The American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) have released joint recommendations on the management and diagnosis of the metabolic syndrome. The full report was published in the October 25, 2005, issue of Circulation and is available athttp://circ.ahajournals.org/cgi/content/full/112/17/2735.

The metabolic syndrome is a constellation of interrelated metabolic risk factors, including atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose levels, that are thought to directly promote the development of atherosclerotic cardiovascular disease (ASCVD). Persons with this syndrome are at increased risk of developing type 2 diabetes and commonly manifest a prothrombotic state and a proinflammatory state.

The metabolic syndrome often is referred to as if it were a discrete entity with a single cause. Available data suggest that it truly is a syndrome (i.e., a grouping of ASCVD risk factors) but one that probably has more than one cause.

Risk Factors

The predominant underlying risk factors for the metabolic syndrome are abdominal obesity and insulin resistance; other risk factors include physical inactivity, older age, and hormonal imbalance. An atherogenic diet (i.e., one rich in saturated fat and cholesterol) can increase the risk of developing cardiovascular disease in persons with the syndrome, although this diet is not listed specifically as an underlying risk factor for the condition.

One theory holds that insulin resistance is the essential cause of the metabolic syndrome. Multiple metabolic pathways also have been proposed to link insulin resistance and compensatory hyperinsulinemia to other metabolic risk factors. It is recognized that some persons who are not obese by traditional measures nevertheless are insulin resistant and have abnormal levels of metabolic risk factors. Although insulin-resistant persons may not be clinically obese, they commonly have abnormal fat distribution that is characterized by predominant upper-body fat, which can accumulate viscerally or subcutaneously. Abdominal (or upper-body) obesity correlates more strongly with insulin resistance and the metabolic syndrome than does lower-body obesity.

One feature of upper-body obesity is an unusually high release of nonesterified fatty acids from adipose tissue; this contributes to accumulation of lipids in sites other than adipose tissue. Ectopic lipid accumulation in muscle and the liver predisposes persons to insulin resistance and dyslipidemia. In addition, adipose tissue in obese persons exhibits abnormalities in the production of several adipokines that may affect insulin resistance or modify risk for ASCVD. These include increased production of inflammatory cytokines, plasminogen activator inhibitor-1, and other bioactive products. At the same time, levels of the potentially protective adipokine, adiponectin, are reduced. All of these changes have been implicated as causes of the metabolic risk factors.

The metabolic syndrome has been associated with a state of chronic, low-grade inflammation. Some researchers speculate that this inflammation underlies or exacerbates the syndrome. For example, inflammatory cytokines reportedly induce insulin resistance in adipose tissue and muscle. In obese persons, adipose tissue produces excessive cytokines, and output of adiponectin is diminished. These responses appear to heighten the connection between obesity and inflammation.

The metabolic risk factors seemingly have a direct effect on atherosclerotic disease. Atherogenic dyslipidemia consists of an aggregation of lipoprotein abnormalities, including elevated serum triglyceride and apolipoprotein B levels, increased small low-density lipoprotein (LDL) particles, and a reduced level of high-density lipoprotein (HDL) cholesterol. Other metabolic risk factors such as hypertension, elevated plasma glucose levels, a prothrombotic state, and a proinf lammatory state also appear to be atherogenic.

Diagnosis

In an effort to introduce the term “metabolic syndrome” into clinical practice, several organizations, including the World Health Organization, National Cholesterol Education Program, and International Diabetes Foundation, have proposed criteria for its diagnosis. The AHA and NHLBI require at least three of the following criteria for the diagnosis of the metabolic syndrome:

• Waist circumference of at least 40 inches (102 cm) in men or 35 inches (89 cm) in women, measured at the top of the iliac crest at the end of a normal expiration

• Triglyceride level of at least 150 mg per dL (1.70 mmol per L), or receiving pharmacologic therapy for elevated triglyceride levels

• HDL cholesterol level of less than 40 mg per dL (1.05 mmol per L) in men or less than 50 mg per dL (1.30 mmol per L) in women, or receiving pharmacologic therapy for reduced HDL cholesterol levels

• Systolic blood pressure of at least 130 mm Hg or diastolic blood pressure of at least 85 mm Hg, or receiving pharmacologic therapy for hypertension

• Fasting glucose level of at least 100 mg per dL (5.6 mmol per L), or receiving pharmacologic therapy for elevated fasting glucose levels.

Clinical Management

The primary goal of caring for patients with the metabolic syndrome is to reduce the risk for clinical atherosclerotic disease. First-line therapy is directed toward the major risk factors: elevated LDL cholesterol levels, hypertension, and diabetes. Prevention of type 2 diabetes is another goal. For patients with established diabetes, risk factor management must be intensified to diminish the higher risk of ASCVD.

Although many persons may be genetically susceptible to the metabolic syndrome, it rarely manifests clinically in the absence of obesity and physical inactivity. Consequently, the key emphasis in management of the metabolic syndrome is to mitigate modifiable risk factors (i.e., obesity, physical inactivity, smoking, and atherogenic diet) through lifestyle changes. Then, if the absolute risk is high enough, consideration can be given to incorporating drug therapy into the regimen.

ABDOMINAL OBESITY

Weight reduction is the first priority in persons with abdominal obesity and the metabolic syndrome. Weight reduction and maintenance of a lower weight are best achieved by a combination of reduced caloric intake and increased physical activity. Over six to 12 months, total body weight should be decreased by 7 to 10 percent, which requires decreasing caloric intake by 500 to 1,000 calories per day. Increasing physical activity will enhance the caloric deficit. Achieving the recommended weight loss will reduce the severity of most or all of the metabolic risk factors. Currently available weight-loss drugs have limited effectiveness in the management of obesity; nevertheless, they may be helpful in some patients.

PHYSICAL INACTIVITY

Increasing physical activity assists in weight reduction, has beneficial effects on metabolic risk factors, and reduces overall ASCVD risk. Current recommendations call for at least 30 minutes of moderate-intensity exercise (e.g., brisk walking) on most, and preferably all, days of the week. However, more exercise will be particularly beneficial for persons with the metabolic syndrome. At least 60 minutes of continuous or intermittent aerobic activity, preferably done every day, will promote weight loss or weight-loss maintenance. Avoiding common sedentary activities (e.g., television watching, computer games) also is advised.

Clinical assessment of risk for ASCVD events is recommended before initiating a new exercise regimen. This includes a detailed history of physical activity. For high-risk patients (e.g., those with recent acute coronary syndromes or recent revascularization), physical activity should be performed under medical supervision. Exercise testing also is recommended in select patients with cardiovascular disease and in other symptomatic or high-risk patients. However, it is not necessary for all persons beginning a moderate-intensity exercise program to undergo an exercise stress test.

DIET

Beyond weight control and reduction of total calories, the diet should be low in saturated fats,trans fats, cholesterol, sodium, and simple sugars. In addition, there should be ample intake of fruits, vegetables, and whole grains; fish intake should be encouraged, with recognition of concerns about the mercury content of some fish.

There has long been an interest in whether changing macronutrient ratios can promote weight reduction. For many years, a low-fat diet was advocated because the high caloric density of fat could increase the likelihood of obesity. More recently, interest has grown in the possibility that high-protein, low-carbohydrate diets will enhance weight reduction. However, preoccupation with macronutrient composition fails to identify the key factors affecting body weight. Effective weight loss requires a combination of caloric restriction, physical activity, and motivation; effective lifelong maintenance of weight loss essentially requires a balance between caloric intake and physical activity.

ATHEROGENIC DYSLIPIDEMIA

Atherogenic dyslipidemia consists of abnormal levels of triglycerides and apolipoprotein B, small LDL cholesterol particles, and low HDL cholesterol levels. Atherogenic dyslipidemia should be targeted for lipid-lowering therapy only after the goal for LDL cholesterol has been attained. In other words, as long as LDL cholesterol levels are above goal level, LDL cholesterol is the primary target of therapy, and other lipid risk factors are secondary. In patients with atherogenic dyslipidemia in whom serum triglyceride levels are at least 200 mg per dL (2.26 mmol per L), non-HDL cholesterol is the next target of treatment after the LDL goal is reached. Goals for non-HDL cholesterol parallel those for LDL cholesterol except that the former are 30 mg per dL (0.80 mmol per L) higher.

Use of triglyceride-lowering drugs should be considered to prevent the development of acute pancreatitis in patients with triglyceride levels of 500 mg per dL (5.64 mmol per L) or greater. To achieve non-HDL cholesterol goals in patients with triglyceride levels of less than 500 mg per dL, triglyceride-lowering drugs may be useful in combination with LDL-lowering therapy. Beyond lowering of non-HDL cholesterol, a tertiary aim in patients with atherogenic dyslipidemia is to raise HDL levels when they are reduced. No specific HDL goal is recommended, but HDL levels should be raised to the extent possible after attaining LDL and non-HDL goals.

If non-HDL cholesterol levels remain elevated after the LDL goal is reached, at least two therapeutic options are available. First, intensification of LDL-lowering therapy often reduces non-HDL cholesterol levels. For example, statins lower LDL and non-HDL levels by a similar percentage; moreover, statins reduce the risk for ASCVD events in patients with the metabolic syndrome. A triglyceride-lowering drug also can be added to LDL-lowering therapy. Fibrates and nicotinic acid reduce non-HDL cholesterol, triglyceride, and small LDL particle levels, and they increase HDL levels in patients with the metabolic syndrome or type 2 diabetes. For this reason, combining a fibrate or nicotinic acid with LDL-lowering treatment is an option.

If a statin is being used as LDL-lowering therapy, fenofibrate (Tricor) is preferable to gemfibrozil (Lopid) because risk for severe myopathy appears to be lower in patients taking fenofibrate in combination with statins. Patients with impaired fasting glucose (IFG) levels, impaired glucose tolerance (IGT), or diabetes who are treated with nicotinic acid should be monitored for worsening of hyperglycemia. Lower doses of nicotinic acid lessen this risk.

ELEVATED BLOOD PRESSURE

When overt hypertension is present in patients without diabetes or chronic kidney disease, the goal for antihypertensive therapy is a blood pressure of less than 140/90 mm Hg. In patients with diabetes or chronic kidney disease, the blood pressure goal is less than 130/80 mm Hg. Lifestyle changes should be emphasized in persons with the metabolic syndrome, with the goal of reducing blood pressure as much as possible even in the absence of overt hypertension. Mild elevations of blood pressure often can be managed with weight control, increased physical activity, moderation of alcohol consumption, sodium reduction, and increased consumption of fresh fruits and vegetables and low-fat dairy products. If hypertension cannot be controlled adequately by lifestyle changes, antihypertensive drugs usually are necessary to prevent long-term adverse effects (e.g., myocardial infarction, stroke, chronic kidney disease). The benefits of therapy extend to patients with type 2 diabetes whose blood pressure is above the goal level, and presumably to hypertensive patients with the metabolic syndrome.

Some investigators support the use of angiotensin-converting enzyme (ACE) inhibitors as first-line therapy for hypertension in patients with the metabolic syndrome, especially when type 2 diabetes or chronic renal disease is present. Angiotensin receptor blockers may be used in patients who cannot tolerate ACE inhibitors or as an alternative to ACE inhibitors in patients who have left ventricular dysfunction. Although the possibility recently has been raised that the use of diuretics in patients with IFG levels or IGT may increase the likelihood of progression to type 2 diabetes, the potential benefit of low-dose diuretics in combination with antihypertensive therapy outweighs their risk.

ELEVATED FASTING GLUCOSE

Weight reduction, increased physical activity, or both may delay or prevent the onset of type 2 diabetes in patients with the metabolic syndrome and IFG (or IGT, if assessed). In addition, metformin (Glucophage), thiazolidinediones, and acarbose (Precose) will lower the risk of type 2 diabetes in persons with IFG or IGT. Except for a preliminary trial with acarbose, no clinical evidence is yet available to document that oral hypoglycemic agents can reduce the risk of cardiovascular events. Moreover, neither metformin nor thiazolidinediones are recommended for the sole purpose of preventing diabetes because their cost-effectiveness and long-term safety have not been documented.

PROTHROMBOTIC STATE

Patients with the metabolic syndrome typically have elevated levels of fibrinogen, plasminogen activator inhibitor-1, and other coagulation factors. However, these abnormalities are not detected routinely in clinical practice. For primary prevention, the only available long-term approach to prevent arterial thrombosis is low-dose aspirin or other antiplatelet agents. These agents are recommended in patients with established ASCVD. Their effectiveness in patients with type 2 diabetes without ASCVD has not been established conclusively, although they are widely recommended for these patients. In patients with the metabolic syndrome who are at moderately high risk of ASCVD events, aspirin prophylaxis is a reasonable therapeutic option.

PROINFLAMMATORY STATE

Patients with the metabolic syndrome often have elevated cytokines (e.g., tumor necrosis factor G and interleukin-6) and acute-phase reactants (e.g., C-reactive protein [CRP], fibrinogen). Measurement of CRP is the simplest way to identify a proinflammatory state in clinical practice. CRP levels of greater than 3 mg per L (28.6 nmol per L) can define a proinflammatory state in a person without other detectable causes. Lifestyle changes (particularly weight reduction) are necessary if CRP levels are elevated. No drugs that act exclusively through this mechanism are available for reducing cardiovascular risk. However, several drugs used to treat other metabolic risk factors have been reported to reduce CRP levels (e.g., statins, nicotinic acid, fibrates, ACE inhibitors, thiazolidinediones). These drugs are not recommended to reduce a proinflammatory state independent of their indications for other risk factors.