ABSTRACT

Significant interest exists in understanding the shared metabolic dysregulation leading to obesity, diabetes, and cardiovascular disease (CVD). Hence came the concept of the “metabolic syndrome” (MetS). Reaven first described MetS in his 1988 Banting lecture as “Syndrome X”. Reaven suggested that the syndrome hinged on the existence of insulin resistance and resulted in glucose intolerance, hypertension and dyslipidemia. The World Health Organization (WHO) produced the first formalized definition of the MetS in 1998. 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. The National Health and Nutrition Examination Survey (NHANES) estimated the overall prevalence of MetS in adults (aged ≥ 20 years) in the United States as 33% from 2003 to 2012. The high prevalence is particularly alarming given that MetS also predisposes to a number of serious conditions beyond diabetes and CVD including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), polycystic ovarian syndrome (PCOS), obstructive sleep apnea (OSA), cancer, and many other serious disease states. Hence, early identification and intervention are warranted. Lifestyle modification is the foundational intervention in treatment of MetS. Specifically, a healthy low-calorie, low fat diet and moderate physical activity of at least 150 minutes/week, resulting in a weight reduction of 7%. Obesity, hypertension and dyslipidemia may also be treated pharmacologically to meet individualized patient goals. Beyond the clinic imperative around MetS are its pathophysiologic underpinnings. This review will focus on the investigative work into the proximal origins of the MetS. Defects in insulin signaling occur in a shared environment of pro-inflammation, untoward adipokines coming from dysregulated fatty acid metabolism, as well as novel pathways involving the gut microbiota. Collectively, MetS continues to exist as a fertile area of research yielding significant insights into early events leading to the most prevalent cause of human morbidity and mortality. For in depth review of all related aspects of endocrinology, visit www.endotext.org.

HISTORY AND DEFINITIONS

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 CVD. 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-C (<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; pediatric definitions use standardized Z-scores rather than waist circumference (8)), 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 (9). 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 (9).

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 (10). 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) (11) including diabetes and those with a prior diagnosis of or treatment of any of these conditions (10).

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 (12). 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 mg/dl, which was also consistent with the IDF guidelines.

Finally, 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 (13). 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.

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 (10,14,15). Subsequent to the establishment of the harmonized definition, waist to height ratio has been demonstrated to be superior to waist circumference and BMI as a screening tool for cardiometabolic risk factors (diabetes, hypertension, cardiovascular disease, and all outcomes) as well as predicting whole-body fat percentage and visceral adipose tissue mass (16,17). It is not clear 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 certain ethnic groups, especially South Asian populations, have higher degrees of visceral adiposity for given waist circumference measurements compared to Europeans (10,13,18).

PREVALENCE

The prevalence of MetS 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 studied (25). Regardless of which criteria are used, however, the prevalence of MetS is high and is on the rise in many Western societies(26).

The National Health and Nutrition Examination Survey (NHANES) reported the overall prevalence of MetS in adults (aged ≥ 20 years) in the United States from 2003 to 2012 was 33% with the prevalence increasing with age, a finding that has been seen in other studies (24,25,27,28). The NHANES report indicates the highest prevalence amongst Hispanics followed by non-Hispanic whites and blacks. Other studies have shown that American Indian, Hawaiian, Polynesian, and Filipino populations develop MetS more than individuals of European descent (27,29-33). Urban populations have higher rates of MetS than rural populations (34,35). Similar to trends in Western societies, recent studies demonstrate rising rates of MetS in many developing countries (36,37). The development of these countries, bringing along a higher calorie diet and decreased physical activity, is thought to be largely responsible for the increased rate of MetS that is being observed (26,38,39). In summary, MetS affects a significant number of individuals worldwide.

CLINICAL UTILITY

The clinical utility of a diagnosis of MetS – vs. the individual components - has been studied extensively. Most recently, Pajunen and colleages compared 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, as well as when compared to the Framingham risk score, but this was not the case for the prediction of T2DM (19). Importantly, extensive, frequently conflicting literature exists examining the ability of the various definitions of MetS to predict outcomes. Further, skeptics 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 (20,21).

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 that people with established diabetes or known cardiovascular disease should be excluded (22). They also stated that further attempts to redefine it are inappropriate in light of current knowledge and understanding (23). Despite the conclusions of the panel, the diagnosis of MetS is still commonly encountered in clinical practice as well as in the research arena and arguably applies to roughly one-third of the US adult population (24). It also predisposes to a number of serious conditions beyond diabetes and CVD including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), polycystic ovarian syndrome (PCOS), obstructive sleep apnea (OSA), cancer, and many others.

PATHOGENESIS

There are many different factors that contribute to the development of MetS. However, as initially proposed by Reaven, insulin resistance is thought to play a central role in connecting the different components of MetS and adding to the syndrome's development (1,40). Elevated free fatty acids (FFA) and abnormal adipokine profiles can both cause and result in insulin resistance and can manifest as MetS (41). In this section, we will discuss how these factors contribute to the development of the metabolic abnormalities that characterize insulin resistance and MetS.

Insulin Action and Signaling

Through its complex signaling cascades, insulin regulates glucose and fat metabolism. Pancreatic β-cells release insulin in response to increased circulating glucose levels and 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 by mobilization of the insulin-responsive glucose transporter 4 (GLUT4) (Fig. 1) (42). Through actions on hormone sensitive lipase, nuclear receptor PPARγ, and fatty acid synthase, insulin inhibits lipolysis, promotes adipogenesis and adipose tissue differentiation, and under conditions of chronic hyperinsulinemia paradoxically increases fatty acid synthase(41,43).

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 muscle.

Insulin resistance is most simply defined by its end organ effects; a decreased ability of insulin to suppress lipolysis and hepatic glucose production, as well as facilitate glucose uptake from peripheral tissues. There are numerous factors thought to mediate insulin resistance and its adverse effects in MetS. Despite its widespread appreciation in metabolic disease, insulin resistance is still not fully understood and remains an area of intense scientific investigation. In the following section, we will review the ways in which known factors affect insulin resistance in MetS.

It has been thoroughly documented that FFAs mediate many undesirable metabolic effects, especially insulin resistance (44). FFAs are thought to be increased in obesity secondary to increased fat mass. Additionally, under conditions of insulin resistance, insulin’s inhibitory effects on lipolysis are reduced, leading to a further increase in FFAs. Increased FFAs are not only a result of insulin resistance, but a cause as well, thus creating a vicious cycle. FFAs can lead to insulin resistance via a variety of mechanisms that include but are not limited to the Randle cycle, the accumulation of intracellular lipid derivatives such as diacylglycerol and ceramides, inflammatory signaling, oxidative stress and mitochondrial dysfunction.

Randle et al. first demonstrated that an elevation in FFA in the diaphragm and heart was associated with an increase in fatty acid oxidation and impaired glucose utilization (45). Via the Randle cycle effect, increased FFAs and fatty acid oxidation lead to increased intracellular glucose content and decreased glucose uptake (46). Studies in rodents and humans have demonstrated that conditions of increased FFA either via lipid infusions or secondary to T2DM lead to impaired glucose uptake and utilization in insulin sensitive tissues (47). This occurs secondary to the inhibition of the insulin signaling pathway.

As FFA levels increase, the capacity of the adipose tissue to take up and store FFAs can be exceeded. When this occurs, FFAs accumulate in tissues with limited ability for lipid storage, such as the liver and skeletal muscle. This phenomenon is known as ectopic fat deposition and is strongly associated with insulin resistance (48). Fatty acids accumulate in myocytes as fatty acid derivatives. Of these fatty acid derivatives, diacylglycerol (DAG), triacylglycerol, and ceramides directly correlate with insulin resistance. DAG interferes with normal insulin signaling by its interaction with a group of novel kinases, members of the protein kinase C family, that serine phosphorylate IRS, thereby impairing tyrosine phosphorylation and activation by insulin (41,48,49) Ceramide activates the enzyme protein phosphatase 2A, leading to dephosphorylation of AKT, thwarting insulin signaling and GLUT4 translocation to the cell membrane. This impairs insulin-mediated glucose uptake into the skeletal muscle (50).

FFAs increase inflammatory signaling pathways through direct interaction with members of the Toll-like receptor (TLR) family and indirectly through the secretion of cytokines, namely tumor necrosis factor-α (TNF-α), and interleukins (IL), IL-1β and IL-6 (49). TLR are the pathogen recognition receptors of the innate immune system that function to facilitate the detection of microbes and transmit inflammatory signaling (51,52). In vitro, FFA can signal through TLR-2 and TLR-4 on macrophages, thereby inducing pro-inflammatory gene expression (52,53). Studies in mice with a loss of function mutation of the TLR-4 receptor are protected from diet-induced obesity and saturated fatty acid-induced insulin resistance (54). Similarly, animal studies in which TLR-2 is either absent or inhibited, demonstrate a resolution of high fat diet induced insulin resistance (55,56). A recent study in humans corroborates the importance of TLR-2 and TLR-4 in the development of FFA induced insulin resistance. Jialal and colleagues studied individuals with and without MetS (according to the NCEP ATP III definition) and found that those with MetS had increased expression and activity of TLR-2 and TLR-4 (51). TLR-4 activity leads to activation of c-Jun N- terminal kinase (JNK) and Iκβ kinase (IKK), which results in degradation of the inhibitor κβ (Iκβα) and activation of Nuclear Factor- κβ (NF- κβ). Through JNK and IKK activation, FFA lead to Ser phosphorylation of IRS-1 and impaired insulin signaling (57,58). Ding and colleagues assessed 1628 Chinese adults and reported that levels of IL-6 and C-reactive protein were significantly associated with MetS (using the Harmonized definition) which also increased concurrent to the increased number of MetS components, further supporting that MetS is a pro-inflammatory state (59).

In obesity, adipose tissue infiltration by macrophages is increased. This leads to a pro-inflammatory state as macrophages produce TNF-α, IL-6 and IL-1β (60,61). Along with FFA signaling through TLR, these macrophage-derived inflammatory cytokines activate JNK and IKK to further interfere with insulin signaling and action (61). Additionally suppressor of cytokine signaling (SOCS) proteins are induced downstream of these inflammatory cytokines which terminate insulin signaling by promoting the ubiquitination and proteasomal degradation of IRS (62).

Reactive oxygen species (ROS) production increases with fat accumulation. FFAs activate ROS production by adipose tissue by stimulating NADPH oxidase and decreasing the expression of anti-oxidative enzymes (63). When adipose tissues is exposed to oxidative stress, there is a decrease in the anti-inflammatory adipokine, adiponectin (to be discussed in greater detail below) (64). In MetS, there is increased ROS production as a result of elevated levels of inflammatory cytokines and decreased levels of adiponectin (65). Increased levels of ROS lead to hindered insulin signaling by inducing IRS phosphorylation and impairing GLUT4 translocation and gene transcription (66).

It has been shown that there is a connection between mitochondrial dysfunction and insulin resistance in skeletal muscle that precedes the development of obesity and hyperglycemia. Animal studies demonstrate that mitochondrial number and function are intact, if not increased, under conditions of insulin resistance (67,68). On the other hand, studies in obese, insulin-resistant individuals as well as those with T2DM have skeletal muscle mitochondria that are fewer in size as well as number. It has also been shown that these individuals exhibit down-regulation of the genes involved in mitochondrial oxidative phosphorylation, the process by which mitochondria produce energy in the form of ATP (69-72). Studies demonstrate that PPARγ coactivator-1α (PGC-1α), a transcriptional activator involved in mitochondrial biosynthesis, has diminished expression in patients with T2DM, obesity, or a family history of T2DM (73,74). Increased FFA uptake and their incomplete oxidation have also been implicated in mediating mitochondrial dysfunction in the skeletal muscle under insulin resistant conditions (75). Furthermore, mitochondrial dysfunction leads to increased oxidative stress and the formation of ROS, which further diminishes mitochondrial mass and function.

As discussed above, increased FFAs in obesity and MetS are thought to lead to insulin resistance via several different mechanisms. These different mechanisms are not exclusive of one another and interact in such a way as to create a vicious cycle of insulin resistance.

TREATMENT

Lifestyle modification is the foundational 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% (124). 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 (12). 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 (12). 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.

Historically, 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 (125). However, in the last decade, an increasing number of pharmacotherapies have become FDA approved. Currently available FDA-approved pharmacotherapy for obesity includes phentermine, orlistat, phentermine/topiramate, locaserin, buproprion/naltrexone and liraglutide 3.0 mg. Further, individuals with morbid obesity (BMI> 40 kg/m² or >35 kg/m² with comorbidities) may be candidates for bariatric surgery (126). 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 (127). Some studies demonstrate superiority of surgical to nonsurgical treatment in weight loss and MetS (128).

There are no pharmacologic agents specifically approved for prediabetes or the 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 compared to patients receiving placebo (124). 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 (129,130).

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 (131).

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 (132). 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 polyunsaturated fatty acids (n-3 PUFA) in fish oil can also be used to lower triglycerides with recent data from the REDUCE-IT trial demonstrating a reduced risk of ischemic events in patients with elevated triglycerides despite statin therapy receiving icosapent ethyl.

CONCLUSION

The metabolic syndrome is a collection of related risk factors that predispose an individual to the development of T2DM and CVD. It affects a large number 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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