CHAPTER 26: THE METABOLIC SYNDROME

The metabolic syndrome (MetS) is a theoretic construct from clustering of interrelated processes to better represent complex pathophysiology into actionable and effective clinical decision making. Specifically, the rationale and practical utility of MetS is to facilitate early diagnosis, risk stratification, and management of cardiometabolic risk factors. This topic is relevant but also remains controversial because many aspects remain unproven. Nevertheless, the core principle is that the value of MetS is related to the impact of residual risk (total risk minus the aggregate of known specific risk factors) on cardiovascular disease (CVD). A recent consensus statement has advanced the discussion and relevance of MetS by proposing different subtypes and severity levels in the context of a public health care model.¹

Energy homeostasis is coordinated by hormone signal pathways that integrate the metabolic activities of multiple tissues and organ systems. Insulin resistance disrupts metabolic efficiency, thereby driving many chronic metabolic diseases, including type 2 diabetes (T2D), atherosclerosis, hypertriglyceridemia, hepatosteatosis, polycystic ovary syndrome, and obesity. Informally, insulin resistance may also be classified as prediabetes. As a common pathophysiologic pathway, insulin resistance affects and is affected by metabolism in adipose tissue, skeletal muscle, vascular endothelium, bone, liver, kidneys, pancreatic islets of Langerhans, hypothalamic nuclei, and the immune system.

In general, the diagnosis of MetS is based on the complex of increased adiposity/obesity, hypertension, hypertriglyceridemia, and insulin resistance.¹ The prevalence of MetS varies depending on the specific definition used (Table 26–1)^2,3,4,5,6,7 but has nevertheless increased substantially over the past few decades in parallel to the rise in obesity. This rise is associated with modern (westernized) lifestyles, food preferences and availability, agricultural changes, environmental exposures, and other related epigenetic factors. Depending on the specific criteria used, approximately 20% to 35% of various reported worldwide adult populations have MetS (Table 26–2), substantially increasing the risk of atherosclerotic disease.⁸

The etiology of MetS is not clear but is thought to be related to adipose tissue pathology, insulin resistance, inflammation, other processes, or combinations of these. Accumulation of fat in adipose and nonadipose tissue, a core feature of MetS, results in obesity in many cases, which is defined by a body mass index (BMI) above 30 kg/m² in Caucasians (a BMI of 25–29.9 kg/m² corresponds to “overweight”), but cutoff points as low as 25 to 27 kg/m² in various Asian regions (with varying BMI cutoff points in the 23–26.9 kg/m² range for overweight).⁹ Even these definitions can be modified by a blurring of the overweight-obesity demarcations through the incorporation of weight-related complications or other anthropometrics, such as waist circumference (WC).¹⁰ Additionally, a subset that comprises about 10% of the obese population does not demonstrate signs of insulin resistance or inflammation. These people with obesity have been described as metabolically healthy,¹¹ although the true healthy nature of these people is highly debatable.^12,13 In fact, the vast majority of people with obesity, unhealthy or healthy, have some degree of insulin resistance, are at risk for associated metabolic diseases, and have increased mortality.⁷ In this sense, BMI may still serve as a predictor of adverse outcomes and should not be entirely abandoned, although because of the overlap of obesity, insulin resistance, and MetS, better predictive and treat-to-target parameters based on risk are needed.

Currently, the diagnosis of MetS is based on a set of commonly measured metabolic markers: abdominal girth (WC), hyperglycemia, hypertriglyceridemia, hypertension, and low high-density lipoprotein (HDL) levels. However, debate still exists over the relative weighting of each of these measures in a predictive model for morbidity and mortality risk. Definitions given for MetS vary among major organizations, based on different interpretations of the scientific evidence as well as expert consensus/opinions (see Table 26–1), but common to each of these is a constellation of metabolic disturbances centered on insulin resistance and obesity.

Cardiovascular risk is nearly doubled in people with MetS and further increases as people acquire more of the defining criteria. Moreover, quality of life is substantially reduced and the risk of other weight-related complications rises in the presence of MetS. If we stipulate that MetS is a complex pathophysiological state, then it makes sense that a multifaceted approach to treatment, rather that a singular intervention, can reduce these risks and lead to improved quality of life.^5,6

The observation that specific metabolic factors—obesity, hypertension, insulin resistance, and dyslipidemia—commonly occur together and influence cardiovascular risk was first proposed by Reaven et al² nearly three decades ago. Since this seminal observation, a number of organizations have recognized the aggregate risk of MetS, although they differ slightly in the specific definition of the syndrome.

A decade after the first proposed version of MetS, the World Health Organization (WHO) affirmed the classification of clustered metabolic disorders that impart high risk of atherosclerotic disease.³ The WHO definition of MetS emphasized the importance of abdominal obesity as a marker of impaired metabolic function and included measures of insulin resistance in the presence of at least two other metabolic criteria to qualify as having MetS. Shortly after this publication, the European Group for the study of Insulin Resistance (EGIR) emphasized the contribution of insulin resistance to MetS.¹⁴

The 2002 report of the National Cholesterol Education Program (NCEP) reiterates these concepts of abdominal obesity, hypertension, and insulin resistance that yield a proinflammatory and prothrombotic state and enhance the risk of atherosclerotic disease.⁴ The NCEP stresses the importance for addressing each individual factor to diminish cardiovascular risk.

The American Heart Association (AHA), in conjunction with the National Heart, Lung, and Blood Institute (NHLBI), recognizes the atherogenic properties associated with the pattern of dyslipidemia of the MetS and proposes the use of a low threshold to pharmacologically treat elevated low-density lipoprotein (LDL) cholesterol.¹⁵

More recently, the International Diabetes Federation (IDF) added several other biomarkers of impaired energy homeostasis that can be considered in the diagnosis of MetS.¹⁶ These adjunct criteria include markers of adiposity such as plasma leptin and adiponectin concentration, hepatic fat content, apolipoprotein B, LDL particle size, endothelial dysfunction, urinary microalbumin levels, and markers of systemic inflammation and thrombosis.

The minor differences in emphasis and in measurement of each component for the diagnosis of MetS (see Table 26–1) highlight the true syndromic nature of this condition. Individuals may vary in their presentation and may be included or excluded depending on the exact definition utilized. Overall, atherosclerotic risk rises in association with severity of MetS.^17,18 The practical decisions of diagnosis and clinical intervention should take into consideration the continuum of risk imposed by MetS.

The term residual risk compliments the concept of the MetS. Specifically, residual risk describes the remaining increased potential for atherosclerotic CVD, after the treatment of a specific risk factor, such as using cholesterol-lowering agents with dyslipidemia.¹⁹ Factors that contribute to residual risk include lifestyle factors, such as eating patterns and nutrient content, endocrine-disrupting compounds (EDCs), physical activity, sleep hygiene, and others. Fundamentally, as a driver of atherosclerotic disease, lifestyle components of MetS pose a tantalizing public health issue.¹⁵

Since the first description of MetS, prevalence has been increasing in parallel with increases in obesity and T2D. According to the 2001-2010 National Health and Nutrition Examination Survey, the prevalence of MetS in the United States is 22% using NCEP criteria and 37% using AHA/NHLBI criteria.⁸ In contrast, the MetS prevalence using NCEP criteria is 28% in Mexican Americans and 24% in African Americans.²⁰ These differences highlight important cultural and biological variables when evaluating MetS on a population scale within a particular region.

Worldwide, different regional populations demonstrate similar, as well as unique phenotypic expressions and related epidemiologies of MetS. For instance, the prevalence of MetS is 22% in South Korea using NCEP criteria,²¹ the same as in the United States. But in Iran, the prevalence of MetS is higher at 33% by NCEP criteria (and 18% by WHO criteria).²² In Nigeria, the prevalence is 28% to 31%, based on NCEP, WHO, or IDF criteria.²³ A cohort of German autoworkers demonstrated a surprisingly low prevalence of 11% by WHO criteria.²⁴ A cohort study in Catalonia, Spain, demonstrated a 22% prevalence of MetS by WHO criteria.²⁵ And finally, the prevalence of MetS in India has been reported as high as 46%.²² The consistently high but varying prevalence of MetS on a global scale raises many important questions about specific drivers, both biological and cultural; the dominant role of lifestyle; and the overarching relevance of and need for transculturalizing evidence-based recommendations from one region to another to improve clinical outcomes.²⁶

Lifestyle and Environmental Factors

Sedentary Behavior

The modern-day western lifestyle is largely responsible for the high prevalence of MetS in many populations, as well as the rapidly rising prevalence in populations undergoing economic, demographic, nutritional, and cultural transitions.²² Along these lines, modification of the multiple drivers and contributing factors within modern living can reduce specific and residual risks. Among these, sedentary behavior figures prominently.¹⁷ Physical activity has multiple effects on metabolism, including activation of brown fat, improvement in insulin sensitivity, as well as modulation of endothelial function and adipose tissue function.^27,28 Shifts in internal energy use among highly active individuals may also contribute to more efficient carbohydrate processing and reduced insulin resistance.²⁹ Additionally, gene activation following physical activity can influence insulin resistance and mitochondrial function.³⁰ Interventional studies consistently demonstrate great reduction in the prevalence and severity of MetS within highly active subjects.¹⁷ Most notably, trials that incorporate increased physical activity demonstrate a 29% to 58% reduction in incidence of T2D among at-risk subjects.³¹

Modern Agriculture

The potential adverse metabolic effects of modern agricultural techniques, food processing, and the resultant food chain in the United States, with respect to nutrient content and endocrine disruptors, are only just becoming clarified but still not without controversy. For example, the use of corn for animal feed rather than grass for beef production or seeds for poultry yields a higher n-6 fatty acid content, which may have proinflammatory effects.³² Maintaining livestock in small cages promotes adipose tissue growth, potentially raising saturated and n-6 fatty acid and lowering n-3 fatty acid content in the animals.³² The use of antibiotics among livestock may also lead to increased adipose tissue mass and saturated fat content.³³

The early harvesting of fruits and vegetables, which allows for ease of transportation, reduces micronutrient and antioxidant content. The use of industrial fertilizers can affect nitrogen and phosphorus content, although the metabolic effects of these changes are not fully understood. High amounts of corn and soy production yield a vast array of derivative food products, including trans-fatty acids, peroxidized fatty acids, and high-fructose corn syrup. These compounds are commonly added to processed foods and can promote insulin resistance, hepatosteatosis, and atherosclerosis.³⁴

Endocrine Disruptors

A number of man-made industrial chemicals have properties that allow interruption of normal hormone signaling either through molecular mimicry of natural hormones, blockade of hormone activity, or by affecting hormonal synthesis, transport, binding, or catabolism. Animal models and population exposure studies identify specific EDCs, such as pesticides, plasticizers, preservatives, and artificial sweeteners, among other chemicals that hinder glucose metabolism and cause insulin resistance.^35,36,37,38

EDCs have multiple entry points in the food chain and many are retained within individuals because of lack of clearance pathways. However, the degree to which EDCs contribute to the high prevalence of MetS is presently unclear. Considering the seemingly endless introduction of novel industrial chemicals, the pathophysiologic effects on metabolism and range of chemicals that act as EDC may never be fully understood. A prudent approach of minimizing exposure has been recommended.³⁹

Fructose

Prior to the industrial production of sugars, dietary fructose was relatively scarce; natural sources of fructose included fruits (which contained only small amounts), honey (which was relatively unavailable), and agave extract (which was not widely consumed). Now, the high content of fructose within industrially produced sugars, such as sucrose and high-fructose corn syrup, makes this inefficiently metabolized monosaccharide highly available.

Fructose enters energy metabolism downstream of important regulatory steps and without hormonal control.^40,41 Nearly all consumed fructose is taken up and metabolized by hepatocytes, leading to fatty acid synthesis and hepatosteatosis.⁴²

Multiple longitudinal and cross-sectional studies demonstrate a strong association among high fructose intake and the development of obesity, MetS, and/or vascular disease.^43,44,45,46 These associations are corroborated in several controlled trials demonstrating increased insulin resistance and increased circulating triglyceride levels after 3 to 6 months of increased fructose consumption compared to isocaloric diets containing starch and low in fructose.^47,48,49

Sleep Hygiene

Many studies demonstrate that a reduced amount of sleep, generally 6 hours or less per night, is associated with increased insulin resistance, hypertension, and obesity.⁵⁰ One large study demonstrated that reduced time of slow-wave sleep was specifically associated with increased waist circumference.⁵¹ Quality of sleep can also affect metabolism. Shift workers, with frequent changes in circadian patterns have higher rates of obesity and T2D compared to the general population. Insulin resistance also worsens in the presence of obstructive sleep apnea. Current trends over the past 50 years demonstrate a 1.5- to 2-hour reduction in time spent sleeping each night, which may further contribute to the rising prevalence of MetS.⁵²

Other Factors

The rising use of certain antidepressant and other psychotropic medications that affect metabolic control within the hypothalamus leads to insulin resistance and weight gain. Even the widespread use of antibiotics may influence metabolism through alteration of intestinal microbiota.⁵³ The average American adult is given one to two prescriptions for antibiotics annually, which has been associated with the development of obesity.⁵³ Macrolides confer the greatest risk, perhaps reflecting a greater effect on intestinal microbiota.^53,54

Behavioral patterns related to nutrition also contribute to the development of MetS. The shift in practice from breastfeeding newborns and infants to formula feeding that has occurred over the past century is associated with insulin resistance in the mother and risk of obesity in the child.^55,56 Population survey data demonstrate that the reduced time dedicated to food preparation is also associated with the development of obesity, insulin resistance, and MetS.^57,58 In some cases, the effect culture has on nutritional choices can be detrimental for insulin resistance.²⁶ One example is the high intake of rice among specific cultures, representing high dietary carbohydrate intake. Many of these behavioral factors can be modified within individuals at risk for MetS. However, given their wide acceptance as part of modern culture and lack of immediate benefit or repercussions, change is difficult.

Biological Factors

At the cellular and molecular levels, each of the MetS components has the potential to synergistically influence one another. These simultaneous mechanistic processes alter multiple aspects of metabolism, contribute to specific risk factors, create residual risk, and ultimately generate MetS. In other words, the biological complexity of metabolic pathophysiology translates into various expressions of MetS in susceptible people.

Metabolic Pathways

It is useful to view a common starting pathway as the accumulation of fat in adipose and/or nonadipose tissue (Table 26–3), which increases systemic inflammation and insulin resistance. Pancreatic β-cell dysfunction ensues via degeneration or transformation to inactive cells.⁵⁹ Impaired insulin signaling leads to further accumulation of fat mass.⁶⁰

Reduced release and reduced activity of glucagon-like peptide-1 (GLP-1) by L-cells of the distal ileum worsens insulin resistance and drive further increases in adipose tissue.⁶¹ Nutrient sensing within the paraventricular nucleus of the hypothalamus becomes impaired and resistance to leptin develops within the arcuate nucleus.⁶² Adiponectin production within adipose tissue is also diminished, which further promotes insulin resistance.⁶³

Lipoprotein metabolism is affected by this process. Insulin resistance reduces endothelial and adipose lipoprotein lipase activity, yielding elevated triglycerides.⁶⁴ Hepatic lipoprotein synthesis shifts to produce small, dense LDL particles that enter the circulation and are highly atherogenic.⁶⁵ Circulating free fatty acids further drive insulin resistance through oxidative stress and accumulation of intracellular derivatives such as ceramides.⁶⁶ Visceral fat stores increase, leading to hepatosteatosis and fat accumulation within the pancreas, promoting insulin resistance and β-cell dysfunction.^67,68

Within the vascular endothelium, insulin resistance also impairs nitric oxide (NO) synthase activity, which diminishes NO production, affecting vasodilation and leading to the development of essential hypertension.⁶⁹ Low circulating adiponectin and resistance to leptin induce increased expression of endothelin-1, further driving vasoconstriction and promoting hypertension.⁶⁹

High levels of circulating lipid particles naturally oxidize and are taken up by macrophages that become activated.⁷⁰ Free fatty acids also bind toll-like receptor 4 on macrophage cell surfaces.⁷¹ Both processes trigger the release of inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin (IL)-1, and IL-6. These cytokines promote the degradation of insulin receptor substrate-1, a downstream mediator of insulin activity, further driving insulin resistance.⁷⁰

This narrative describing an interconnected cascade of dysregulated energy metabolism provides a candidate molecular basis for MetS as a true emergent syndrome, greater in risk than the aggregate of its individual components. Hence, interventions should target multiple aspects within these processes to mitigate network-based mechanisms (represented by residual risk) involved in the development of MetS.

Genetic and Epigenetic Effects

Very few genes have been identified that specifically confer risk of MetS.⁷² This finding is consistent with the relatively unchanged human gene pool over the past century, despite significant increases in the prevalence of obesity and MetS during this time. However, epigenetic phenomena secondary to behavioral and environmental factors have great potential to influence the development of obesity and MetS. One example is the observation that children born to women with obesity prior to bariatric surgery are more likely to develop obesity than their younger siblings born after bariatric surgery and weight loss.⁷³

A number of animal studies demonstrate the effect of diet on metabolic regulatory genes through methylation of DNA or methylation/acetylation of histones.⁷⁴ For example, leptin gene methylation increases following the consumption of a high-fat diet.⁷⁵ Also, hypothalamic proopiomelanocortin gene methylation increases following the consumption of a diet high in fat and sucrose.^76,77 These epigenetic changes can persist in animal models for at least three generations.⁷⁸

Following moderate intense physical activity, skeletal muscle glucose transporter-4 expression is enhanced, promoting insulin sensitivity.⁷⁹ Also, there is increased hexokinase and lipoprotein lipase expression, increasing glucose and fatty acid metabolism,^80,81 respectively. In addition, there is activation of peroxisome proliferator-activated γ coactivator-1α, a nuclear receptor cofactor expressed in skeletal muscle that induces expression of genes involved in mitochondrial function.⁸²

While specific mechanisms are being worked out, the epigenetic changes that result from modern behaviors over the past several generations are likely to contribute to the increasing prevalence of MetS.

The high prevalence of MetS should trigger aggressive case finding in a large portion of the general population.¹ Signs of obesity, weight gain, hypertension, hyperlipidemia, and hyperglycemia can be early markers of MetS. People with a family history of T2D, hypertension, and CVD should also be evaluated for MetS. Additionally, the presence of other conditions associated with insulin resistance, such as polycystic ovary syndrome, hepatosteatosis, obstructive sleep apnea, or gestational diabetes, should raise suspicion for MetS. Assigning a diagnosis of MetS to an individual emphasizes the decision to intervene (Table 26–4).

The annual risk of T2D is approximately 2.5% when stratified by fasting glucose.⁸³ In people with obesity and MetS, the annual risk of T2D is nearly 5%, although annual regression of hyperglycemia is about 10%, emphasizing the need for intensive lifestyle changes as part of a preventive care paradigm.⁸³ By virtue of its syndromic nature, this preventive care approach to individuals at high risk for MetS should follow the same treatment strategies for MetS. The intensity of intervention should parallel the severity of each MetS component.¹ A striking theme among the major clinical trials investigating individual criteria of MetS is that early, intensive intervention is best at reducing adverse outcomes, especially with the intention of atherosclerotic risk reduction (Table 26–5).^{31,84,85,86,87,88}

Once the diagnosis of MetS is made, aggressive interventions should be adopted that in the form of lifestyle changes, pharmacology, or procedures.

Lifestyle Intervention

In early MetS, when the severity of component risks are mild, lifestyle interventions should be implemented that minimize refined carbohydrates, avoid processed foods; favor meats that are lean; and contain large amounts of fruits, vegetables, and fish. Debate continues over the ideal diet, but beneficial dietary pattern examples include the Mediterranean diet, the New Nordic diet, the Dietary Approaches to Stop Hypertension (DASH) diet, and the Ornish diet. The use of very low carbohydrate diets, such as the Atkins diet, can also be considered. The most important consideration for dietary intervention is the ability of the individual to maintain this new lifestyle over the long term.⁸⁹

The Mediterranean Diet

The relatively low prevalence of atherosclerotic disease in the Mediterranean region prompted interest in the metabolic health benefits of the local diet.⁹⁰ There are many types of Mediterranean diets with varying degrees of pork, meat, and wine consumption, depending on the region and specific culture. The key features of this general lifestyle are subject to debate but likely to include a high polyphenol content, a diversity of fruits and vegetables, and healthy protein sources.⁹¹

Numerous observational studies demonstrate reduced rates of obesity, T2D, and CVD in people consuming a Mediterranean diet.⁹¹ In a large randomized controlled trial, subjects assigned to the Mediterranean diet had the greatest weight loss, as well as significant reduction in LDL, triglycerides, fasting serum glucose, and fasting plasma insulin levels, compared to subjects assigned to a very low carbohydrate diet or a low-fat diet.⁹² In another randomized trial, individuals on the Mediterranean diet demonstrated a 30% reduction in cardiovascular events and cardiovascular mortality over 6 years, compared to subjects assigned a low-fat diet.⁹³ Additionally, there was a 30% reduction in the incidence of T2D among subjects on the Mediterranean diet in this trial.⁹⁴

The content of the Mediterranean diet provides a nutritional basis that addresses many of the molecular mechanisms of MetS. Approximately 30% of calories are derived from carbohydrates in the form of whole grains and fruits, which are high in fiber and in polyphenols. At least three to four fruits are consumed daily. Additionally, three to four servings of vegetables are consumed daily. These are comparable to the recommended fruit and vegetable intake given by the Institute of Medicine, which suggests six to eight total servings daily.⁹⁵

Another 35% to 40% of the total calories of the Mediterranean diet are in the form of fats and oils. Sources include high amounts of olive oil, nuts, cheese, poultry, and fish. These foods are generally rich in n-3 fatty acid content and low in saturated fats. There is a low content of red meat and minimal amounts of refined grains and simple sugars.

A moderate amount of wine consumption is included in most of the Mediterranean diets, which may provide metabolic benefits. A recent randomized trial demonstrated improved fasting blood glucose, reduced fasting insulin, and increased HDL levels in subjects already on the Mediterranean diet that were provided red wine with dinner.⁹⁶ These benefits, possibly related to the higher polyphenol content in red wine, were not observed in individuals provided white wine or water. Many other small trials corroborate these results that moderate red wine consumption, defined as zero to one servings of wine daily for women and one to two servings daily for men, may confer clinical benefits in obesity and MetS.^95,97

Other Dietary Patterns

The Ornish and New Nordic diets are similar to the Mediterranean diet in that they contain high amounts of fruits, vegetables, legumes, and nuts, with minor differences in animal and fish protein sources. A recent large randomized study demonstrates that after 6 months of follow-up, subjects with obesity assigned the New Nordic diet had greater weight loss, reduced fasting serum glucose by 5 mg/dL, reduced fasting insulin, and reduced fasting triglyceride levels by 18 mg/dL, compared to those assigned a western diet.⁹⁸ Studies of the Ornish diet are limited in that they are observational in nature. Still, cohort studies of subjects on the Ornish diet demonstrate reduced fasting glucose and hemoglobin A1c levels, as well as reduced total LDL content and shifts to larger LDL particle size.^99,100

Pharmacologic Intervention

Insulin Resistance

Although they are not approved by the US Food and Drug Administration, several agents that improve glucose metabolism and potentially reduce insulin resistance are effective treatments for people with MetS. In the Diabetes Prevention Program, the use of metformin reduced the incidence of T2D by 27% in subjects with insulin resistance and increased BMI.³¹ In comparison studies focusing specifically on people with MetS, the use of metformin is similar in efficacy to intensive lifestyle interventions and has been shown to reduce weight, fasting serum glucose, triglyceride, and LDL levels.¹⁰¹ In people taking antipsychotic medication, metformin has been shown to protect against obesity and MetS, with greater efficacy than lifestyle changes alone.¹⁰² Through effects on glucose and lipid metabolism within the liver, metformin can improve hepatosteatosis that is commonly present in people with MetS.¹⁰³ Metformin use is also associated with reduced TNFα and increased adiponectin levels when administered to adolescents with obesity, and it raises endothelial NO production, which mitigates MetS development.^104,105 Because of the relative low cost, long history of use, and favorable safety profile, metformin is a first-line agent in the treatment of MetS.

In addition, agents that more directly influence insulin sensitivity can be considered. The GLP-1 receptor analog liraglutide is presently approved for the treatment of obesity and T2D. The class of drugs achieves supraphysiologic plasma GLP-1 activity; serves to supplement the relatively low GLP-1 activity in MetS; and exerts a plurality of beneficial effects, such as improved insulin sensitivity, improved pancreatic β-cell function, activation of central controls of satiety, and reduced hepatic glucose release.¹⁰⁶ Together, these effects lead to weight loss and reduced insulin resistance, which can lead to improved outcomes, although direct confirmatory data are lacking.¹⁰⁶

Acarbose, an α-glucosidase inhibitor, acts to slow the hydrolysis and absorption of dietary carbohydrates. The use of acarbose in T2D is limited by a relatively low efficacy on serum glucose reduction. However, the preventive use of acarbose in people with obesity and insulin resistance reduces the incidence of T2D by approximately 20%.¹⁰⁷ A post-hoc analysis of subjects with MetS included in this study demonstrated a reduction in the incidence of T2D by 38%.¹⁰⁷

Pioglitazone and rosiglitazone (thiazolidinediones) activate peroxisome proliferator-activated receptor (PPAR)-γ, which enhances insulin signaling, especially in adipose and muscle tissues. Although these agents have the potential to improve both insulin resistance and lipid profiles in individuals with MetS,¹⁰⁸ concerns about their safety and potential for weight gain may limit their utility in MetS.

Inhibitors of sodium glucose cotransporter type 2 have been approved for treatment of T2D. Mechanistically, these agents prevent reuptake of glucose in the proximal collecting tubules, lowering the renal glucose threshold and promoting glucose excretion within urine.¹⁰⁹ In addition to minimizing hyperglycemia, these agents induce weight loss, increase GLP-1 levels and may preserve normal pancreatic β-cell function.¹¹⁰ All of these effects would be beneficial in MetS, although studies addressing this specific use have not been conducted. An observed reduction of cardiovascular events with the use of empagliflozin in T2D demonstrates the therapeutic potential for this class of agents.¹¹¹

Weight Loss Pharmacotherapy

Drugs that are directed specifically for weight loss may also be beneficial in the treatment of MetS. In general, currently available weight-loss agents induce a modest weight reduction of 3% to 5% that is maintained over 1 to 2 years of follow-up.^112,113 Lorcaserin reduces appetite through modulation of serotonin receptors within the hypothalamus.¹¹² The combination of phentermine and topiramate also reduces appetite, although there are concerns for use in patients with underlying CVD resulting from tachycardia induced by phentermine.¹¹³ The combination of Wellbutrin and naltrexone affects both appetite regulation and reward pathways. These agents demonstrate similar degrees of modest weight reduction, although to date, improvements in cardiovascular events and other outcomes have not been demonstrated.

The use of orlistat, a pancreatic lipase inhibitor, may also be beneficial in MetS because of effects of modest weight loss and decreased lipid absorption. Clinical trials of orlistat demonstrate reduced fasting glucose levels, triglycerides, and blood pressure, as well as improvements in hepatosteatosis.¹¹⁴ These benefits should be weighed against the potential adverse effect of loose bowel movements and malabsorption of fat-soluble vitamins.¹¹⁵

Rapid development of novel therapeutic agents for the treatment of obesity continues. Potential targets include ghrelin inhibition, peptide YY analogs, and inhibition of the Dyrk family of proteins involved in the nutrient-sensing cascade.¹¹⁶

Hypertension

The treatment target for hypertension with MetS should be a systolic blood pressure of 120 mm Hg or less.¹¹⁷ Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers demonstrate the greatest protection from atherosclerotic and renal disease and may be protective against the development of T2D.⁸⁷ Agents from either of these classes should be considered as first-line therapy for hypertension in the setting of MetS.¹¹⁸

Hyperlipidemia

Treatment targets for hyperlipidemia with MetS should involve lowering LDL cholesterol (< 100 mg/dL)^1,4 while also addressing severe hypertriglyceridemia. The LDL reduction achieved by statin therapy significantly reduces cardiovascular risk in MetS. PCSK-9 inhibitors are presently approved for individuals with familial hypercholesterolemia or those with atherosclerotic disease unable to achieve therapeutic targets with statins. Ezetimibe can be considered as an adjunct to statin therapy, although its LDL-lowering effect is only modest in comparison.

Colesevelam deserves special attention in the case of MetS. This bile acid sequestrant lowers LDL cholesterol by approximately 18% and slows dietary carbohydrate absorption, which lowers serum glucose levels and insulin requirements.¹¹⁹ Several randomized trials demonstrate reduced incidence of T2D with the use of colesevelam.^120,121 In a trial of men with MetS already taking statins, colesevelam treatment increased insulin sensitivity and reduced fasting serum glucose by 6 mg/dL, postprandial serum glucose by 17 mg/dL, and LDL cholesterol by 22 mg/dL.¹¹⁹

Treatment of hypertriglyceridemia is also beneficial. Several large trials suggest pharmacologic intervention in individuals with triglyceride levels greater than approximately 200 mg/dL and HDL levels less than approximately 35 mg/dL can reduce the risk of cardiovascular events.^122,123,124 Fibrate medications reduce circulating triglycerides through activation of PPAR-α, which increases lipoprotein lipase activity and reduces hepatic triglyceride synthesis. Administration of concentrated long-chain n-3 fatty acids can also reduce hypertriglyceridemia. However, preventive cardiovascular effects of long-chain n-3 supplementation are not consistently demonstrated in clinical trials.^125,126,127

Procedural Intervention

Several surgical and nonsurgical procedures have been developed and approved for the treatment of obesity, but they also mitigate the severity of MetS components. Approved bariatric surgical procedures include the Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), biliopancreatic diversion with or without duodenal switch (BPD), and laparoscopic gastric banding (LGB). Approved nonsurgical procedures include the insertion of a gastric balloon or a duodenal sleeve (endoluminal barrier).¹²⁸ Other nonsurgical procedures are being tested and hold promise, including vagal nerve stimulation.¹²⁹

Surgically induced changes in the gastrointestinal tract affect energy physiology, insulin resistance, hypertension, hyperlipidemia, and other weight-related complications.¹³⁰ Additionally, many of the factors contributing to MetS improve and the risk of cardiovascular events and mortality is reduced.¹³¹ In people undergoing RYGB, SG, or BPD, insulin resistance improves in the immediate postoperative period, signifying the predominance of improved energy regulatory hormone signaling well before weight loss occurs.¹³² Following LGB, insulin resistance declines in association with weight loss.¹³² The significant improvement and possible resolution of T2D is also substantially higher following RYGB, SG, and BPD, when compared to LGB.^133,134,135 These observations suggest that the metabolic benefits of RYGB, SG, and BPD may confer additional improvement to people with MetS.

At present, bariatric surgery is approved for people with BMI of (1) at least 40 kg/m² or (2) at least 35 kg/m² in the presence of T2D, CVD, or other weight-related complications. Special consideration should be given to people with obesity and MetS, in whom bariatric surgical procedures can drastically alter their risk of atherosclerotic disease and T2D.¹³⁶ In the case of people with MetS and mild obesity, defined as a BMI ranging from 30 to 35 kg/m² (or just over the BMI cutoff for Asians), clinical evidence is mounting for reduction in the incidence of T2D following bariatric surgery.¹³⁷

Evidence for the reduction in atherosclerotic risk or improvement in components of MetS would be expected at the levels of weight loss associated with nonsurgical procedures for obesity. Specifically, results from current published trials demonstrate reductions in hemoglobin A1C (0.4%–1.6%), LDL, triglycerides, and blood pressure following endoscopic bariatric procedures or gastric electrical stimulation.^128,129

The worldwide epidemic of noncommunicable diseases, especially obesity and diabetes, places a large portion of the population at risk for atherosclerotic CVD. Through complex pathophysiologic mechanisms, the emergence of MetS places those individuals at even greater risk. Clinical interventions should be multifaceted, applied early, and in proportion to the severity of metabolic dysregulation. Changes in lifestyle are the most important approach, with a special focus on beneficial behaviors that can be maintained for the long term. The use of medications to improve insulin sensitivity, induce weight loss, control blood pressure, and address dyslipidemia in concert can mitigate the risk of atherosclerotic disease. Procedural interventions such as bariatric surgery are generally more effective than medication therapy and should be considered in appropriate individuals. The constellation of interwoven etiologies and effects of MetS necessitates a comprehensive, patient-centered clinical approach in a preventive care paradigm.