The Metabolic Syndrome: Early Clues, Effective Management

The metabolic syndrome represents a clustering of conditions and/or risk factors that lead to an increased incidence of type 2 diabetes mellitus and cardiovascular disease. These conditions include abdominal obesity, dyslipidemia, hypertension, insulin resistance, and a proinflammatory state. Each component is independently associated with an increased risk of cardiovascular disease and diabetes; the combined effect is much greater. Early diagnosis and aggressive treatment with lifestyle modification and/or pharmacotherapy are associated with reduced morbidity and mortality.

In this article, I review the diagnostic criteria for the metabolic syndrome and discuss management strategies that can reduce the risk of diabetes and cardiovascular disease.

DEFINITIONS

The most widely used diagnostic criteria for the metabolic syndrome are those of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III.¹ Any 3 of the following criteria establish the diagnosis:

• Abdominal obesity (waist circumference more than 40 in in men and more than 35 in in women).

• A fasting triglyceride level of 150 mg/dL or higher.

• A fasting high-density lipoprotein cholesterol (HDL-C) level lower than 40 mg/dL in men and 50 mg/dL in women.

• Blood pressure (BP) of 130/85 mm Hg or higher.

• A fasting serum glucose level of 110 mg/dL or higher.

A proinflammatory, prothrombotic state; oxidant stress; and endothelial dysfunction may also be present.

The World Health Organization (WHO) has also developed criteria for the metabolic syndrome.² WHO criteria differ from those of ATP III in that they require the presence of insulin resistance and proteinuria and use different BP cutoff points and HDL-C levels. The diagnosis is established in the presence of hyperinsulinemia or a fasting plasma glucose level higher than 110 mg/dL, plus at least 2 of the following:

• Abdominal obesity (waist-hip ratio greater than 0.90 in men and 0.85 in women or body mass index [BMI] higher than 30).

• Dyslipidemia (triglyceride level of 150 mg/dL or higher, or HDL-C level lower than 35 mg/dL in men and 39 mg/dL in women).

• Hypertension (BP of 140/90 mm Hg or higher, or the use of antihypertensive medication).

• Urinary albumin excretion rate of 20 µg/min or higher, or albumin- creatinine ratio of 30 mg/g or higher.

Recently, the American College of Endocrinology also established a set of criteria³:

• BMI of 25 or higher.

• Fasting glucose level of 110 to 126 mg/dL.

• Two-hour postglucose challenge higher than 140 mg/dL.

• Triglyceride level of 150 mg/dL or higher.

• HDL-C lower than 40 mg/dL in men and 50 mg/dL in women.

• BP of 130/85 mm Hg or higher.

EPIDEMIOLOGY

The metabolic syndrome is quickly becoming an epidemic. This condition has been diagnosed in about 45 million adults⁴ and 1 million adolescents.⁵ Minority groups and women are disproportionately affected. The prevalence among African American women is more than 50% higher than it is among African American men; the prevalence among Mexican American women is 25% higher than it is among Mexican American men. Mexican Americans have the highest age-adjusted prevalence--nearly 32%.

The incidence of the metabolic syndrome has increased significantly during the past 2 decades, largely because of increased obesity. This trend is expected to continue. Recent estimates show that about 34% of the adult population is overweight (BMI between 25 and 29.9) and 27% is obese (BMI higher than 30).⁶

PATHOPHYSIOLOGY

The cause of the metabolic syndrome is unknown. Abdominal obesity is a strong risk factor for insulin resistance, type 2 diabetes, and a number of abnormalities associated with the metabolic syndrome. These include hypertension, hyperinsulinemia, endothelial dysfunction, elevated levels of C-reactive protein and other inflammatory markers, increased blood viscosity and fibrinogen levels, and premature atherosclerosis. Visceral, or abdominal, fat differs from peripheral fat in that it is more resistant to the action of insulin and more sensitive to lipolytic hormones, which increase the release of free fatty acids. These fatty acids provide additional substrates for the synthesis of triglycerides by the liver, which results in a dyslipidemia profile characterized by elevated triglyceride and low HDL-C levels and small, dense atherogenic low-density lipoprotein (LDL) particles. A high-calorie, low-nutrientdiet and inadequate physical activity are associated with several of the criteria that contribute to the metabolic syndrome.

DIAGNOSIS

There are usually no specific symptoms; the metabolic syndrome tends to develop insidiously, and it is relatively uncommon in the absence of obesity and physical inactivity.

An evaluation of patients for the metabolic syndrome includes:

• Measurement of vital signs (including sitting and standing BP).

• Measurement of height, weight, and waist circumference.

• Calculation of BMI.

Laboratory studies include basic serum chemistry, complete blood cell count, fasting blood glucose level, and a lipid profile.

TREATMENT

The goal of treatment is to prevent or slow the progression of diabetes, hypertension, and cardiovascular disease. Weight loss improves all facets of the metabolic syndrome; a loss of 5% to 10% of body weight can lead to significant reductions in morbidity and mortality.⁷ First-line therapy consists of dietary modification and exercise (Table).

Nonpharmacologic*

Nutrition. Despite widespread skepticism in the medical community, dietary counseling is an effective intervention. Medium- to high-intensity counseling interventions (for example, six 30-minute sessions with a clinician, nutritionist, dietitian, or nurse in an individual or group setting) can produce significant changes in average daily intake of key nutrients among adult patients at increased risk for diet-related chronic disease.⁸ Such counseling is likely to improve important health outcomes, and the benefits outweigh potential harms. Assessing patients' dietary patterns and recommending change is critical for success.

One of the most important recommendations for overweight patients is calorie reduction. Between 1971 and 2000, daily caloric intake rose, on average, by more than 7% for men and 20% for women, and a significant proportion of the extra calories was from refined carbohydrates.⁹ Americans were about 25 lb heavier in 2002 than in 1960, principally as a result of increased daily calorie consumption.

Advise patients with a BMI between 27 and 35 to reduce daily intake by 300 to 500 calories and those with a BMI higher than 35 to reduce daily intake by 500 to 1000 calories. These reductions will produce the recommended weight loss of 1 to 2 lb per week in most patients.

Portion control is another key to weight loss. A recent study demonstrated that portion control was associated with greater weight loss during a 24-month period than reduced dietary fat consumption, increased fruit and vegetable consumption, or increased physical activity.¹⁰ Thirty-eight percent of obese patients who consistently practiced portion control lost 5% or more of their baseline weight, whereas 33% of patients who did not consistently practice portion control gained 5% or more of their baseline weight.

Encourage patients to focus less on dieting or on consumption or avoidance of any one food and more on lifestyle changes. The key to healthful eating is moderation. Recommendations for overweight patients, particularly those with the metabolic syndrome, are listed in Box I. These are based on the recent revision of the Dietary Guidelines for Americans.¹¹

I - Dietary Recommendations for Overweight Patients

• Eat at least 5 servings of vegetables and 4 servings of fruit daily.

• Eat few simple carbohydrates, such as sugar, white flour, and white rice.

• Focus on complex carbohydrates, such as unrefined whole-wheat bread, brown rice, and beans.

• Consume 3 or more ounce-equivalents of whole-grain products per day; the rest of the recommended grain consumption should come from enriched or whole-grain products. In general, at least half the grains consumed should be whole grains.

• Consume 21 to 38 g of fiber per day.

• Include 3 daily servings of low-fat or fat-free dairy products.

• Decrease consumption of saturated fats and trans fats by eating more fish (at least twice a week) and less red meat.

• Reduce soft drink consumption.

Physical activity. Physical activity is essential in the treatment of the metabolic syndrome. Exercise contributes to weight loss, reduced BP, improved lipid profiles, and reduced insulin resistance. The Surgeon General recommends 30 minutes of physical activity on most days of the week. Specific recommendations for exercise are provided in Box II.

II - Exercise Recommendations for Patients

Advise patients to strive for an exercise heart rate that is consistently between 50% and 80% of the maximum. (Maximum heart rate can be calculated by subtracting a person's age from 220.) Exercise should not be too intense. If a patient cannot talk or breathe easily while exercising, the intensity should be decreased. The key is to encourage patients to think about being active as opposed to "exercising," and to help them find activities they enjoy. Exercise should not be viewed as a burden or a chore.

The following general advice can be given to patients:

• Plan to exercise/be active at least 3 days and up to 5 days per week. Slowly add days as you become more comfortable.

• Start with 10 to 15 minutes of activity and build up to 30 minutes daily over a few months. Make exercise part of your schedule.

Emphasize to patients that physical activity, even without weight loss, can reduce the risk of heart disease and type 2 diabetes. Recent research indicates that patients can be overweight but still fit if they exercise regularly. In one study, 15,466 healthy men and 3757 men with the metabolic syndrome were studied for 10 years to determine the relationship between cardiorespiratory fitness and mortality.¹² Compared with the healthy participants, men with the metabolic syndrome were twice as likely to die of cardiovascular disease and 1.3 times as likely to die of other causes. However, if they were fit, their risks were similar to those of healthy men.

INTERVENTIONS FOR SPECIFIC CONDITIONS

Obesity. Lifestyle intervention is the primary treatment for obesity. The National Heart, Lung, and Blood Institute (NHLBI) has created evidence-based guidelines to help clinicians identify and treat obesity.⁷ The group recommends a weight management program that includes a reduced-calorie diet and increased physical activity.

Pharmacotherapy. According to the NHLBI guidelines, drug therapy may be considered as an adjunct to diet and physical activity in patients with a BMI of 30 or higher but without concomitant obesity-related risk factors or diseases (such as hypertension, diabetes, or dyslipidemia) and those with a BMI of 27 or higher who have these risk factors or diseases.

Orlistat and sibutramine have been approved by the FDA for weight loss. They are associated with modest weight loss (typically 4.4 to 22 lb) that can be sustained for 2 years if the medication is continued. Orlistat is a gastric and pancreatic lipase inhibitor that reduces absorption of dietary fat by 30%. It acts by reversibly inhibiting pancreatic, gastric, and carboxylester lipases and phospholipase A₂. The adverse effects of orlistat include fecal urgency, oily spotting, and flatulence.

Sibutramine is a norepinephrine, dopamine, and serotonin reuptake inhibitor that functions as an appetite suppressant. The adverse effects of sibutramine include elevations in BP and heart rate, headache, dry mouth, and insomnia. The dose-related increases in BP and heart rate need to be monitored closely.

Because discontinuation of drug therapy often leads to rapid weight regain, pharmacologic agents should be used only as part of a program that includes lifestyle modification interventions, such as intensive diet and exercise counseling and behavioral therapy. Evidence has shown that if a patient does not lose 4.4 lb within the first 4 weeks after initiating therapy, the likelihood of long-term response is very low.

The Agency for Healthcare Research and Quality (AHRQ) recently published an evidence-based report on the pharmacologic treatment of obesity.¹³ Weight loss was typically less than 11 lb at 1 year. No one drug resulted in more weight loss than any other. Thus, the choice of drug is based on tolerance to the expected adverse effects.

Surgery. Surgical intervention may be an option for patients who cannot lose weight with diet, physical activity, and drug therapy. Typically, such patients have a BMI of 40 or higher (or 35 or higher with comorbid conditions). About 6% of the population has a BMI in this range.

The AHRQ report concluded that surgery might be effective for extremely obese patients who have tried and failed to lose weight with exercise and diet and that surgery might be more effective than drugs for persons with a BMI of 35 to 40.¹⁴ About 20% of patients who undergo weight-loss surgery experience complications. These include nutritional deficiencies, staple line breakdown, and deep vein thrombosis. Insufficient evidence exists to assess the safety and efficacy of bariatric surgery in patients older than 65 years.

Insulin resistance. Insulin resistance is associated with a significantly increased risk of type 2 diabetes. Many patients with impaired fasting glucose levels have normal or near-normal levels of glycosylated hemoglobin A_1C.

Lifestyle intervention is first-line therapy for insulin resistance. In a study conducted by the Diabetes Prevention Program, 3234 obese patients with elevated fasting and postload plasma glucose concentrations were randomly assigned to placebo, metformin, or intensive lifestyle changes.¹⁵ Intensive lifestyle therapy (7% weight loss and at least 150 minutes of exercise per week) reduced progression to type 2 diabetes by 58% over an average of 2.8 years. Metformin therapy was less effective (31% relative reduction).

Drug therapy for insulin resistance is not approved for patients without diabetes. The American Diabetes Association (ADA) does not recommend pharmacologic treatment to prevent type 2 diabetes.

Dyslipidemia. An update of the NCEP guidelines for the management of dyslipidemia has recently been published.¹⁶ For all patients with hypercholesterolemia, the target LDL-cholesterol (LDL-C) level is below 100 mg/dL. For persons with the metabolic syndrome and atherogenic dyslipidemia, ATP III recommends the following:

•In high-risk patients (that is, persons with coronary heart disease [CHD] or CHD risk equivalents), an LDL-C goal of less than 70 mg/dL is a therapeutic option. Treatment begins with lifestyle changes. (In high-risk patients, if the LDL-C level is at least 100 mg/dL, an LDL-C-lowering medication is initiated simultaneously with lifestyle changes.) Several studies have demonstrated the effectiveness of lifestyle changes in managing dyslipidemia. For patients who do not reach the goal with diet and exercise, treatment with a cholesterol-lowering agent, usually a statin, is recommended.

•Once the LDL-C goal is reached, non-HDL-C becomes the focus. For patients with triglyceride levels of 200 mg/dL or higher, calculate the non-HDL-C level (total cholesterol minus HDL-C). The non-HDL-C goal equals the LDL-C goal plus 30 mg/dL. If the non-HDL-C level remains elevated, ATP III recommends either increasing the dose of the statin or adding another cholesterol-lowering agent. (Note that the combination of a statin and a fibrate increases the risk of myopathy; however, fenofibrate may be safer than gemfibrozil.¹⁷)

Niacin effectively raises HDL-C and lowers triglyceride levels; however, it has been associated with insulin resistance, particularly in patients with diabetes. The HDL Atherosclerosis Intervention Trial in- vestigated the effects of combination therapy with simvastatin and niacin in diabetic and nondiabetic patients with coronary artery disease and low HDL-C levels.¹⁸ Combination therapy resulted in fewer cardiac events than placebo; in addition, glycemic control was less tight in the simvastatin-niacin group only during the initial few months. After 8 months, the glucose levels had returned to pretreatment levels, and they remained stable for the rest of the study. The ADA guidelines support the judicious use of low-dose niacin (less than 2 g/d) for raising HDL-C.¹⁹ The guidelines also recommend aspirin therapy to modify the prothrombotic state in patients at intermediate and high risk of CHD.

Hypertension. Hypertension remains a significant cause of morbidity and mortality. Fifty million Americans have hypertension, but only 59% of them are being treated. BP reductions do not have to be dramatic to produce benefit. In a study of normotensive patients, each 2-mm Hg reduction in systolic BP reduced the risk of ischemic heart disease mortality by 7% and the risk of a fatal stroke by 10%.²⁰

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP (JNC 7) introduced the category of "prehypertension" to emphasize that persons with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg require health-promoting lifestyle modifications to prevent cardiovascular disease.²¹

JNC 7 recommends antihypertensive therapy for patients with BP above 140/90 mm Hg and in diabetic patients with BP above 130/80 mm Hg. The report suggests that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be particularly useful in patients with diabetes. Although the guidelines recommend a thiazide-type diuretic as initial therapy for most patients with stage 1 hypertension, this class of drugs may not be the best choice for patients with the metabolic syndrome because thiazide diuretics have been associated with the development of type 2 diabetes.²²

CLINICAL HIGHLIGHTS

• Diet and exercise will prevent or slow the progression of diabetes and cardiovascular disease. Weight loss of 5% to 10% can lead to significant reductions in morbidity and mortality.

• Calorie reduction and portion control are key elements of weight-loss programs. Patients with a body mass index (BMI) between 27 and 35 should reduce daily intake by 300 to 500 calories. Those with a BMI higher than 35 should reduce their intake by 500 to 1000 calories. These reductions should help achieve weight loss of 1 to 2 lb per week.

• Persons with the metabolic syndrome should exercise about 30 minutes a day on most days of the week. Encourage patients to find activities they enjoy so that exercise will not be viewed as a burden. Physical activity, even without weight loss, can reduce the risk of heart disease and diabetes.

• Pharmacotherapy may be considered as an adjunct to diet and physical activity in overweight or obese patients. Because discontinuation of drug therapy often leads to rapid weight regain, pharmacotherapy should be used as part of a program that includes lifestyle modification.

• Antihypertensive therapy is warranted for diabetic patients with blood pressure above 130/80 mm Hg. Angiotensin-converting enzyme inhibitors may be particularly useful in these patients.

References:

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