%)(29). Similar to Mexican Americans, other studies have shown that American Indian, Hawaiian, Polynesian and Filipino populations develop MetS more than individuals of European descent (33,35-39). Based on the ATP III criteria, European studies report MetS prevalence rates to be from 10-26%, studies in India report rates between 7.9-46.5% in different populations, studies in Iran find rates of 24% in men and 42% in women, and in Turkey studies report rates of 27% in men and 38.5% in women (33). Rates of MetS in Japan are lower, with a prevalence of 8.1% in men and 9.9% in women (40). Urban populations have higher rates of MetS than rural populations (41,42). Similar to trends in western societies, recent studies demonstrate rising rates of MetS in many developing countries (43,44). The westernization of these countries, bringing along a higher calorie diet and decreased physical activity, is thought to be largely response for the increased rate of MetS that is being observed (32,45,46). In the elderly, the Lifestyle Interventions and Independence for Elders Study, reported a prevalence of 49.8% in a population of community-dwelling sedentary adults aged 70 to 89 (47). In summary, MetS affects a significant amount of individuals worldwide.

PATHOGENESIS

There are many different factors that contribute to the development of MetS. Genetics, lifestyle (such as diet and physical activity), obesity and insulin resistance can all play a role. These are all important elements in the pathogenesis of MetS. However, as initially proposed by Reaven, insulin resistance is thought to play a paramount role in connecting the different components of MetS and adding to the syndrome's development (1,48). Elevated free fatty acids (FFA) and abnormal adipokine profiles can result in the setting of insulin resistance and can contribute to the pathogenesis of MetS (49). In this section, we will discuss how these factors add to the development of the metabolic abnormalities that characterize insulin resistance and MetS.

Insulin Action and Signaling

In order to discuss how dysfunctional insulin action and signaling contribute to MetS, it is important to first review normal insulin action and signaling.

In individuals with normal insulin sensitivity, the pancreatic β-cells release insulin in response to increased circulating glucose levels, as seen in the post prandial state. Insulin subsequently decreases plasma glucose concentrations by coordinately suppressing hepatic glucose production from amino acids and other intermediates of metabolism (gluconeogenesis) and glycogen (glycogenolysis), and enhancing glucose uptake into the muscle and adipose tissue (Fig. 1). In these tissues, insulin increases the mobilization of the insulin-responsive glucose transporter 4 (GLUT4) from intracellular storage vesicles to the cell surface, thereby enhancing glucose uptake (50). GLUT4 expression correlates with insulin sensitivity and it increases with exercise (51).

Aside from its effect on glucose uptake, insulin also inhibits lipolysis in adipose tissue by inhibiting hormone sensitive lipase, an enzyme that mediates the hydrolysis of triglycerides (TG) into FFAs and glycerol (49). Insulin also promotes adipogenesis and adipose tissue differentiation by stimulating the nuclear receptor PPARγ. Thiazolidinediones (TZDs) are PPARγ agonists that promote insulin sensitivity by activating a program of adipogenesis resulting in the storage of glucose as TG. Interestingly, while PPARγ represses GLUT4 under normal conditions, TZDs mediate the de-repression of the GLUT4 by sequestering PPARγ (52). Insulin also activates lipoprotein lipase in adipose tissue, an enzyme that hydrolyzes TG present in very low-density lipoprotein (VLDL) and chylomicrons particles to FFAs, mediating their subsequent uptake into the cells. Insulin has also been shown to inhibit hepatic VLDL synthesis and secretion in a phosphatidylinositol 3-kinase (PI3K) – dependent manner (53,54). Fatty acid synthase is also affected by the presence of insulin; it is inhibited by insulin in the acute setting and paradoxically enhanced by insulin under conditions of chronic hyperinsulinemia (55).

At the cellular level, insulin binds to the insulin receptor (IR) which is a hetero-tetramer belonging to the receptor tyrosine kinase family of cellular receptors. Insulin binding results in activation of the IR by trans-phosphorylation of the IR leading to the subsequent phosphorylation of adaptor proteins, including the insulin receptor substrates 1 and 2 (IRS1, IRS2), Gab, Shc and APS, that form docking sites for further downstream effectors (56). Insulin mediates its metabolic activity via PI3K while its mitogenic effects occur through the mitogen-activated protein kinase (MAPK) pathway (57). Activation of PI3K leads to the activation of protein kinase AKT which is responsible for mediating the effects of insulin on glucose transport and storage, protein synthesis and prevention of lipid degradation (49,58). Additionally, signaling via a second pathway that involves tyrosine phosphorylation of the oncogene Cbl and its associated proteins CAP also results in GLUT4 mobilization to the cell surface and enhanced glucose uptake (59)

One of the prominent targets of insulin is the transcription factor FOXO1 (forkhead box class O member 1) (57,60). FOXO1 affects hepatic gluconeogenesis, and also inhibits the transcription of PPARγ, an important insulin target in the adipose tissue (61,62). Insulin mediates the phosphorylation of FOXO1 downstream of the PI3K/ Akt pathway leading to its nuclear exclusion (62). Under conditions of insulin resistance, increased FOXO1 transcriptional activity mediates hyperglycemia by activating gluconeogenesis and suppressing β-cell proliferation and adipogenesis (63). Insulin resistance can also lead to decreased sensitivity of the muscle and adipose tissue to insulin (64).

In addition to effects on glucose metabolism, insulin resistance leads to a disruption in lipid metabolism. The insulin resistant state has been associated with alterations in chylomicrons, VLDL and LDL (65). Chylomicron levels are increased a result of a loss of normal suppression by insulin and a reduction in hydrolysis due to alterations in lipoprotein lipase activity (66,67). VLDL production has been found to increase in insulin resistant, non-diabetic women with abdominal obesity as a result of increased production (68). In patients with type 2 diabetes, LDL cholesterol catabolism and its affinity for LDL B/E receptors have also been shown to be altered (65).

Apart from its peripheral effects, insulin also acts centrally. Insulin regulates appetite centrally by influencing the expression of orexigenic (neuropeptide Y (NPY) and Agouti-related protein (AgRP)) and anorexigenic (pro-opiomelancortin (POMC)) neuropeptides (69). Insulin decreases NPY synthesis and AgRP release, while increasing POMC synthesis in the arcuate nucleus of the hypothalamus, leading to a decrease in food intake (70) (71). It has been also suggested that in obesity and insulin-resistance, there is a relative CNS insulin resistance that may favor weight gain and increased peripheral insulin resistance (72,73).

Through its complex signaling cascades, insulin regulates glucose and fat metabolism. In conditions of insulin resistance, insulin signaling and action are compromised.

Figure 1

Normal Insulin Action: In individuals with normal insulin sensitivity, the pancreatic β-cells release insulin in response to increased circulating glucose levels (as seen in the postprandial state). Insulin then decreases the plasma glucose concentration by suppressing hepatic glucose output and enhancing glucose uptake into adipose tissue and by skeletal

EFFECTS OF INSULIN RESISTANCE

All of the aforementioned factors involved in the pathogenesis of insulin resistance and MetS lead to the metabolic effects that characterize this syndrome. Below we will discuss some of the important clinical metabolic sequelae of MetS, namely hyperglycemia and T2DM, HTN, Dyslipidemia, NAFLD, PCOS, Obstructive Sleep Apnea (OSA) and Sexual Dysfunction.

TREATMENT

In patients with MetS, aggressive approaches toward lifestyle modification, such as dietary restriction, increased physical activity, smoking cessation and reduction of alcohol intake play a paramount role in treatment, as these factors all play a role in the metabolic dysfunction comprising MetS (227,228). Reducing the risk of cardiovascular disease is at the forefront of treating MetS. Rapid identification of patients with MetS, followed by long-term intervention and monitoring by primary care physicians is imperative. As no single underlying mechanism has been identified, treatment of the individual causes is necessary (Table 2). It is recommended that physicians monitor blood pressure, fasting glucose, lipid profile, liver and kidney functions along with body weight, height and waist circumference. In certain individuals, a hemoglobin A1C or a glucose tolerance test may be necessary as recommended by the American Diabetes Association guidelines(229). To determine a risk category for coronary artery disease, the Framingham risk score can be calculated. In those with an elevated risk for CAD, a cardiac stress test may be warranted (144).

LDL-c: Low density lipoprotein cholesterol, HDL-c: High density lipoprotein cholesterol, NAFLD: non-alcoholic fatty liver disease, n-3 PUFAs: Omega 3 Polyunsaturated Fatty Acids, OCPs: oral contraceptives PCOS: polycystic ovarian syndrome, OSA: obstructive sleep apnea, PDE-5 inhibitors: Phosphodiesterase 5 inhibitors, IGF-1: Insulin like growth factor I, IGF-II: Insulin like growth factor II

Lifestyle modification is perhaps the most important intervention in treatment of MetS. The Diabetes Prevention Program demonstrated that lifestyle intervention reduced the incidence of MetS by 41% compared with placebo. The intensive lifestyle intervention involved a healthy low-calorie, low fat diet and moderate physical activity of at least 150 minutes/week, resulting in a weight reduction of 7% (230). The recommended diet should include < 200 mg/day of cholesterol, < 7% saturated fat, with total fat comprising 25-35% of calories, low simple sugars and increased fruits, vegetables and whole grains(11). Smoking cessation should be instituted in all patients with MetS. Additionally, low dose aspirin is recommended in cases of moderate to high cardiovascular risk where no contraindication to aspirin therapy exists (11).

For those patients in whom lifestyle intervention is not sufficient to treat their MetS, pharmacotherapy for the treatment of many of the components of MetS is available. Many of the medications aimed to treat obesity have failed to gain approval or have been removed from the market by the FDA due to side effects and marginal success in weight reduction (144).

Orlistat, an inhibitor of gastrointestinal lipase activity, is the most widely used medication for weight reduction. In a four year trial, Orlistat when added to lifestyle changes, led to greater weight loss as compared to placebo and significantly reduced the incidence of T2DM (231). Orlistat has also been shown to help in weight loss maintenance. Orlistat, in addition to lifestyle intervention, was associated with maintenance of an extra 2.4kg weight loss after very low energy diet for up to 3 years in obese individuals (232).

Lorcaserin, a selective serotonin (5-HT) 2C agonist received FDA approval in 2012 for the treatment of obesity for adults with BMI > 30 kg/m² or > 27 kg/m² with one weight-related health condition. In the BLOOM study, a mult-center double blinded clinical trial, 47.5% of patients treated with lorcaserin demonstrated > 5% weight loss in the first year which was maintained in the second year by 67.9% of patients (233). In patients with type 2 diabetes, similar weight loss was observed as well as lowering of HbA1C by 0.9-1% in the treated groups (234). . Lorcaserin was well tolerated but in some studies increased the risk of cardiac valvulopathy in patients with diabetes and various malignancies in laboratory animals (235). The combination medication phentermine-topiramate received FDA approval in 2012 for the treatment of obesity in patients with a BMI > 27 kg/m² or higher with at least on comorbidity. Phentermine is a sympathomimetic amine used for appetite suppression, the mechanism of action of topiramate in weight loss is unclear and as monotherapy is used in the treatment of epilepsy and migraine headache prophylaxis. In the EQUIP trial, a 56 week randomized controlled trial comparing placebo with two different doses of the combination medication, up to 67% of patients lost at least 5% of their baseline body weight (236). Another combination medication, buproprion/naltrexone, was approved in 2014 for the treatment of obesity in those with a BMI > 30 kg/m² or > 27 kg/m² with one weight-related health condition. In a phase 3, randomized double-blind trial, change in body weight after 56 weeks of treatment was up to 6.1% in the higher dose treatment arm with 48% of those receiving treatment losing more than 5% of body weight (237).

The most recent medication to receive approval for treatment of obesity is liraglutide, previously approved in the treatment of type 2 diabetes, given in a higher-dose formulation. In a 20 week study with 2 year extension, liraglutide was found to be superior to placebo as well as orlistat in weight loss (238).

Individuals with morbid obesity (BMI> 40 kg/m² or >35 kg/m² with comorbidities) may be candidates for bariatric surgery (239). Bariatric surgery has been demonstrated to be an effective treatment of obesity with improvements in weight, T2DM, hypertension, hyperlipidemia, and sleep apnea. Resolution rates of each component reported in the literature are variable, the type of surgery highly influential on the resolution of comorbidities (240). Some studies demonstrate superiority of surgical to nonsurgical treatment in weight loss and MetS (241).

There are no pharmacologic agents specifically approved for prevention of T2DM. In the Diabetes Prevention Program, Metformin was shown to lead to weight loss and a 31% decrease in the incidence of T2DM than patients receiving placebo (230). It has been suggested that GLP-1 receptor agonists, agents now commonly used in the treatment of established T2DM, may have a role in prevention of T2DM, but more studies are needed. The American Diabetes Association recommends lifestyle modification over medication for the prevention of diabetes. However, they state that Metformin therapy may be considered for the prevention of T2DM in individuals with IGT, IFG or HgA1c 5.7-6.4%, especially for those individuals with BMI> 35 kg/m2, those aged < 60 years and those with a prior diagnosis of GDM (242,243).

Elevated blood pressure is first approached with lifestyle modification. If this fails to bring the blood pressure to goal range <140/90 or <130/80 in patients with diabetes or CKD, medication should be added. First line medications include thiazide diuretics in uncomplicated individuals, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in those with diabetes, congestive heart failure or CKD, or beta blockers in individuals with angina (244).

Drug therapy for dyslipidemia is generally approached with the use of HMG Co-A reductase inhibitors (statins). The primary objective in CVD risk reduction is to lower LDL-c values and the drug of choice for this purposes is statins, which have been shown not only to lower LDL-c, but also to modestly raise HDL-c and lower triglycerides (228). The second targets in lipid improvement to reduce CVD risk are HDL-c and triglycerides. Niacin is effective at raising HDL-c as well as lowering triglycerides and LDL-c. Fibrates are effective at lowering triglycerides but do not have the beneficial effects on HDL-c and LDL-c. Omega-3 polyunsatured fatty acids (n-3 PUFA) in fish oil can also be used to lower triglycerides (49).

There is no proven effective medical therapy for NAFLD. As with the other components of the metabolic syndrome, lifestyle modification is first-line. A small randomized controlled trial demonstrated that weight loss can lead to reduction in the NAS score, an aggregate score of steatosis and NASH histological activity (245). Even without weight loss, exercise alone can reduce hepatic fat content(246). Pharmacologic agents, such as n-3 PUFAs and ezetimibe, may play a role in preventing and improving NAFLD, but further study is necessary to define their role (159). Agents that improve insulin sensitivity, such as metformin and TZDs, have been postulated to be of benefit in the treatment of NAFLD. Pioglitazone was studied compared to vitamin E and placebo for 2 years and demonstrated improvement in histologic features and resolution of steatohepatitis more than placebo (247). A meta analysis of four clinical trials demonstrated improvement in liver histology and fibrosis in patients treated with pioglitazone (248). Current recommendations from the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association do not recommend metformin in the specific treatment for NAFLD due to a lack of evidence supporting significant effect liver histology (249). Both vitamin E and pioglitazone can be used in the treatment of NAFLD according to the same guidelines (249).

However, a meta-analysis failed to demonstrate a clear therapeutic role for these agents in treatment of this disorder (250).

The treatment of PCOS involves decreasing androgen levels to restore fertility, protecting the endometrium, improving hirsutism and minimizing the adverse metabolic effects of insulin resistance (251). Lifestyle modification is essential if the individual with PCOS is obese or overweight. In fact, weight loss as modest as 2-5% has been shown to decrease testosterone levels, restore ovulation and even result in pregnancy (252). Restoration of menstrual cycles and protection of the endometrium are generally accomplished with oral contraceptive agents or progestins (251). Hirsuitism can be treated with local measures (i.e. shaving, bleaching, depilatories, electrolysis and laser therapy) or topical creams such as eflornithine. Certain oral contraceptives can also improve hirsutism, although none are FDA approved for this purpose. Antiandrogens such as spironolactone and flutamide can also be of utility in managing hirsutism (253). If lifestyle changes fail to bring about ovulation, pharmacotherapy should be considered. Clomiphene citrate is often used first to stimulate ovulation induction, with metformin being used for patients who fail to respond to clomiphene citrate alone(11).

OSA is best treated with noninvasive positive pressure ventilation. Other treatments involve oropharyngeal exercises, mandibular advancement oral appliances and surgery (183). Given its connection to insulin resistance, obesity and MetS, lifestyle modification and weight reduction should also be central to the treatment of OSA (189).

Treatments for sexual dysfunction include phosphodiesterase (PDE)-5 inhibitors. Studies have shown improvement in erectile function of men treated with these agents regardless of the presence of comorbidities (254,255). Testosterone can be used to treat hypogonadism, thereby improving erectile dysfunction. Additionally, treatment with testosterone leads to improvement in waist circumference, body weight, waist to hip ratio, fasting blood glucose and HgA1c (256,257). Other treatments that have been used to treat hypogonadism include aromatase inhibitors and clomiphene citrate. Studies have demonstrated an increase in testosterone levels with the use of these agents but no change in metabolic parameters (191).

Given the connection of cancer to hyperinsulinemia and insulin resistance, agents that target the insulin/IGF-1 system are being evaluated for use in treatment of various malignancies. Agents such as metformin, IGF-I, IGF-II and IGF-IR-targeted antibodies and tyrosine kinase inhibitors that target the IR and IGF-1R, are currently under investigation for use in cancer treatment (258).

In patients with MetS, lifestyle modification appears to be integral in decreasing the risk of CVD and treating many of the associated conditions. As no one unique underlying mechanism has been identified, treatment of the individual conditions is often required.

CONCLUSION

The metabolic syndrome is a collection of related risk factors that predispose an individual to the development of T2DM and CV. It affects a significant amount of people worldwide and its prevalence is increasing. The diagnostic criteria for MetS have been harmonized for the purpose of providing more consistency in clinical care and research of patients with MetS. Insulin resistance remains at the core of the syndrome, as it did when it was first introduced by Reaven in 1988, and appears to contribute to the development of MetS, via elevated FFA levels and abnormal adipokine profiles. Insulin resistance has both metabolic and mitogenic effects and can result in the development of hyperglycemia and T2DM, hypertension, dyslipidemia, NAFLD, PCOS, OSA, sexual dysfunction and cancer. In patients with MetS, lifestyle modification is imperative in decreasing the risk of CVD and treating many of the associated conditions. Treatment of the individual conditions is often also required.

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