Metabolic Syndrome

Metabolic syndrome (syndrome X, insulin resistance) is a multifactorial disease with multiple risk factors that arises from insulin resistance accompanying abnormal adipose deposition and function.[1, 2] It is a risk factor for coronary heart disease, as well as diabetes, fatty liver, and several cancers. The clinical manifestations of this syndrome may include hypertension, hyperglycemia, hypertriglyceridemia, reduced high-density lipoprotein cholesterol (HDL-C), and abdominal obesity. (See Prognosis, Workup, Treatment, and Medication.)

Under 2005 revised guidelines by the National Heart, Lung, and Blood Institute (NHLBI) and the American Heart Association (AHA),[6] metabolic syndrome is diagnosed when a patient has at least three of the following five conditions (see Presentation and Workup):

• Fasting glucose ≥100 mg/dL (or receiving drug therapy for hyperglycemia)

• Blood pressure ≥130/85 mm Hg (or receiving drug therapy for hypertension)

• Triglycerides ≥150 mg/dL (or receiving drug therapy for hypertriglyceridemia)

• HDL-C < 40 mg/dL in men or < 50 mg/dL in women (or receiving drug therapy for reduced HDL-C)

• Waist circumference ≥102 cm (40 in) in men or ≥88 cm (35 in) in women; if Asian American, ≥90 cm (35 in) in men or ≥80 cm (32 in) in women (The international diabetes federation [IDF] criteria allow the use of a body mass index [BMI] >30 kg/m2 in lieu of the waist circumference criterion.)

To address variation between professional guidelines, the National Heart, Lung, and Blood Institute (NHLBI), American Hearth Association (AHA), International Diabetes Foundation (IDF), and other organizations have proposed a harmonized definition of metabolic syndrome.[3]

Abundant data suggest that patients meeting these diagnostic criteria have a greater risk of significant clinical consequences, the 2 most prominent of which are the development of diabetes mellitus[7] and of coronary heart disease. Pooled data from 37 studies involving more than 170,000 patients have shown that metabolic syndrome doubles the risk of coronary artery disease.[8] It also increases risk of stroke, fatty liver disease, and cancer.[9] (See Prognosis.)

Controversy

There has been debate over whether obesity or insulin resistance is the unifying feature and underlying cause for metabolic syndrome.[10] However, more fundamentally, the clinical value of the recognition of metabolic syndrome as a distinct entity has been challenged. One study questioned the predictive value of the metabolic syndrome diagnosis for the development of diabetes and cardiovascular events in older populations (aged 70-82 y and 60-79 y).[11]

Neither population showed a relationship between cardiovascular outcomes and three of the metabolic syndrome criteria (for waist circumference, triglycerides, and glucose). Moreover, in this group of older patients, the diagnosis of metabolic syndrome was not more predictive of incident diabetes than was the fasting plasma glucose level alone.

Clearly, the individual clinical features that make up the syndrome are predictive of clinical outcomes, but whether grouping these features together under the umbrella of metabolic syndrome adds additional diagnostic, therapeutic, and prognostic value remains the subject of ongoing debate.[12, 13]

Target organ damage occurs through multiple mechanisms in metabolic syndrome. The individual diseases leading to metabolic syndrome produce adverse clinical consequences. For example, hypertension in metabolic syndrome causes left ventricular hypertrophy, progressive peripheral arterial disease, and renal dysfunction.[14] However, the cumulative risk for metabolic syndrome appears to cause microvascular dysfunction, which further amplifies insulin resistance and promotes hypertension.[15]

Metabolic syndrome promotes coronary heart disease through several mechanisms. It increases the thrombogenicity of circulating blood, in part by raising plasminogen activator type 1 and adipokine levels, and it causes endothelial dysfunction.[16] Metabolic syndrome may also increase cardiovascular risks by increasing arterial stiffness.[17] Additional mechanisms include oxidative stress,[18] which has been associated with numerous components of metabolic syndrome.[19]

The underlying etiology for metabolic syndrome remains unclear.[20] However, known risk factors for metabolic syndrome include family history, poor diet, and inadequate exercise. Two forces that have spread metabolic syndrome globally are the increased availability and consumption of high calorie-low fiber fast food as well as decreased physical activity engendered by sedentary lifestyles and mechanized transportation.[21]  Contributing factors and mechanisms appear to include the following[20] :

• Insulin resistance
• Pancreatic beta-cell dysfunction
• Cellular dysfunction by protein kinases and phoshatases
• Suppression of insulin receptor substrate-1 and 2 (IRS1/IRS2) gene expression and function
• Obesity and lipid toxicity
• Oxidative stress and glucose toxicity
• Chronic inflammation
• Dysrupted circadian rhythm
• Genetics and epigenetics
• Gut microbial imbalance
• Dietary effects

Metabolic syndrome is thought to be caused by adipose tissue dysfunction and insulin resistance. Dysfunctional adipose tissue also plays an important role in the pathogenesis of obesity-related insulin resistance.[22]  Both adipose cell enlargement and infiltration of macrophages into adipose tissue result in the release of proinflammatory cytokines and promote insulin resistance.[23]

Insulin resistance appears to be the primary mediator of metabolic syndrome.[24] Insulin promotes glucose uptake in muscle, fat, and liver cells and can influence lipolysis and the production of glucose by hepatocytes.

Additional contributors to insulin resistance include abnormalities in insulin secretion and insulin receptor signaling, impaired glucose disposal, and proinflammatory cytokines. These abnormalities, in turn, may result from obesity with related increases in free fatty acid levels and changes in insulin distribution (insulin accumulates in fat).

The distribution of adipose tissue appears to affect its role in metabolic syndrome. Fat that is visceral or intra-abdominal correlates with inflammation, whereas subcutaneous fat does not. There are a number of potential explanations for this, including experimental observations that omental fat is more resistant to insulin and may result in a higher concentration of toxic free fatty acids in the portal circulation.[25]

Abdominal fat is known to produce potentially harmful levels of cytokines, such as tumor necrosis factor, adiponectin, leptin, resistin, and plasminogen activator inhibitor.[26]

Psychological characteristics, including anger, depression, and hostility, may be linked to increased risk for metabolic syndrome.[27] However, psychological disorders, especially anxiety, may represent comorbidity or a complication of metabolic syndrome.[28] Clearly, further study is warranted.

Occurrence in the United States

Metabolic syndrome is increasing in prevalence, paralleling an increasing epidemic of obesity. In the United States, almost two thirds of the population in 2008 was overweight or obese, with more than one fourth of the population meeting diagnostic criteria for metabolic syndrome.[29]  2004 Data from a 1999-2000 survey showed that the age-adjusted prevalence of metabolic syndrome among US adults aged 20 years or older had risen from 27% (1988-1994 data) to 32%.[30]  2011-2014 National Health and Nutrition Examination Survey (NHANES) data showed a crude estimate of 36.5% for the prevalence of adult obesity (32.3% in adults aged 20-39 years; 40.2% in those aged 40-59 years; 37.0% in those aged ≥60 years).[20] There was a 38.3% overall prevalence of obesity in women and a 34.3% in men. Among youth aged 2-19 years, there was a 17% prevalence of obesity over the same period (8.9% in those aged 2-5 years; 17.5% in those aged 6-11 years; 20.5% in those aged 12-19 years).[20]  

Fortunately, since peaking in 2001-2002, the overall prevalence of metabolic syndrome in the United States has fallen, primarily due to decreases in the prevalences of hypertriglyceridemia and hypertension—and in spite of increases in the prevalences of hyperglycemia and obesity/waist circumference.[31]  Data from the 2009-2010 NHANES showed that the age-adjusted prevalence of metabolic syndrome had fallen to approximately 24% in men and 22% in women.[32]

International occurrence

Metabolic syndrome is a burgeoning global problem, with an increasing prevalence in urban populations of some developing countries.[10, 21] Approximately one fourth of the adult European population is estimated to have metabolic syndrome, with a similar prevalence in Latin America.[29] It is also considered an emerging epidemic in developing East Asian countries, including China, Japan, and Korea. The prevalence of metabolic syndrome in East Asia may range from 8-13% in men and from 2-18% in women, depending on the population and definitions used.[33, 34, 35]

In Japan, the Ministry of Health, Labor, and Welfare has instituted a screening and interventional program.[36] Metabolic syndrome has been recognized as a highly prevalent problem in many other countries worldwide.[37, 38, 39, 40, 41, 42]

Race-related demographics

The fact that the diagnostic criteria for metabolic syndrome vary between ethnic populations is testimony to significant nuances in the manifestation of metabolic syndrome in these groups. The original metabolic syndrome criteria were derived in mostly Caucasian populations, and some have argued for modification of individual criteria for specific ethnic subgroups, as has been done with waist circumference for patients of Asian origin.[43]

In the United States, metabolic syndrome has a high prevalence in African Americans, particularly African American women, and this has been attributed to the higher prevalence of obesity, hypertension, and diabetes in this population.[44] However, the highest age-adjusted prevalence of metabolic syndrome in the United States is found in Mexican Americans, approximately 31.9% of whom had the condition (compared with 27% of the general population) in a 1988-1994 survey.[45]

A study by Ukegbu et al found that African immigrants have a worse metabolic profile than do African Americans but that they have a similar prevalence of metabolic syndrome. This may mean that metabolic syndrome may underpredict metabolic risk in Africans.[46]

Sex-related demographics

Metabolic syndrome is similarly prevalent in men (24%) and women (22%), after adjusting for age.[32] However, several considerations are unique to women with metabolic syndrome, including pregnancy, use of oral contraceptives, and polycystic ovarian syndrome.[47] Metabolic syndrome and polycystic ovarian syndrome share the common feature of insulin resistance; they therefore share treatment implications as well.[48] Cardiometabolic risk is thought to be elevated in both groups.[49]

In addition, a modest association is apparent between metabolic syndrome and breast cancer, especially in postmenopausal women.[50] Overall, the prevalence of metabolic syndrome in women appears to be increasing, particularly in those of childbearing age.[51]

Bhasin et al, as part of the Framingham Heart Study, found that sex hormone-binding globulin is independently associated with the risk of metabolic syndrome, whereas testosterone is not. Age, body mass index (BMI), and insulin sensitivity independently affect sex hormone-binding globulin and testosterone levels.[52] More recent studies have raised the possibility of an association between testosterone deficiency and metabolic syndrome.[53]

Age-related demographics

The prevalence of metabolic syndrome increases with age, with about 40% of people older than 60 years meeting the criteria.[30] However, metabolic syndrome can no longer be considered a disease of only adult populations. Alarmingly, metabolic syndrome and diabetes mellitus are increasingly prevalent in the pediatric population, again in parallel with a rise in obesity.[54]

In the United States, children are becoming obese at triple the rate compared with the 1960s, making the study and treatment of this problem paramount. The epidemic of metabolic syndrome in children and adolescents is an international phenomenon, leading the International Diabetes Foundation to publish an updated consensus statement to guide diagnosis and further study of the condition.[55, 56]

The complications of metabolic syndrome are broad. Numerous associated cardiovascular complications exist, particularly coronary heart disease, but also atrial fibrillation,[57, 58] heart failure,[59] aortic stenosis,[60] ischemic stroke,[61] and, possibly, venothromboembolic disease.[62]  Cardiovascular disease and diabetes mellitus coexist and are two leading causes of death.[10, 20]  Evidence also exists to indicate that upregulation of the renin-angiotensin-aldosterone system and derangements to metabolic pathways (eg, glucose and fat metabolism) can also promote pulmonary vascular disease (eg, pulmonary arterial hypertension) and right heart failure.[59]

Emerging data suggest an important correlation between metabolic syndrome and risk of stroke.[63] Each of the components of metabolic syndrome has been associated with elevated stroke risk, and evidence demonstrates a relationship between the collective metabolic syndrome and risk of ischemic stroke.[64] Metabolic syndrome may also be linked to neuropathy beyond hyperglycemic mechanisms through inflammatory mediators.[65]

The metabolic derangements that characterize metabolic syndrome have been implicated in the development of nonalcoholic fatty liver disease.[66, 67] Indeed, the fatty liver is thought to play an important role in the development of metabolic syndrome.[68]

In addition, metabolic syndrome has been implicated in the pathophysiology of several other diseases, including obstructive sleep apnea. Breast cancer has also been linked to metabolic syndrome, possibly through dysregulation of the plasminogen activator inhibitor-1 (PAI-1) cycle.[69] Additional studies have linked metabolic syndrome with cancers of the colon, gallbladder, kidney, and, possibly, prostate gland.[70] Evidence is emerging of an association with psoriasis.[71, 72]

Metabolic syndrome between pregnancies increases the risk of recurrent preeclampsia, according to a retrospective cohort study of 197 women who had preeclampsia during their first pregnancy. Of the 197 women, 40 (20%) had metabolic syndrome between pregnancies. Of these 40 women, 18 (45%) had preeclampsia during their second pregnancy, compared with 27 (17%) of the 157 women without metabolic syndrome between pregnancies. The risk of recurrent preeclampsia increased with the number of components of the metabolic syndrome present.[73, 74]

Additional research has raised the possibility that metabolic syndrome adversely affects neurocognitive performance.[75] In particular, metabolic syndrome has been blamed for accelerated cognitive aging.[76] Patients with mental illnesses also face increased cardiometabolic risk due at least in part to socioeconomic factors such as greater poverty and poorer access to medical care.[77, 78]

Paradoxically, metabolic syndrome was associated with a lower risk of bone fractures in a meta-analysis.[79] Further study is warranted.

As with other diseases, careful history taking is important in metabolic syndrome. Even though the condition is diagnosed based on physical and laboratory features, it may be suspected if symptoms of any of the component disorders are present, such as the increased hunger, thirst, or urination that may accompany hyperglycemia.

Patients reporting a history of hypertension, dyslipidemia, or hyperglycemia warrant screening for metabolic syndrome. Symptoms suggesting the rise of cardiovascular and other complications, such as chest pain or shortness of breath, must be investigated carefully. As lifestyle changes can ameliorate the condition, attention should be paid to the patient’s dietary habits and exercise routines so that areas for improvement can be identified.

The patient’s social history is important for identifying additional risks, such as tobacco use, which may exacerbate the increased cardiovascular complications associated with metabolic syndrome.

A family history should be obtained because genetics may play an important role in metabolic syndrome. This feature of the disease is under active investigation; however, no gene or group of genes has yet been implicated consistently, suggesting that environment exerts substantial influence.[80]

Finally, a thorough review of systems may help to identify related problems, such as menstrual irregularities that can be seen in polycystic ovarian syndrome.

The physical examination is crucial in patients with metabolic syndrome, as the findings of elevated blood pressure and abdominal obesity are 2 of the 5 diagnostic criteria. Measurement and documentation of waist circumference are important routines when screening for metabolic syndrome.

The examination may also reveal findings reflective of the other criteria. For example, patients with insulin resistance and hyperglycemia or with diabetes mellitus may have acanthosis nigricans, hirsutism, peripheral neuropathy, and retinopathy. Patients with severe dyslipidemia may have xanthomas or xanthelasmas. The presence of arterial bruits may portend a higher risk of cardiovascular complications.

Initial laboratory studies in patients suspected of having metabolic syndrome should include standard chemistries to assess for hyperglycemia and renal dysfunction and lipid studies to assess for hypertriglyceridemia or low HDL levels.

If a family history of early coronary or other atherosclerotic disease is present, consider including, in addition to HDL-C and low-density lipoprotein cholesterol (LDL-C), studies of lipoprotein(a), apolipoprotein-B100, high-sensitivity C-reactive protein (CRP), and (if the patient does not already merit the lowest LDL-C target [< 70]), homocysteine and fractionated LDL-C.

In view of the various associations between metabolic syndrome and other conditions discussed elsewhere in this article, additional helpful blood tests may include thyroid and liver studies, hemoglobin-A1C levels, and uric acid. Increased thyroid stimulating hormone (TSH) has been linked to a higher prevalence of metabolic syndrome.[81] Hyperuricemia appears to be much more common in patients with metabolic syndrome than in the general population, and this is attributed to the inflammatory effects of metabolic syndrome.[82] Further studies should be pursued as clinical findings dictate.

Imaging studies

Imaging studies are not routinely indicated in the diagnosis of metabolic syndrome. However, they may be appropriate for patients with symptoms or signs of the many complications of the syndrome, including cardiovascular disease. Complaints of chest pain, dyspnea, or claudication may warrant additional testing with electrocardiography (rest/stress ECG), ultrasonography (vascular or rest/stress echocardiography), stress single-photon emission computed tomography (SPECT), cardiac positron emission tomography (PET), or other imaging studies.

Testing for sleep-related breathing disorder

Investigation into other causes or exacerbating factors should be considered. For example, sleep-related breathing disorders, such as obstructive sleep apnea, are becoming increasingly relevant and novel risk factors for metabolic syndrome.[4]

The difficulty in clarifying the associations between obstructive sleep apnea and metabolic syndrome lie in part with the confounding effect of obesity.[83] Nevertheless, patients reporting significant sleep disturbances, snoring, possible pauses, and/or daytime drowsiness may benefit from further investigation for a treatable sleep-related breathing disorder, including through polysomnography.

Cardiovascular risk assessment

New guidelines on the assessment of cardiovascular risk, released in late 2013 by the American Heart Association/American College of Cardiology (AHA/ACC), recommend use of a revised calculator for the risk of developing a first atherosclerotic cardiovascular disease (ASCVD) event, which is defined as one of the following in a person who was initially free from ASCVD[84] :

• Nonfatal myocardial infarction

• Death from coronary heart disease

• Stroke (fatal or nonfatal)

The calculator uses 9 clinical and laboratory risk factors to determine 10-year and lifetime risk.

For patients 20-79 years of age who do not have existing clinical ASCVD, the guidelines recommend assessing clinical risk factors every 4-6 years. For patients with low 10-year risk (< 7.5%), the guidelines recommend assessing 30-year or lifetime risk in patients 20-59 years old. Regardless of the patient’s age, clinicians should communicate risk data to the patient and refer to the AHA/ACC lifestyle guidelines, which cover diet and physical activity. For patients with elevated 10-year risk, clinicians should communicate risk data and refer to the AHA/ACC guidelines on blood cholesterol and obesity.[84]

The initial management of metabolic syndrome involves lifestyle modifications, including changes in diet and exercise habits.[85] Indeed, evidence exists to support the notion that the diet, exercise, and pharmacologic interventions may inhibit the progression of metabolic syndrome to diabetes mellitus.[86]

Treatment of hypertension had been based on the recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) guidelines, to achieve a goal blood pressure of less than 140/90 mm Hg or, in patients meeting diagnostic criteria for diabetes mellitus, less than 130/80 mm Hg. However, the 2014 report of the Eight Joint National Committee (JNC-8) has led to less stringent recommendations for drug therapy (140/90 mm Hg for most populations, 150/90 mm Hg for patients aged 60 or older),[87] with continued emphasis on the importance of promoting healthy diet and exercise behaviors, as addressed by 2013 guidelines from the American College of Cardiology.[88, 89]  Nevertheless, more recent study data continue to support a more aggressive blood pressure goal of 120/80 mm Hg.

Surgical considerations

At present, no surgical interventions for metabolic syndrome have been widely accepted. However, trials of bariatric surgery in patients who were morbidly obese and had metabolic syndrome suggested beneficial results, including decreased insulin resistance and lower levels of inflammatory cytokines.[90]

Importantly, metabolic syndrome raises specific perioperative issues that should be considered in patients with metabolic syndrome undergoing any major surgical procedure.[91]

Treatment of obstructive sleep apnea

Treatment of associated obstructive sleep apnea may play a significant role in the management of metabolic syndrome.[92] In a 2011 study, patients with at least moderate obstructive sleep apnea who used continuous positive airway pressure (CPAP) therapy for 3 months showed significant improvements in their metabolic profile, including reductions in systolic and diastolic blood pressure, LDL-C, triglycerides, and glycated hemoglobin. Furthermore, reversal of metabolic syndrome occurred to a greater degree in the CPAP therapy group than in patients who underwent sham treatment (13% vs 1%, respectively).[93]

Consultations

Patients with diabetes should be referred to a diabetic nutritionist, if not an endocrinologist. Patients with cardiac symptoms (chest pain, shortness of breath, palpitations) or an abnormal stress test may merit referral to a cardiologist. Consider referral to a preventive cardiologist for primary or secondary prevention of cardiovascular disease in these high-risk patients. Consultation with a sleep specialist is indicated if there are symptoms suggestive of sleep apnea, such as excessive fatigue or daytime somnolence, a history of snoring and witnessed apneas, or physical signs of untreated apnea such as resistant hypertension.

Patients who are at high risk for obesity-associated morbidity and mortality with a BMI greater than 40 kg/m2 or with a BMI greater than 35 kg/m2 plus 1 or more significant comorbid conditions may be referred for consideration of bariatric surgery when less invasive methods of weight loss have failed.

Some advocate using the 130/80 mm Hg goal in all patients with metabolic syndrome, as well as using angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) rather than diuretics or beta blockers when medication is indicated.[94]

Correction of LDL-C and HDL-C levels

Management of elevated LDL-C includes consideration of all statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) at all indicated ranges, as there are several formulations available with different doses and potencies. Statins affect the lipid profile favorably and provide possible pleiotropic benefits.[95] The choice of drug and dose should be individualized to the patient and titrated to achieve guideline-recommended goals. As a class, statins are pregnancy category "X" (contraindicated; benefit does not outweigh risk).

Management of reduced HDL-C remains controversial, but starts with diet/exercise modifications and may include niacin. Certain statins (such as rosuvastatin) may help, but this is not yet a widely accepted indication.

Cholesteryl ester transfer protein (CETP) inhibitors have been studied as potential agents to raise HDL-C levels in a clinically meaningful manner. Though torcetrapib increased HDL-C levels, it failed to improve clinical outcomes in the ILLUSTRATE (Investigation of Lipid level Management Using Coronary Ultrasound To Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation) trial.[96] Another CETP inhibitor, anacetrapib, remains in development, and the ongoing DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial is expected to shed light on this agent’s potential for reducing clinical cardiovascular events.[97]

Fibrate therapy may serve as an important adjunct in overweight patients with elevated triglyceride and low HDL-C levels (a combination known as atherogenic dyslipidemia).[98]

Niacin raises low HDL-C levels and reduces cardiovascular events but may exacerbate hyperglycemia, especially in high doses (>1500 mg/day), so careful monitoring is recommended.[99]

The latest cholesterol guidelines from the American College of Cardiology emphasize the use of statins over nonstatin therapies, and recommend re-emphasis on adherence to statin and lifestyle therapies before resorting to nonstatin therapies.[100]

Triglyceride treatment

When lifestyle modifications fail, medical therapy for elevated triglycerides may include niacin and fibrates, though a distinction should be made between gemfibrozil and fenofibrate/fenofibric acid due to their different dosing patterns and different propensities for drug interactions, particularly if combined with a statin. The addition of omega-3 fatty acids to treatment is also likely to help lower triglyceride levels.[101]

Hyperglycemia treatment

Drug therapy for hyperglycemia in patients with metabolic syndrome typically begins with an insulin-sensitizing agent, such as metformin. Some literature suggests that metformin may help to reverse the pathophysiologic changes of metabolic syndrome. This includes when it is used in combination with lifestyle changes[102] or with peroxisome proliferator-activated receptor agonists, such as the fibrates[103] and thiazolidinediones (eg, pioglitazone, rosiglitazone),[104, 105] each of which may produce favorable metabolic alterations as single agents in patients with metabolic syndrome.[106]

Management of diabetes mellitus, including screening for end-organ complications, should proceed under current guidelines.[107]

Preventive cardiovascular treatment

Aspirin therapy may be helpful in the primary prevention of cardiovascular complications,[108] particularly in patients with at least an intermediate risk of suffering a cardiovascular event (ie, >6% 10 y risk).[109]

Complementary and alternative medicine

The use of complementary and alternative medications for metabolic syndrome has limited literature support. Traditional Chinese medicines may have a role, as a variety of agents, including ginseng, berberine, and bitter gourd, have demonstrated some favorable metabolic effects, but large-scale clinical trials are needed to fully investigate their safety and efficacy.[110]

A variety of other complementary and alternative treatments may have a potential role in the management of metabolic syndrome[111] and additional study remains warranted.

Lifestyle change and weight loss are considered the most important initial steps in treating metabolic syndrome. Studies comparing ethnically similar populations exposed to different dietary environments suggested that Westernized diets are strongly associated with a higher risk of developing metabolic syndrome.[5]

On the other hand, diets rich in dairy, fish, and cereal grains may be associated with a lower risk of developing metabolic syndrome.[112, 113] Not surprisingly, Mediterranean-style diets appear to be associated with a much lower risk and possibly with resolution of metabolic syndrome in patients who have met diagnostic criteria, especially when coupled with adequate exercise regimens.[114]

A meta-analysis of multiple population studies associated chocolate consumption with a substantial risk reduction (approximately 30%) for cardiometabolic disorders, including coronary disease, cardiac deaths, diabetes, and stroke.[115] The apparent benefits of chocolate may accrue from a beneficial impact of polyphenols present in cocoa products that increase the bioavailability of nitric oxide.

Epidemiologic studies, particularly in males, suggest that moderate wine intake may protect against the development and complications of metabolic syndrome, an effect that is at least partially attributable to polyphenols, such as resveratrol, found in red wines.[116, 117]

The impact of sugar consumption on the risk of developing metabolic syndrome is controversial. Evidence suggests that absolute fructose intake may relate to incident metabolic syndrome.[118] Higher fructose diets have been blamed for elevated rates of metabolic syndrome in African American populations.[119]

However, glycemic load or intake does not appear to predispose persons to the development of metabolic syndrome, though avoidance of high-glycemic-index foods in patients with metabolic syndrome may improve characteristic parameters such as atherogenic dyslipidemia.[120]

In a single-blind, parallel, controlled, dietary intervention study, subjects with metabolic syndrome (n=472) from 8 European countries classified by different insulin resistance (IR) levels according to a homeostasis model assessment of insulin resistance (HOMA-IR) were randomly assigned to 4 diets: a high-saturated fatty acid (HSFA) diet; a high-monounsaturated fatty acid (HMUFA) diet; a low-fat, high-complex carbohydrate (LFHCC) diet supplemented with long-chain n-3 polyunsaturated fatty acids (1.2 g/d); or an LFHCC diet supplemented with placebo for 12 weeks (control). The results provided evidence that subjects’ degree of insulin resistance determines response to the quantity and quality of dietary fat on metabolic syndrome risk factors.[121]

Exercise is thought to be an important intervention,[122] and the current recommendation is for patients to perform regular moderate-intensity physical activity for at least 30 minutes continuously at least 5 days per week (ideally, 7 days per week). Maintaining long-term adherence, however, remains a challenge.[123]  Achieving moderate intensity activity for 120 to 150 minutes a week may reduce the risk of developing metabolic syndrome.[124]  Among patients who already have metabolic syndrome, physical activity correlates with a much lower (about 50%) risk of developing coronary heart disease.[125]

In a prospective study, cardiorespiratory fitness was linked to the risk of developing metabolic syndrome in a dose-dependent manner, with male patients in the highest category of fitness having the lowest risk of developing new-onset metabolic syndrome.[126]

Evidence suggests that excessive sitting and other behaviors that are low in activity and energy expenditure may trigger unique cellular responses that contribute to the development of metabolic syndrome.[127]

In 2010, the American Heart Association-American Stroke Association (AHA-ASA) updated their guidelines for the primary prevention of stroke. These are described below.[128]

Hypertension

Regular blood pressure screening, lifestyle modification, and drug therapy are recommended. A lower risk of stroke and cardiovascular events are seen when systolic blood pressure levels are less than 140 mm Hg and diastolic blood pressure is less than 90 mm Hg. In patients who have hypertension with diabetes or renal disease, the blood pressure goal is less than 130/80 mm Hg. However, the 2014 JNC-8 guidelines recommend more lenient targets (150/90 mm Hg in patients ≥60 y, and 140/90 mm Hg for most other populations).

Diabetes

Blood pressure control is recommended in types 1 and 2 diabetes. Hypertensive agents that are useful in the diabetic population include ACE inhibitors or ARBs.

Treating adults with diabetes with statin therapy, especially patients with other risk factors, is recommended, and monotherapy with fibrates may also be considered to lower stroke risk. Taking aspirin is reasonable in patients who are at high cardiovascular disease risk. However, the benefit of taking aspirin in diabetic patients for the reduction of stroke risk has not been fully demonstrated.

Dyslipidemia

Statin therapy is recommended in patients with coronary heart disease and certain high-risk conditions for the primary prevention of ischemic stroke. In addition to statin therapy, therapeutic lifestyle changes and LDL-cholesterol goals are also recommended.

Niacin may be used in patients with low HDL cholesterol or elevated lipoprotein (a), but its efficacy in preventing ischemic stroke is not established. Fibric acid derivatives, niacin, bile acid sequestrants, and ezetimibe may be useful in patients who have not achieved the target LDL-C level with statin therapy or who cannot tolerate statins; however, their effectiveness in reducing the risk of stroke has not been established.

Diet and nutrition

A diet that is low in sodium and high in potassium is recommended to reduce blood pressure. Diets that promote the consumption of fruits, vegetables, and low-fat dairy products, such as the DASH (Dietary Approaches to Stop Hypertension)–style diet, help to lower blood pressure and may lower the risk of stroke.

Physical activity

Increases in physical activity are associated with a reduction in the risk of stroke. The goal is to engage in at least 30 minutes of moderate intensity activity on a daily basis

Obesity and body fat distribution

Weight reduction among persons who are overweight or obese is recommended to reduce blood pressure and risk of stroke.

Sleep health

Care should be taken to ensure that patients with metabolic syndrome practice healthy sleep behaviors. Even in patients who do not have sleep apnea or suspected sleep apnea, some studies have suggested a relationship between sleep deprivation or inadequate sleep time and metabolic syndrome.[129] Shift workers, who tend to have poor quality sleep, may also be at higher risk of developing metabolic syndrome.[130]

An insulin-sensitizing agent, such as metformin, is typically used at the start of hyperglycemia treatment in patients with metabolic syndrome. Some literature suggests that metformin may help to reverse the pathophysiologic changes of metabolic syndrome. This includes when it is used in combination with lifestyle changes[102] or with peroxisome proliferator-activated receptor agonists, such as fibrates[103] and thiazolidinediones (eg, pioglitazone, rosiglitazone),[104, 105] each of which may produce favorable metabolic alterations as single agents in patients with metabolic syndrome.[106]

When statin therapy and therapeutic lifestyle modifications are not successful, niacin may aid in the management of reduced HDL-C and in the treatment of elevated triglycerides.

Aspirin may contribute to the primary prevention of cardiovascular complications in metabolic syndrome, particularly in patients with at least an intermediate risk of suffering a cardiovascular event (ie, >6% 10-y risk).[108, 109]

Additional therapies have found early support from more recent data. For example, a small trial of high-dose resveratrol therapy (1000 mg daily) was found to lead to greater new bone formation and mineralization in men with metabolic syndrome.[131, 132]

Class Summary

These agents reduce blood glucose levels.

Metformin (Glucophage, Fortamet, Glumetza, Riomet)

Metformin reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in the peripheral tissues (muscle and adipocytes). It is a major drug for use in patients who are obese and have type 2 diabetes. Metformin enhances weight reduction and improves lipid profile and vascular integrity. Individualize treatment with monotherapy or in combination with insulin or sulfonylureas.

Class Summary

Thiazolidinediones may produce favorable metabolic alterations as single agents in patients with metabolic syndrome. These agents are highly selective agonists for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulate insulin-responsive gene transcription involved in glucose production, transport, and use, thereby reducing blood glucose concentrations and reducing hyperinsulinemia.

Rosiglitazone (Avandia)

Rosiglitazone is available only via a restricted access program. It is an insulin sensitizer with a major effect in the stimulation of glucose uptake in skeletal muscle and adipose tissue. It lowers plasma insulin levels and is used to treat type 2 diabetes associated with insulin resistance.

Pioglitazone (Actos)

Pioglitazone improves target cell response to insulin without increasing insulin secretion from the pancreas. It decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and, possibly, in liver and adipose tissue.

Class Summary

Management of elevated LDL-C includes consideration of all statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) at all indicated ranges, as there are several formulations available with different doses and potencies. Statins affect the lipid profile favorably and provide possible pleiotropic benefits. The choice of drug and dose should be based on guidelines but individualized to the patient.

Atorvastatin (Lipitor)

Atorvastatin is an HMG-CoA reductase inhibitor that inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase.

Rosuvastatin (Crestor)

Rosuvastatin is an HMG-CoA reductase inhibitor that inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase.

Fluvastatin (Lescol, Lescol XL)

Fluvastatin is an HMG-CoA reductase inhibitor that inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase.

Lovastatin (Altoprev, Mevacor)

Lovastatin is an HMG-CoA reductase inhibitor that inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase.

Simvastatin (Zocor)

Pravastatin (Pravachol)

Pitavastatin (Livalo)

Class Summary

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and lower aldosterone secretion. They are effective and well-tolerated drugs with no adverse effects on plasma lipid levels or glucose tolerance. They prevent the progression of diabetic nephropathy and other forms of glomerulopathies but appear to be less effective in black patients than in white patients.

Patients with high plasma renin activity may have an excessive hypotensive response to ACE inhibitors. Patients with bilateral renal vascular disease or with single kidneys, whose renal perfusion is maintained by high levels of angiotensin II, may develop irreversible acute renal failure when treated with ACE inhibitors.

ACE inhibitors are contraindicated in pregnancy. Cough and angioedema are less common with newer members of this class than with captopril. Serum potassium and serum creatinine concentrations should be monitored for the development of hyperkalemia and azotemia. Examples of agents from this class include captopril, lisinopril, and enalapril.

Captopril

Captopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. It is rapidly absorbed, but bioavailability is significantly reduced with food intake. Captopril achieves a peak concentration in 1 hour and has a short half-life. It is cleared by the kidney; impaired renal function requires reduction of the dosage. The drug is absorbed well orally.

Give captopril at least 1 hour before meals. If it is added to water, use it within 15 minutes. The dose can be low initially, then titrated upward as needed and as tolerated by the patient.

Enalapril (Vasotec)

Enalapril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It helps control blood pressure and proteinuria. It decreases the pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance.

Enalapril has a favorable clinical effect when administered over a long period. It helps prevent potassium loss in distal tubules. The body conserves potassium; thus, less oral potassium supplementation is needed.

Lisinopril (Prinivil, Zestril)

Lisinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Benazepril (Lotensin)

Benazepril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

When pediatric patients are unable to swallow tablets or the calculated dose does not correspond with tablet strength, an extemporaneous suspension can be compounded. Combine 300 mg (15 tablets of 20-mg strength) in 75 mL of Ora-Plus suspending vehicle and shake well for at least 2 minutes. Let the tabs sit and dissolve for at least 1 hour, and then shake again for 1 minute. Add 75 mL of Ora-Sweet. The final concentration is 2 mg/mL, with a total volume of 150 mL. The expiration time is 30 days with refrigeration.

Fosinopril

Fosinopril is a competitive ACE inhibitor. It prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It decreases intraglomerular pressure and glomerular protein filtration by decreasing efferent arteriolar constriction.

Quinapril (Accupril)

Quinapril is a competitive ACE inhibitor. It reduces angiotensin II levels, decreasing aldosterone secretion.

Class Summary

ARBs lower blood pressure by blocking the final receptor (ie, angiotensin II) in the renin-angiotensin axis. Like ACE inhibitors, they are contraindicated in pregnancy. Serum electrolyte and creatinine levels should be monitored.

Irbesartan (Avapro)

Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II at the tissue receptor site. It may induce a more complete inhibition of renin-angiotensin system than do ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema.

Losartan (Cozaar)

Losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of renin-angiotensin system than do ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. It is suitable for patients unable to tolerate ACE inhibitors.

Olmesartan (Benicar)

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to angiotensin I receptors in vascular smooth muscle. Its action is independent of the pathways for angiotensin II synthesis.

Valsartan (Diovan)

Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from angiotensin I receptors and may lower blood pressure by antagonizing angiotensin I–induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Valsartan may induce a more complete inhibition of renin-angiotensin system than do ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. It is suitable for patients unable to tolerate ACE inhibitors.

Telmisartan

Class Summary

These agents are used to improve lipid profile in patients.

Niacin (Niacor, Niaspan, Slo-Niacin)

Niacin is used in tissue respiration, lipid metabolism, and glycogenolysis. Nicotinic acid has lipid-lowering properties, but nicotinamide and niacinamide do not. Inositol hexanicotinate is a "no flush" form that may not release enough niacin to be effective.

Niacin is available as a prescription, Niaspan, or over the counter as Slo-Niacin. Allergies are common, but another form may be tolerated. In addition to improving low HDL-C levels, niacin may lower triglycerides and LDL-C levels.

Fenofibrate (TriCor, Triglide, Lipofen, Lofibra)

Fenofibrate increases VLDL catabolism by enhancing synthesis of lipoprotein lipase, fatty acid oxidation, and elimination of triglyceride-rich particles. This results in decreased triglyceride levels by 30-60%; HDL may increase.

Fenofibric acid (Trilipix, Fibricor)

Fenofibric acid increases VLDL catabolism by enhancing synthesis of lipoprotein lipase, fatty acid oxidation, and elimination of triglyceride-rich particles. This results in decreased triglyceride levels by 30-60%; HDL may increase.

Gemfibrozil (Lopid)

Gemfibrozil may decrease serum VLDL levels by inhibiting lipolysis, decreasing subsequent hepatic fatty acid uptake, and by inhibiting hepatic secretion of VLDL.

Omega-3 polyunsaturated fatty acid (Lovaza)

Class Summary

These agents inhibit platelet aggregation.

Aspirin (Ecotrin, Ascriptin, Bayer Aspirin, Buffinol)

Aspirin is an odorless, white, powdery substance available in 81mg, 325mg, and 500mg form for oral use. When exposed to moisture, aspirin hydrolyzes into salicylic acid and acetic acids.

Aspirin is a stronger inhibitor of prostaglandin synthesis and platelet aggregation than are other salicylic acid derivatives. The acetyl group is responsible for inactivation of cyclooxygenase via acetylation. Aspirin is hydrolyzed rapidly in plasma, and elimination follows zero order pharmacokinetics.

Aspirin irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to prostaglandin I2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregating agent). Platelet inhibition lasts for the life of the cell (approximately 10 days).

Aspirin may be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. It reduces the likelihood of myocardial infarction and is also very effective in reducing the risk of stroke. Early administration of aspirin in patients with acute myocardial infarction may reduce cardiac mortality in the first month.

Class Summary

These agents lower the renal glucose threshold.

Canagliflozin (Invokana)

Canagliflozin is a selective sodium-glucose transporter-2 (SGLT2) inhibitor. SGLT-2 inhibition lowers the renal glucose threshold (ie, the plasma glucose concentration that exceeds the maximum glucose reabsorption capacity of the kidney); lowering the renal glucose threshold results in increased urinary glucose excretion. Indicated as an adjunct to diet and exercise, canagliflozin therapy is aimed at improving glycemic control in adults with type 2 diabetes. Also, it is indicated to reduce the risk of end-stage renal disease (ESRD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure (HF) in adults with type 2 diabetes (T2D) and diabetic nephropathy with albuminuria >300 mg/day.

Empagliflozin (Jardiance)

Empagliflozin, an SGLT2 inhibitor, decreases blood glucose by increasing urinary glucose excretion. SGLT-2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose.

Indicated as an adjunct to diet and exercise, empagliflozin therapy is aimed at improving glycemic control in adults with type 2 diabetes. It is also indicated for lowering the cardiovascular death risk in adults with type 2 diabetes and cardiovascular disease.

Dapagliflozin (Farxiga)

Dapagliflozin reduces glucose reabsorption in the proximal renal tubules and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM). It is indicated as monotherapy, as initial therapy with metformin, or as an add-on to other oral glucose-lowering agents, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. It is also indicated to reduce hospitalization risk for heart failure in adults with T2DM and established cardiovascular disease (CVD) or multiple CV risk factors. 

Class Summary

Glucagonlike peptide–1 (GLP-1) agonists mimic the endogenous incretin GLP-1, stimulating glucose-dependent insulin release (as opposed to oral insulin secretagogues, which may cause non–glucose-dependent insulin release and hypoglycemia), reducing glucagon, and slowing gastric emptying.

Evidence from the LEADER clinical trial resulted in liraglutide’s approval for risk reduction of major cardiovascular (CV) events (CV death, nonfatal myocardial infarction [MI], and nonfatal stroke) in adults with type 2 diabetes mellitus (T2DM) and established CV disease.[133]

Similarly, once weekly semaglutide SC is also indicated for CV risk reduction in adults with T2DM and heart disease. Results from the SUSTAIN 6 clinical trial (N = 3297) showed that patients treated with semaglutide SC had a significant 26% lower risk for the primary composite outcome of first occurrence of CV death, nonfatal MI, or nonfatal stroke compared with placebo.[134]

Liraglutide (Victoza)

Liraglutide is a once-daily SC injectable GLP-1 receptor agonist that stimulates G-protein in pancreatic beta cells. It increases intracellular cyclic adenosine monophosphate (cAMP), leading to insulin release in the presence of elevated glucose concentrations. Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Additionally, it is indicated to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease.

Semaglutide (Ozempic)

When blood glucose is high, semaglutide, a GLP-1 receptor agonist, lowers it by stimulating insulin secretion and reducing glucagon secretion. Additionally, the once-weekly SC product is also indicated for cardiovascular risk reduction in adults with T2DM and heart disease.

Dulaglutide (Trulicity)

Dulaglutide is a glucagonlike peptide-1 (GLP-1) agonist that acts as an incretin mimetic. It increases insulin secretion in the presence of elevated blood glucose, delays gastric emptying to decrease postprandial glucose, and decreases glucagon secretion. It is administered as a once-weekly SC injection. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is also indicated to reduce risk of major adverse cardiovascular (CV) events (CV death, nonfatal MI, or nonfatal stroke) in adults with T2DM who have established CV disease or multiple CV risk factors.