CardioMetabolic Health Alliance: Metabolic Syndrome Model
A unifying definition is needed to facilitate communication within the scientific community and between providers and patients, and to underscore the importance of incorporating MetS into a comprehensive preventive care assessment. There is significant heterogeneity of expert opinion as to what constitutes MetS, to what degree it represents a syndrome or a disease, and whether it has any health-related effects beyond that of its component disorders. The importance of MetS in cardiometabolic risk remains widely under-recognized, as highlighted by the fact that several of the most recent professional society guidelines on heart disease and stroke prevention give little or no attention to its role in disease prevention. Furthermore, noncardiovascular conditions promoted by MetS, such as endocrine, respiratory, and renal disorders, remain underemphasized in clinical practice. Last, the current approach to MetS diagnosis does not take into account that a greater number of MetS components translate to a higher risk for adverse outcomes.
The past 2 decades have seen great debate over what term most precisely articulates the adverse cardiovascular and metabolic effects of MetS ( Table 2 ). In 1988, Reaven noted that hypertension, insulin resistance, atherogenic dyslipidemia, and obesity tended to cluster to form a complex syndrome, syndrome X, defined by a unifying pathophysiology leading to multiplicative risk for ASCVD. A decade later, the World Health Organization introduced the term metabolic syndrome, with a primary focus on insulin resistance and hyperglycemia, creating controversy about whether the prime driver of MetS was insulin resistance or obesity. In 1999, the European Group for the Study of Insulin Resistance (EGIR) modified the World Health Organization definition, replacing it with insulin resistance syndrome. Later, the NCEP-ATP III report codified the term metabolic syndrome, highlighting abdominal obesity—specifically increased waist circumference—and an inflammatory/prothrombotic state as major components of the syndrome. Terms for MetS have continued to evolve, each focused around varying aspects of its pathophysiology, and have included the dysmetabolic syndrome, insulin resistance syndrome, and cardiometabolic syndrome, originally introduced by the pharmaceutical industry. The position of others, such as the International Chair on Cardiometabolic Risk, has been to identify excess visceral/ectopic fat as the most prevalent form of MetS. In 2009, several major organizations released a statement harmonizing the criteria for MetS, which is in use today. Until recently, medical billing codes experienced a lack of uniform terminology as well, with the descriptor dysmetabolic syndrome X (277.7) chosen to represent a diagnosis of MetS. The more recent International Classification of Diseases-10 coding terminology, however, has shifted to the more accepted term, metabolic syndrome (E88.81).
These definitions are organized around the concepts that MetS: 1) is a chronic and progressive pathophysiological state; 2) represents a clustering of risk factors that form a complex syndrome defined by a unifying pathophysiology; and 3) is associated with increased risk for ASCVD, T2D, and other related disorders. It is imperative to recognize that MetS is not just a repackaging of its individual risk components, but, as demonstrated in at least 1 analysis, is a clinical entity associated with an increased risk of ASCVD or death, even after controlling for its component risk factors (risk ratio: 1.54; 95% confidence interval: 1.32 to 1.79). Furthermore, MetS incorporates so-called residual risk markers that associate with cardiovascular and metabolic disease risk, but are not universally agreed upon as criteria for MetS diagnosis. These include elevated levels of apolipoprotein B and small, dense LDL particles; a prothrombotic and proinflammatory state signified by high levels of circulating inflammatory markers, such as C-reactive protein and fibrinogen; and microalbuminuria. It is important to recognize this construct because it provides an opportunity to identify and treat residual risk markers beyond the standard management of established risk factors.
Another concept essential to the MetS definition is that people with MetS have or are at risk for multi–end-organ damage. This includes, but is not limited to, cardiovascular (atherosclerosis and nonatherosclerosis types), metabolic (e.g., T2D and dyslipidemia), hormonal (e.g., polycystic ovarian syndrome), sleep-disordered breathing, certain malignancies, psychological distress (e.g., depression), chronic kidney disease, orthopedic/joint diseases, and nonalcoholic fatty liver disease (NAFLD). Substantial variability in end-organ consequences emphasizes a need to identify subtypes of MetS on the basis of their underlying pathophysiology and predisposition to adverse consequences, which can then be targeted for specific preventive and therapeutic management strategies (Figure 1).
(Enlarge Image)
Figure 1.
Paradigm for Subtyping MetS
Substantial variability in end-organ consequences related to MetS underscores a need to identify subtypes of MetS on the basis of pathophysiology that can be targeted for specific evidence-based management strategies. ASCVD = atherosclerotic cardiovascular disease; MetS = metabolic syndrome.
Obesity. Recently, the AACE and the American College of Endocrinology developed an advanced framework for defining obesity as a chronic disease characterized by pathophysiological processes that result in increased adipose tissue mass and can result in increased morbidity and mortality, with MetS as 1 such important consequence. MetS is strongly linked to the obesity epidemic in the United States. The latest prevalence estimates of MetS in men and women are 35% and 33%, respectively. Because forecasts suggest that over one-half of the U.S. population will be obese by the year 2030, rates of MetS will almost certainly increase over the next decade. However, there is a growing appreciation that obesity per se, as defined by simple anthropometric measures, such as BMI or waist circumference, is neither a necessary nor a sufficient descriptor of MetS and its consequences. Rather, it appears that risk for MetS varies substantially by distribution of both adipocyte and nonadipocyte (ectopic) fat, as well as by adipocyte size and function. Excess intra-abdominal (i.e., visceral) adipose tissue may be a primary driver of the cardiometabolic complications of obesity, and ectopic fat may be linked to VAT and may itself play a key contributory role. An increase in VAT is thought to reflect the relative inability of the subcutaneous adipose tissue depot to sufficiently expand its clearance and storage capacity in response to caloric excess. Defects in adipocyte maturation and differentiation cause adipocyte dysfunction, resulting in spillover of excess triglycerides and promotion of ectopic fat deposition in the viscera, liver, heart, and skeletal muscle. The ensuing milieu of overactive lipolysis, altered glucose homeostasis, proinflammatory adipocytokine release, and endothelial dysfunction appears to be a primary cause of the pathophysiological alterations observed in MetS. The several ectopic fat depots associated with increased cardiometabolic risk include excess liver, pericardial and epicardial, retroperitoneal, and intramuscular fat. Further evidence for the role of adipocyte dysfunction in adverse metabolic changes comes from the lipodystrophies, a group of rare genetic disorders that result in severe, generalized loss of adipose tissue. Although obesity and lipodystrophy represent 2 extremes of the physiological spectrum, the underlying mechanisms causing insulin resistance and MetS in both sets of patients may be similar; specifically, limited storage capacity in adipose tissue results in diversion of excess triglycerides to ectopic sites, with adverse metabolic sequelae. Notably, ectopic fat-associated cardiometabolic risk in MetS may be further modulated by race (e.g., South Asians are predisposed), nutritional factors, and lifestyle behaviors.
Although an increased waist circumference is central to the current clinical diagnosis of MetS and identifies individuals at increased risk for atherosclerosis and mortality across different levels of BMI, it is an imprecise surrogate for the VAT phenotype. First, the correlation among BMI, waist circumference, and VAT is highly variable among different racial groups, prompting the American Diabetes Association and the International Diabetes Federation to define different cutoffs for abnormal BMI and waist circumference, respectively, in Asian populations. Second, waist circumference measurement includes both VAT and abdominal subcutaneous adipose tissue compartments. These 2 depots are anatomically and physiologically distinct, especially within the obese population, and are differentially associated with markers of cardiometabolic risk. VAT, but not abdominal subcutaneous fat, has been shown to associate with incident T2D and pre-T2D, incident hypertension, and alterations in left ventricular structure and function, and has also been linked to increased risk of developing CVD and cancer. Therefore, the TT recognized the central role of ectopic fat and/or visceral adipose tissue in the pathophysiology of MetS and endorsed evidence-based strategies to identify and treat these dangerous fat depots in individuals with or at risk for MetS.
Insulin resistance. Insulin resistance tracks very closely with MetS, playing a key role in MetS pathogenesis and relation to ASCVD risk. Although insulin resistance may be associated with impairment of fasting glucose, insulin resistance itself seems to worsen in severity across added components of the syndrome, suggesting an independent association with MetS beyond glycemic effects and strengthening the evidence for a pathogenic role of insulin resistance. Moreover, insulin resistance has been associated with atherogenic dyslipidemia, including elevated levels of triglycerides and low concentrations of HDL-C; prothrombotic and proinflammatory markers, such as plasminogen activator inhibitor-1, fibrinogen, and C-reactive protein; increased sympathetic nerve activity and sodium retention predisposing to hypertension; androgen excess and polycystic ovarian syndrome; sleep-disordered breathing; chronic kidney disease; and some cancers. It remains unclear whether the insulin resistance seen in MetS is a purely independent etiological factor, or mostly a downstream consequence of ectopic/dysfunctional adiposity, or a combination of both.
TT participants affirmed the concept of residual MetS risk indicators. This concept recognizes that there are additional markers/factors not incorporated within the traditional diagnostic framework of MetS that nonetheless relate to MetS and are associated with adverse health outcomes. These may vary by individual or group, may be modifiable or nonmodifiable, and may have genetic or environmental determinants. This is critical because differences in risk factor burden early in life translate into marked differences in the risk of adverse health outcomes later in life. One element of this has been highlighted in the "ticking-clock" hypothesis, which recognizes the detrimental effects of long-term exposure to MetS on future development of end-organ damage. For example, multiple factors that begin before birth and continue through delivery, such as low birth weight, small head circumference, gestational diabetes, and lack of breastfeeding, place children at risk for MetS in adolescence and adulthood. It is important for practitioners to recognize these and other social determinants of MetS susceptibility, such as low socioeconomic status and parental history of MetS; to consider providing "primordial prevention" when possible; and to move toward identification and treatment of vulnerable families and communities to improve public health.
The TT recognized lifestyle, referring to physical activity and nutrition, as being a modifiable factor crucial to prevent and treat MetS and its consequences. Many observational studies show an association between higher levels of physical activity and lower rates of chronic diseases and increased longevity. Even in the presence of MetS, increased physical activity is associated with a substantially lower risk of ASCVD. The proposed mechanisms include beneficial effects on blood pressure and lipids, key components of MetS. Appropriate nutritional choices can also modify the risk of cardiometabolic disease. The Strong Heart Study identified specific dietary patterns associated with improved health outcomes. Several dietary patterns, such as the DASH (Dietary Approaches to Stop Hypertension) and Mediterranean diets, may reduce blood pressure, improve lipids, reduce inflammation, and reduce risk for ASCVD. Emphasis should be placed on dietary patterns, rather than specific macronutrients, given inconclusive evidence to date for an independent effect of macronutrient composition on outcomes. Emerging from these recent data is the belief that focused research and improved education on lifestyle interventions should be prioritized.
The TT identified disparity in care of patients with MetS to be a critical area for improvement. Disparity can manifest as decreased accessibility to health care and failure to recognize or appropriately treat at-risk populations. For example, current guidelines do not recognize racial-specific differences in lipid levels between Caucasian and African-American populations. On average, African-Americans have higher HDL-C and lower triglyceride levels. This paradox may translate to underdiagnosis of MetS in African-Americans using current diagnostic criteria, which would likely result in lack of treatment of MetS in this population. In addition to this and other race-specific issues, however, TT participants recognized that well-intentioned alteration of existing diagnostic criteria around racial differences could stigmatize minority populations and lead to undesirable consequences. Other nonracial, high-risk, under-represented populations likely requiring more intensive consideration include patients with human immunodeficiency virus/acquired immunodeficiency syndrome, cancer survivors, individuals with severe mental illness, and children with developmental disabilities.
What Is MetS and Why Does It Matter?
Definition: Syndrome Versus Disease
A unifying definition is needed to facilitate communication within the scientific community and between providers and patients, and to underscore the importance of incorporating MetS into a comprehensive preventive care assessment. There is significant heterogeneity of expert opinion as to what constitutes MetS, to what degree it represents a syndrome or a disease, and whether it has any health-related effects beyond that of its component disorders. The importance of MetS in cardiometabolic risk remains widely under-recognized, as highlighted by the fact that several of the most recent professional society guidelines on heart disease and stroke prevention give little or no attention to its role in disease prevention. Furthermore, noncardiovascular conditions promoted by MetS, such as endocrine, respiratory, and renal disorders, remain underemphasized in clinical practice. Last, the current approach to MetS diagnosis does not take into account that a greater number of MetS components translate to a higher risk for adverse outcomes.
The past 2 decades have seen great debate over what term most precisely articulates the adverse cardiovascular and metabolic effects of MetS ( Table 2 ). In 1988, Reaven noted that hypertension, insulin resistance, atherogenic dyslipidemia, and obesity tended to cluster to form a complex syndrome, syndrome X, defined by a unifying pathophysiology leading to multiplicative risk for ASCVD. A decade later, the World Health Organization introduced the term metabolic syndrome, with a primary focus on insulin resistance and hyperglycemia, creating controversy about whether the prime driver of MetS was insulin resistance or obesity. In 1999, the European Group for the Study of Insulin Resistance (EGIR) modified the World Health Organization definition, replacing it with insulin resistance syndrome. Later, the NCEP-ATP III report codified the term metabolic syndrome, highlighting abdominal obesity—specifically increased waist circumference—and an inflammatory/prothrombotic state as major components of the syndrome. Terms for MetS have continued to evolve, each focused around varying aspects of its pathophysiology, and have included the dysmetabolic syndrome, insulin resistance syndrome, and cardiometabolic syndrome, originally introduced by the pharmaceutical industry. The position of others, such as the International Chair on Cardiometabolic Risk, has been to identify excess visceral/ectopic fat as the most prevalent form of MetS. In 2009, several major organizations released a statement harmonizing the criteria for MetS, which is in use today. Until recently, medical billing codes experienced a lack of uniform terminology as well, with the descriptor dysmetabolic syndrome X (277.7) chosen to represent a diagnosis of MetS. The more recent International Classification of Diseases-10 coding terminology, however, has shifted to the more accepted term, metabolic syndrome (E88.81).
These definitions are organized around the concepts that MetS: 1) is a chronic and progressive pathophysiological state; 2) represents a clustering of risk factors that form a complex syndrome defined by a unifying pathophysiology; and 3) is associated with increased risk for ASCVD, T2D, and other related disorders. It is imperative to recognize that MetS is not just a repackaging of its individual risk components, but, as demonstrated in at least 1 analysis, is a clinical entity associated with an increased risk of ASCVD or death, even after controlling for its component risk factors (risk ratio: 1.54; 95% confidence interval: 1.32 to 1.79). Furthermore, MetS incorporates so-called residual risk markers that associate with cardiovascular and metabolic disease risk, but are not universally agreed upon as criteria for MetS diagnosis. These include elevated levels of apolipoprotein B and small, dense LDL particles; a prothrombotic and proinflammatory state signified by high levels of circulating inflammatory markers, such as C-reactive protein and fibrinogen; and microalbuminuria. It is important to recognize this construct because it provides an opportunity to identify and treat residual risk markers beyond the standard management of established risk factors.
Another concept essential to the MetS definition is that people with MetS have or are at risk for multi–end-organ damage. This includes, but is not limited to, cardiovascular (atherosclerosis and nonatherosclerosis types), metabolic (e.g., T2D and dyslipidemia), hormonal (e.g., polycystic ovarian syndrome), sleep-disordered breathing, certain malignancies, psychological distress (e.g., depression), chronic kidney disease, orthopedic/joint diseases, and nonalcoholic fatty liver disease (NAFLD). Substantial variability in end-organ consequences emphasizes a need to identify subtypes of MetS on the basis of their underlying pathophysiology and predisposition to adverse consequences, which can then be targeted for specific preventive and therapeutic management strategies (Figure 1).
(Enlarge Image)
Figure 1.
Paradigm for Subtyping MetS
Substantial variability in end-organ consequences related to MetS underscores a need to identify subtypes of MetS on the basis of pathophysiology that can be targeted for specific evidence-based management strategies. ASCVD = atherosclerotic cardiovascular disease; MetS = metabolic syndrome.
Focus on Pathophysiology
Obesity. Recently, the AACE and the American College of Endocrinology developed an advanced framework for defining obesity as a chronic disease characterized by pathophysiological processes that result in increased adipose tissue mass and can result in increased morbidity and mortality, with MetS as 1 such important consequence. MetS is strongly linked to the obesity epidemic in the United States. The latest prevalence estimates of MetS in men and women are 35% and 33%, respectively. Because forecasts suggest that over one-half of the U.S. population will be obese by the year 2030, rates of MetS will almost certainly increase over the next decade. However, there is a growing appreciation that obesity per se, as defined by simple anthropometric measures, such as BMI or waist circumference, is neither a necessary nor a sufficient descriptor of MetS and its consequences. Rather, it appears that risk for MetS varies substantially by distribution of both adipocyte and nonadipocyte (ectopic) fat, as well as by adipocyte size and function. Excess intra-abdominal (i.e., visceral) adipose tissue may be a primary driver of the cardiometabolic complications of obesity, and ectopic fat may be linked to VAT and may itself play a key contributory role. An increase in VAT is thought to reflect the relative inability of the subcutaneous adipose tissue depot to sufficiently expand its clearance and storage capacity in response to caloric excess. Defects in adipocyte maturation and differentiation cause adipocyte dysfunction, resulting in spillover of excess triglycerides and promotion of ectopic fat deposition in the viscera, liver, heart, and skeletal muscle. The ensuing milieu of overactive lipolysis, altered glucose homeostasis, proinflammatory adipocytokine release, and endothelial dysfunction appears to be a primary cause of the pathophysiological alterations observed in MetS. The several ectopic fat depots associated with increased cardiometabolic risk include excess liver, pericardial and epicardial, retroperitoneal, and intramuscular fat. Further evidence for the role of adipocyte dysfunction in adverse metabolic changes comes from the lipodystrophies, a group of rare genetic disorders that result in severe, generalized loss of adipose tissue. Although obesity and lipodystrophy represent 2 extremes of the physiological spectrum, the underlying mechanisms causing insulin resistance and MetS in both sets of patients may be similar; specifically, limited storage capacity in adipose tissue results in diversion of excess triglycerides to ectopic sites, with adverse metabolic sequelae. Notably, ectopic fat-associated cardiometabolic risk in MetS may be further modulated by race (e.g., South Asians are predisposed), nutritional factors, and lifestyle behaviors.
Although an increased waist circumference is central to the current clinical diagnosis of MetS and identifies individuals at increased risk for atherosclerosis and mortality across different levels of BMI, it is an imprecise surrogate for the VAT phenotype. First, the correlation among BMI, waist circumference, and VAT is highly variable among different racial groups, prompting the American Diabetes Association and the International Diabetes Federation to define different cutoffs for abnormal BMI and waist circumference, respectively, in Asian populations. Second, waist circumference measurement includes both VAT and abdominal subcutaneous adipose tissue compartments. These 2 depots are anatomically and physiologically distinct, especially within the obese population, and are differentially associated with markers of cardiometabolic risk. VAT, but not abdominal subcutaneous fat, has been shown to associate with incident T2D and pre-T2D, incident hypertension, and alterations in left ventricular structure and function, and has also been linked to increased risk of developing CVD and cancer. Therefore, the TT recognized the central role of ectopic fat and/or visceral adipose tissue in the pathophysiology of MetS and endorsed evidence-based strategies to identify and treat these dangerous fat depots in individuals with or at risk for MetS.
Insulin resistance. Insulin resistance tracks very closely with MetS, playing a key role in MetS pathogenesis and relation to ASCVD risk. Although insulin resistance may be associated with impairment of fasting glucose, insulin resistance itself seems to worsen in severity across added components of the syndrome, suggesting an independent association with MetS beyond glycemic effects and strengthening the evidence for a pathogenic role of insulin resistance. Moreover, insulin resistance has been associated with atherogenic dyslipidemia, including elevated levels of triglycerides and low concentrations of HDL-C; prothrombotic and proinflammatory markers, such as plasminogen activator inhibitor-1, fibrinogen, and C-reactive protein; increased sympathetic nerve activity and sodium retention predisposing to hypertension; androgen excess and polycystic ovarian syndrome; sleep-disordered breathing; chronic kidney disease; and some cancers. It remains unclear whether the insulin resistance seen in MetS is a purely independent etiological factor, or mostly a downstream consequence of ectopic/dysfunctional adiposity, or a combination of both.
Residual Risk
TT participants affirmed the concept of residual MetS risk indicators. This concept recognizes that there are additional markers/factors not incorporated within the traditional diagnostic framework of MetS that nonetheless relate to MetS and are associated with adverse health outcomes. These may vary by individual or group, may be modifiable or nonmodifiable, and may have genetic or environmental determinants. This is critical because differences in risk factor burden early in life translate into marked differences in the risk of adverse health outcomes later in life. One element of this has been highlighted in the "ticking-clock" hypothesis, which recognizes the detrimental effects of long-term exposure to MetS on future development of end-organ damage. For example, multiple factors that begin before birth and continue through delivery, such as low birth weight, small head circumference, gestational diabetes, and lack of breastfeeding, place children at risk for MetS in adolescence and adulthood. It is important for practitioners to recognize these and other social determinants of MetS susceptibility, such as low socioeconomic status and parental history of MetS; to consider providing "primordial prevention" when possible; and to move toward identification and treatment of vulnerable families and communities to improve public health.
Lifestyle
The TT recognized lifestyle, referring to physical activity and nutrition, as being a modifiable factor crucial to prevent and treat MetS and its consequences. Many observational studies show an association between higher levels of physical activity and lower rates of chronic diseases and increased longevity. Even in the presence of MetS, increased physical activity is associated with a substantially lower risk of ASCVD. The proposed mechanisms include beneficial effects on blood pressure and lipids, key components of MetS. Appropriate nutritional choices can also modify the risk of cardiometabolic disease. The Strong Heart Study identified specific dietary patterns associated with improved health outcomes. Several dietary patterns, such as the DASH (Dietary Approaches to Stop Hypertension) and Mediterranean diets, may reduce blood pressure, improve lipids, reduce inflammation, and reduce risk for ASCVD. Emphasis should be placed on dietary patterns, rather than specific macronutrients, given inconclusive evidence to date for an independent effect of macronutrient composition on outcomes. Emerging from these recent data is the belief that focused research and improved education on lifestyle interventions should be prioritized.
Disparities
The TT identified disparity in care of patients with MetS to be a critical area for improvement. Disparity can manifest as decreased accessibility to health care and failure to recognize or appropriately treat at-risk populations. For example, current guidelines do not recognize racial-specific differences in lipid levels between Caucasian and African-American populations. On average, African-Americans have higher HDL-C and lower triglyceride levels. This paradox may translate to underdiagnosis of MetS in African-Americans using current diagnostic criteria, which would likely result in lack of treatment of MetS in this population. In addition to this and other race-specific issues, however, TT participants recognized that well-intentioned alteration of existing diagnostic criteria around racial differences could stigmatize minority populations and lead to undesirable consequences. Other nonracial, high-risk, under-represented populations likely requiring more intensive consideration include patients with human immunodeficiency virus/acquired immunodeficiency syndrome, cancer survivors, individuals with severe mental illness, and children with developmental disabilities.