Diabetes Management in Primary Care

Authors: Unger, Jeff

Title: Diabetes Management in the Primary Care Setting, 1st Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > 2 - Diagnosing and Managing the Metabolic Syndrome in Adults, Children, and Adolescents

2

Diagnosing and Managing the Metabolic Syndrome in Adults, Children, and Adolescents

Take Home Points

• The term metabolic syndrome refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathophysiology is believed to be related to insulin resistance

• Although metabolic syndrome (MS) is widely recognized as an important disease state, the exact defining criteria that qualify a patient as having MS remain open to considerable debate and controversy

• Obesity appears to be the cornerstone of MS pathophysiology

• The treatment of MS relies heavily on behavioral and lifestyle interventions. Weight reduction, increased physical activity, and adoption of an antiatherogenic and antidiabetogenic diet should be strongly encouraged

• Drug therapies are appropriate first line only for accepted risk reduction interventions such as treating hypertension, hyperlipidemia, and hyperglycemia. The prothrombotic state of MS should be treated with low-dose aspirin. Novel drug therapies for treating obesity, hyperlipidemia, and insulin resistance will soon be available in the United States

• Primary care physicians (PCPs) should carefully evaluate patients for MS criteria. Those patients who qualify as having the syndrome should be aggressively managed to reduce their likelihood of developing CVD, stroke, and diabetes

• Four percent to 7% of children and adolescents have MS and are at risk for developing premature cardiovascular-related complications as well as diabetes. Early recognition of the disease criteria and aggressive behavioral interventions on behalf of the physician and their parents is critical.

P.44

Case 1

Robert, age 45, was sent in by his wife for his annual physical exam. Appearing somewhat rushed for time, and certainly anxious, Robert explains that he has no physical complaints. The concerns that his wife wanted addressed included making certain that his prostate was examined and that someone scheduled him for a colonoscopy because his father was diagnosed with a polyp at age 76. While attempting to obtain additional history, Robert's cell phone rang three times. Sorry, Doc, said Robert, the market has reached an all time high and my clients are wanting to get in on the ride. How much longer do you think I'll be here today?

Between phone calls the following additional history was obtained by the physician:

• Robert has gained 10 pounds over the past year.

• The patient does no exercise, but is always on the run.

• He smokes 1 pack of cigarettes per day.

• Mom had borderline diabetes before dying of a stroke at age 60.

• His 43-year-old brother had an acute myocardial infarction (MI) at age 41 and underwent coronary artery bypass grafting at age 42.

• Robert's last visit to a doctor for any reason was 8 years ago for a hernia repair.

The doctor notes the following abnormalities on the nurse's notes for this visit:

• Body mass index (BMI): 40 kg per m²

• Blood pressure: 150/102 mm Hg

• Random blood glucose: 189 mg per dL

• Urine: 2+ protein

Once the doctor was successful in using his secret patient cell phone jamming device and encouraging his patient to listen to words of wisdom from someone other than an investment banker, the physician was able to confront his very busy patient. Robert, I do believe you have some significant metabolic abnormalities which may increase your risk for developing heart disease. You may also have prediabetes. I suggest we perform a comprehensive metabolic risk assessment and determine how we might work together to incorporate behavioral and pharmacologic interventions into your busy lifestyle. In so doing, we may be able to prevent or delay cardiovascular disease and the onset of diabetes. I am very happy that you came to see me today, Robert. I know how busy you are, but your health is important for you and your family. Preventing a heart attack or a stroke is much easier than reversing the damage caused by an acute event!

Robert replied: Thanks, Doctor, you've got my attention. Frankly, I haven't been feeling really good about myself lately. This is a great time to get myself in shape for the rest of my life!

The term metabolic syndrome (MS) refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathophysiology is believed to be related to insulin resistance.¹ Patients with MS are also at

P.45

Practitioners should be on alert for patients who possess the diagnostic criteria for MS. PCPs are on the front lines of medical practice, and as such are often consulted by patients for many medical issues unrelated to CVD or diabetes. A patient who presents for a routine physical exam or back pain, may have physical and metabolic characteristics that could suggest a higher risk of developing CVD. Early recognition of these metabolic abnormalities in high-risk patients should encourage the physician to suggest lifestyle modification and pharmacologic intervention when indicated to reduce premature morbidity and mortality.² Our efforts at encouraging exercise and making healthy food choices while reducing dependency on nicotine and alcohol will be appreciated by the vast majority of our patients and their families.

Patients with MS are twice as likely to die of a heart attack or stroke and three to five times more likely to develop diabetes than individuals who do not meet the MS diagnostic criteria.³ Furthermore, there may be gradations within MS, with the higher CVD risk occurring among persons who have a greater number of components.⁴ MS is associated with aortic calcification, with the combination of low high-density lipoprotein (HDL) and high triglyceride doubling the likelihood of increased aortic calcification.⁵ In addition to the increased risk of developing diabetes and CVD, individuals with MS are susceptible to polycystic ovary syndrome, fatty infiltration of the liver, gallstones, asthma, sleep apnea, and some forms of cancer.⁶

History of the Metabolic Syndrome

The link between obesity and chronic disease states such as diabetes, hyperlipidemia, and hypertension was first suggested in 1947 by Professor Jean Vague from the University of Marseille.⁷ Vague used the term android obesity to define the pattern of fat distribution characterized by an accumulation of adipose tissue over the trunk and referred to gynoid obesity as the fat pattern present in the hips and thighs. Vague also noted that gynoid obesity was not associated with CVD. In 1965, Albrink and Meigs⁸ reported an association between android obesity and hypertriglyceridemia. Avagaro et al.⁹ documented the simultaneous presence of obesity, hyperinsulinemia, hypertriglyceridemia, and hypertension. In 1985, Ohlson et al.¹⁰ suggested documenting increasing waist-to-hip ratios as a means to predict CVD in patients with diabetes. In 1987, Ferrannini et al.¹¹ reported the relationship between hyperinsulinemia and hypertension.

The concept of a constellation of abnormalities linked by their physiologic relationship to insulin resistance was pioneered in 1988 by Gerald Reaven.¹² Reaven postulated that insulin resistance and its compensatory hyperinsulinemia predisposed patients to hypertension, hyperlipidemia, and diabetes and thus was the underlying pathophysiology related to CVD. Although

P.46

At the same American Diabetes Association (ADA) meeting in 1988, DeFronzo¹⁴ noted the importance of skeletal muscle, liver, and beta-cell abnormalities as a cause for type 2 diabetes mellitus (T2DM). He noted that the insulin resistance occurred at several sites, including the skeletal muscle, adipocyte, and liver. Progressive insulin resistance would progress, in time, to diabetes in many patients based on the ability to produce enough endogenous insulin through the pancreatic beta cells to normalize fasting and postprandial glucose levels. Once beta cells were unable to produce enough insulin to maintain euglycemia, patients would convert from a prediabetic state to diabetes. In theory, beta-cell preservation could preserve insulin resistance and delay the onset of diabetes. In 2003, DeFronzo included the role of adipose tissue insulin resistance and related alterations in free fatty acid (FFA) metabolism in his disease state model¹⁵ (Fig. 2-1).

The development of imaging techniques [computed tomography (CT) scanning] allowed investigators to distinguish between visceral (intra-abdominal)

P.47

Metabolic Syndrome Diagnostic Criteria

In 2001 the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) identified six key components of MS that are most closely related to CVD: abdominal obesity, atherogenic dyslipidemia, hypertension, glucose intolerance, and insulin resistance. Patients with MS also were characterized as likely to have a proinflammatory and prothrombotic state.¹⁸ Other groups such as the International Diabetes Federation (IDF), the World Health Organization (WHO), and the American Association of Clinical Endocrinologists (AACE) have established their own criteria for diagnosing MS, believing that insulin resistance, rather than abdominal obesity, promotes atherosclerosis (Table 2-1).

Prevalence of Metabolic Syndrome in the United States

MS is becoming increasingly common. The National Health and Nutrition Examination Survey (NHANES)¹⁹ is a population-based survey designed to collect information of the health and nutrition of the U.S. household population. Using the guidelines developed by the 2001 NCEP-ATP III (Table 2-1), the NHANES III database determined the age-adjusted prevalence of MS among adults in the United States to be 27%,²⁰ an increase of 5% when compared with the prevalence data collected from 1988 to 1994.²¹ Prevalence rates were similar among men and women and increased with age. Among specific population groups, Mexican Americans had the highest prevalence (32%). Adolescents also have a high prevalence of MS features. Based on population-weighted estimates, more than 2.1 million (or 6.7% of the adolescent population) have MS.²² Current census data estimate that approximately 47 million Americans have the MS phenotype.²

Controversies Surrounding the Diagnostic Criteria and Definition of the Metabolic Syndrome

Although the WHO and ATP III definition generally identify the same individuals, important differences do exist. Approximately 15% of patients in the NHANES database meet the criteria for one but not both definitions.²³ Defining MS within

P.48

P.49

P.50

Some of the criteria used for defining MS are considered by some clinicians to be ambiguous or incomplete. For example, the blood pressure cut-off for hypertension as a risk factor for MS is a systolic pressure of 130 mm Hg or higher and a diastolic pressure of 85 mm Hg or higher. One could question whether or not a patient qualifies for having MS if the diastolic pressure is 90 mm Hg but the systolic pressure is 120 mm Hg. In addition, if one is successful in lowering a patient's blood pressure to 120/75 mm Hg, does that patient still qualify as having one of the MS components? The guidelines also provide no information as to how the blood pressure should be measured supine, standing, repeated after 5 minutes, when the patient first arrives in the office, using home blood pressure monitoring or even how many readings must be taken before the diagnostic criteria are achieved.

Some of the criteria (e.g., waist circumference, HDL) have sex-specific cutpoints, implying that the relationship between the risk factor level and outcomes differs between the sexes. However, few epidemiologic data have been published that establish the sex-specific cut off points as being relative to CVD risk.¹³ Still to be determined is whether the same quantity of intra-abdominal fat mass carries a different cardiovascular risk for men than for women.

By definition, a syndrome consists of individual components linked by a common pathophysiology that can predict future adverse events. In addition, the risk of adverse events associated with that syndrome should be greater than the sum of the individual components. Some clinicians believe that the current accepted definitions of MS fail to address some important risk factors associated with insulin resistance such as physical inactivity, family history, age, and proinflammatory and prothrombotic markers. Other emerging risk factors are clearly identified as increasing cardiovascular risk, yet have not been added officially to the list of diagnostic criteria for MS. For example, patients with levels of C-reactive protein (CRP) higher than 3.0 mg per dL are twice as likely to develop CVD when compared with patients having either MS or elevated CRP but not both concurrently.^25,26 Other markers of vascular inflammation appear to be associated with insulin resistance, yet are not included in the syndrome. Adiposity is associated with elevated levels of inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor- (TNF- ). These markers are significantly elevated in obese, insulin-resistant patients when compared with obese insulin-sensitive individuals.²⁷ Although the adipose tissue inflammatory markers are strongly associated with dyslipidemia, hypertension, and insulin resistance, and as such are predictive of CVD, they have been excluded from the MS diagnostic criteria.

Adiponectin, a cytoprotective hormone produced by adipocytes, is inversely associated with CVD risk factors such as hypertension, low-density lipoprotein cholesterol (LDL-C), and triglycerides.²⁸ Adiponectin has been shown to be a potent inverse independent risk factor for CVD and diabetes.²⁹

P.51

Whether or not PCPs believe that MS is a specific disease state whose somewhat arbitrary diagnostic components are believed to impart a greater cardiovascular risk than isolated hypertension, hyperlipidemia, or obesity, MS should be viewed from a patient's perspective. Any patient who is obese, is hypertensive, and has hyperlipidemia should be offered an opportunity to use lifestyle changes that should reduce the future likelihood of developing a heart attack or stroke. No one could argue the benefits of incorporating healthy lifestyle changes into one's daily routine. Reducing one's daily caloric intake while increasing one's level of daily activity can improve one's quality of life, reduce depression, and enhance longevity. The point of making the observation that a patient has MS is to begin to aggressively manage potential life-threatening diseases, including stroke, heart attacks, and diabetes, which could result in significant morbidity and mortality. Most patients appreciate the opportunity to use a more healthy lifestyle and look to their family physician as their coach to help them accomplish this goal.

Metabolic Syndrome Pathophysiology

The pathogenesis of MS is shown in Figure 2-2. The thrifty gene hypothesis³¹ suggests that the likelihood of an individual's surviving times of famine would be increased if he or she could maximize energy storage (as fat) during times of surplus food availability. The stored fat could be used as an energy source during periods of starvation. Adipocytes accumulate and store FFAs. Unlike triglycerides and phospholipids, FFAs are not protein bound and accumulate as a result of the breakdown of triglycerides into fatty acids and glycerol. FFAs are an essential source of fuel for the heart and skeletal muscle cells because they can yield large quantities of adenosine triphosphate (ATP). The brain relies on the insulin-independent uptake of glucose as its obligate energy source, using ketone bodies produced by the liver from fatty acid metabolism during periods of starvation or low carbohydrate consumption.

Elevated levels of FFAs can cause insulin resistance and deficient insulin secretion.³² Therapies that improve glycemic control will also lower levels of circulating FFAs (see Chapter 4).

The body consists of two primary types of adipose tissue. Subcutaneous fat comprises up to 80% of the body's total adipocytes, whereas VAT stores 10% of the total fat. The rest of the adipocytes lie within the perirenal and peritoneal fat tissue.³³ During the fasting state, the body uses FFAs as a source of fuel. However, an elevation in circulating levels of FFAs for 2 to 4 hours will result in insulin resistance.³⁴ In certain conditions, the FFA-induced insulin resistance has the beneficial effect of preserving carbohydrate for use by vital

P.52

Elevated levels of FFAs and other fat metabolites, including diacylglycerol (DAG), induce insulin resistance by impairing insulin signaling and subsequent glucose transport that occurs in skeletal muscle cells^35,36 (Fig. 2-3). DAG, a by-product of triglyceride metabolism, is a potent activator of protein kinase C (PKC).³⁷ When the PKC enzyme system is activated, insulin signaling

P.53

A change in intracellular DAG levels is also accompanied by activation of the nuclear factor (NF) pathway, which appears to play a role in the pathogenesis of CVD.

FFAs produce insulin resistance in the liver by blocking the ability of insulin to suppress glycogenolysis.³⁸ This results in an increase in hepatic glucose production while the patient is already in the hyperglycemic state. Hyperinsulinemia promotes the hepatic uptake of FFAs and the production of intracellular triglycerides, resulting in fatty liver disease.

Visceral fat also influences insulin resistance by modulating the synthesis, storage, and release of inflammatory mediators, including TNF, IL-6, and peptides such as leptin, resistin, and adiponectin.³⁹

Genetic variation may play a significant role in mediating the metabolic abnormalities associated with obesity. In the United States, the prevalence of MS increases in direct proportion to one's body mass index (BMI). Other population groups, such as Asians and Pacific Islanders, exhibit significant insulin resistance despite having near-normal BMIs. Asian and Pacific Island patients with normal BMIs and MS produce higher levels of FFAs and CRP and lower levels of adiponectin as if they were obese. This discrepancy in

P.54

Not all obese individuals are insulin resistant, and many obese, insulin-resistant people will never progress to develop diabetes. In some obese people with normal pancreatic beta-cell function, FFAs are potent insulin secretagogues able to compensate for their self-induced insulin resistance.⁴¹ First-degree relatives of individuals with T2DM who are genetically predisposed to develop diabetes as well as patients with IGT demonstrate a reduction in FFA-stimulated insulin secretion.^42,43 As long as pancreatic beta cells can produce enough endogenous insulin to maintain euglycemia, diabetes will not develop.

The atherogenic dyslipidemia associated with abdominal obesity is manifested by elevated triglycerides and low concentrations of high-density lipoprotein cholesterol (HDL-C). More detailed lipid analysis often reveals increased remnant lipoproteins, elevated apolipoprotein B, small dense low-density lipoprotein (LDL) particles, and small HDL particles. Each of these lipid abnormalities is independently atherogenic. The non-HDL-C value has been shown to correlate with cardiovascular risk.⁴⁴ The non-HDL-C value is computed by subtracting the HDL-C value from the total cholesterol. For example, a patient with a total cholesterol of 234 mg per dL and an HDL-C of 34 mg per dL has a non-HDL-C value of 200 mg per dL. Patients who have a triglyceride level higher than 200 mg per dL plus a non-HDL-C of higher than 130 mg per dL are at high risk for heart disease⁴⁵ and require aggressive pharmacologic management to improve their lipid profiles.

Drugs that can target alterations in FFA metabolism might be useful in not only slowing one's progression toward diabetes and limiting insulin resistance but also reducing cardiovascular risk. Nicotinic acid and nicotinic acid analogs pharmacologically reduce plasma FFA levels. Their usefulness is limited because the initial lowering of plasma FFA levels by nicotinic acid is invariably followed by a sharp FFA rebound⁴⁶ that increases short-term insulin resistance. The most clinically useful targets for pharmacologic intervention involve the peroxisome proliferator-activated receptors (PPARs). PPAR activation can have a positive effect on fatty acid oxidation, lipid metabolism, glucose metabolism, wound healing, carbohydrate metabolism, and endothelial cell inflammation.^47,48,49

Inflammatory Cytokines

Obesity contributes to the proinflammatory and prothrombotic states of MS by increasing levels of CRP. CRP is a pivotal acute-phase reactant, which is a strong, independent predictor of both diabetes⁵⁰ and CVD.⁵¹ CRP levels are elevated in acute coronary syndrome and correlate with several other components of MS, including insulin resistance, microalbuminuria, and impaired fibrinolysis.^52,53,54,55 All of the primary diagnostic criteria associated with the ATP III guidelines for MS are associated with elevated levels of CRP. The standard CRP test is inadequate for detecting the low grade levels of inflammation measured with the preferred hs-CRP (high sensitivity or cardiac CRP ) test.

P.55

The NHANES III showed that participants with MS had higher CRP levels when compared with those with no metabolic abnormalities. Furthermore, the higher the number of abnormalities of MS involved, the higher the CRP value.^53,56 CRP can destabilize and rupture atherosclerotic plaque and disable normal vascular endothelial cell protective mechanisms.⁵⁷

Patients with CRP levels greater than 3 mg per L have a higher risk of CVD. Women who have three to five characteristics of MS and CRP levels greater than 3 mg per L have additive risk for CVD and increased mortality rates.²⁵

Adiponectin

Activation of the adipocyte nuclear receptor PPAR- results in the synthesis and secretion of adiponectin.⁵⁸ Once released, adiponectin acts to improve insulin sensitivity within the hepatocytes, to increase fatty-acid transport, and to normalize levels of plasma lipids.⁵⁹ Although the exact mechanism leading to decreased levels of adiponectin is uncertain, both insulin and TNF are inhibitors of adiponectin. Therefore, the hyperinsulinemia associated with obesity-induced insulin resistance in conjunction with an enhanced expression of TNF may modify and reduce the secretion of adiponectin. Table 2-2 lists

P.56

Insulin Resistance

Not everyone who is obese has evidence of insulin resistance. Associated with the rise in endogenous insulin secretion observed in patients with IGT and prediabetes is an elevation in plasma triglycerides and hypertension. The elevated triglycerides are responsible for the development of fatty liver infiltration [nonalcoholic steatohepatitis (NASH)] and atherogenic dyslipidemia. Rapid weight reduction has been shown to lower levels of triglycerides, visceral adiposity, and insulin resistance. Declines in visceral adiposity and reduced FFA levels following weight-loss diets have been associated with improved insulin sensitivity.⁶⁰

Primary Care Management of the Metabolic Syndrome

The cornerstone for managing MS must focus on weight reduction. Dietary modifications recommended in ATP III guidelines include reductions in saturated fat, reductions in dietary cholesterol, and weight loss. Table 2-3 lists dietary recommendations that can reduce LDL-C from 5% to 8%. The metabolic changes associated with moderate weight reduction include the following⁶¹:

• Improvement in insulin resistance

• Improvement in fasting blood glucose levels

• XReduction in LDL-C

• Reduction in CRP

• Reduction in triglycerides

• Reduction in VAT

  Table 2-3 Dietary Modifications Required for Managing Metabolic Syndrome

  Reduce saturated fat to less than 7% of calories Dietary cholesterol to less than 200 mg/d Weight loss of 10 lb From Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Baltimore, MD: US Department of Health and Human Services. National Institutes of Health. National Heart, Lung and Blood Institute; September 2002. (NIH publication 02 5215); Comuzzie AG, Funahashi T, Sonnenberg G, et al. The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome. J Clin Endocrinol Metab. 2001;86:4321 4324.

P.57

• Reduction in blood pressure

• Slowed progression toward the development of T2DM

• Elevation in HDL-C

• Elevation in adiponectin

Moderate weight reduction has a significant effect on metabolic parameters. Each 3-kg weight reduction improves HDL-C by 1 mg per dL.⁶² Modest reduction in body weight also reduces levels of CRP. Fourteen nondiabetic obese women placed on a very low calorie diet for 21 days⁶³ reduced their BMI by a mean of 2.1 kg per m² and their CRP concentrations by 17%.

The nutritional recommendations for each patient's weight management program should be personalized and consistent with the patient's current eating habits and lifestyle, as well as ethnicity and culture. Weight reduction of to 1 lb per week can be safely achieved by reducing daily caloric intake by only 150 calories per day.⁶⁴

Providing Nutritional Counseling to Your Patients with Metabolic Syndrome

Although some patients are willing and able to count calories, most should be instructed to control food portions. The intake of starchy foods (breads, pasta, potatoes, rice, and cereals) as well as fat and meat should be reduced by 25%. Fullness and satiety can be maintained if fruits and vegetables are used to replace high-calorie foods.

Patients can be advised to visualize their meal as a plate divided into four quadrants. A meal promoting gradual weight reduction would have 25% of the plate filled with lean protein (lean meat, chicken, fish, or vegetarian proteins), 25% filled with starch, and the remaining half filled with nonstarchy vegetables or fruits. Large restaurant portions, sweetened drinks, and fried foods should be avoided.

The carbohydrate content of the diet is important to determine because of its influence on blood glucose and triglyceride levels. Diets containing more than 60% of calories as carbohydrates (sugars and starches) are likely to increase triglyceride levels, speed gastric emptying, and increase insulin resistance. Rapid gastric emptying can cause postabsorptive hyperglycemia. Popularized carbohydrate-restricted plans such as the Atkins Diet and South Beach Diet lack nutritional variety and should not be continued indefinitely. The NCEP-ATP III expert panel⁶⁴ recommends that fat intake be in the range of 25% to 35% of calories to maintain a total carbohydrate intake of 45% to 55%.

Sugary drinks and alcohol are a source of wasted calories. One 12-oz can of regular soda contains 10 teaspoons of sugar and 150 calories. Unsweetened fruit juice contains up to 175 calories per 8 oz, making it a poor substitute for regular soda. Caloric content of a 12-oz beer can range from 130 to 190 calories. A person who drinks six beers in a single day will consume nearly half of his or her daily caloric requirement in the form of alcohol. If the same person snacks while drinking, one could easily imagine the excessive number

P.58

Dividing food consumption into at least three meals per day is recommended to avoid extremes of hunger and higher postprandial glucose levels. A patient with MS whose prescribed daily caloric intake is 1,800 calories would have a total carbohydrate goal of 225 g per day (1,800 calories 50% of calories as carbohydrates divided by 4 calories per gram of carbohydrate = 225 g). An optimal distribution of carbohydrates for this patient would be 60 g for each of three meals, with the remaining 45 g spread over the day as snacks. Patients can learn about carbohydrate content of foods from food labels, from Web sites (http://diabetes.about.com/od/mealplanning/ss/carbcounting.htm), or from carbohydrate counter books.

Total fat intake should comprise 25% to 35% of calories.⁶⁴ Within this total fat recommendation, 7% or less should come from saturated and trans fat to help control LDL-C levels. Saturated fats typically are derived from animal sources such as regular milk and dairy products, egg yolk, high-fat meat, butter, and shortening. Clinicians should instruct patients to always select foods that are low in saturated fats. Have some sample food labels on hand for demonstration purposes. Only lean meats should be chosen. For example, lean ground beef that contains 4% fat is preferred over that labeled as having 7% fat. If no label is on the package, meat that is not marbled in appearance should be purchased. Meat high in fat appears to have white streaking throughout, whereas lean meat is more uniformly red. Beginning in January 2006, all food labels for foods sold in the United States are required to include the amounts of trans fats contained within commercial foods. Commonly, trans fats are found in commercial cakes, cookies, crackers, pies, and fried foods (French fries) as well as in margarines that are not labeled no trans fats. The fat that our bodies do need should come from monounsaturated and polyunsaturated sources such as soybeans, nuts, safflower, olive, and canola oils.

Dietary cholesterol is highest in organ meats and egg yolks. Whole milk, cheese, meats, and shellfish also contain high amounts of cholesterol. Reading food labels is important because they may state that the item is cholesterol free (such as a box of crackers) yet be high in unhealthy saturated fat and/or trans fat.

The American Heart Association Web site (http://www.americanheart.org) has information on dietary measures that can provide free resources for fat- and cholesterol-reducing diets.

The Dietary Approaches to Stop Hypertension (DASH) Eating Plan (http://www.nhlibi.nih.gov/heath/public/heart/hbp/dash/) provides an excellent framework for improving metabolic parameters of obese patients (Table 2-4). This plan is low in sodium (<2,400 mg per day) and includes lean meats, low-fat dairy, whole grains, and nuts while emphasizing at least 8 to 10 servings of fruits and vegetables per day. The DASH Eating Plan has been shown to reduce systolic blood pressure by 11.5 mm Hg in hypertensive patients and 7.1 mm Hg in normotensive patients⁶⁵ while improving waist circumference, HDL-C, triglycerides, and weight in obese patients with MS.⁶⁶

P.59

Alcohol use can increase blood pressure, raise triglyceride levels, and add to excessive caloric intake. Men should limit alcohol consumption to 8 ounces per day and women no more than 4 ounces per day. Patients with poorly controlled hypertension or hypertriglyceridemia should avoid alcohol consumption completely.^64,67

Encouraging Your Patients with Metabolic Syndrome to Get Moving

The WAVE (Weight, Activity, Variety, Exercise) tool was developed by Brown University to assist practitioners in conducting a quick assessment of patient's nutritional and activity status (Fig. 2-4).

The ATP III guidelines emphasize the benefits of exercise in the management of MS. Exercise can improve lipid profiles by decreasing triglycerides, total cholesterol, and LDL-C while increasing HDL-C levels. Exercise facilitates weight reduction and improves insulin sensitivity. The exercise prescription should be individualized and based on the level of the patient's physical conditioning. (The reader is referred to Chapter 9 for assistance in developing and prescribing individualized exercise programs.) Successful weight reduction can occur when one combines an active lifestyle with a caloric-restricted diet. Table 2-5 matches caloric expenditure with common forms of daily physical activities. With encouragement, patients may begin to incorporate energy expenditure into their daily routines and limit their exposure to the cardiovascular risks associated with MS.

P.60

Inactive or unmotivated patients should be provided with a pedometer and asked to walk at least 4,000 steps per day, the equivalent of 1 mile. If a mother who claims that she gets her exercise by chasing the kids around all day long records only 1,200 steps on the pedometer by 6 PM, she must make up the remaining 2,800 steps by taking a walk. Many patients are surprised to learn that although they consider themselves active individuals, they are walking only 1,000 to 1,500 steps per day, certainly not enough to promote

P.61

P.62

Many patients may need to begin with low-intensity and shorter duration exercise programs. A chronically inactive patient may not be able to perform intense activity for 30 minutes, much less 60 minutes. Suggest short-interval exercise occurring more frequently throughout the course of the day (i.e., walking 10 minutes before each meal) until their stamina allows longer durations at a higher intensity. Table 2-6 lists ways people can incorporate more physical activity into their lives.

How to Help Your Patient Succeed in Smoking Cessation without Even Trying

One of the more frustrating behavioral interventions for PCPs is the successful implementation of smoking cessation. Effective strategies that help patients

P.63

Indications for Pharmacologic Intervention of the Metabolic Syndrome

Pharmacologic therapy is appropriate for patients with MS at high risk for developing cardiovascular complications. Physicians should treat metabolic cardiovascular risk factors (LDL-C, triglycerides, hypertension, inflammation, hypercoagulation, and hyperglycemia) to target. Although metformin and thiazolidinediones (TZDs) might be considered useful in managing insulin resistance, the primary interventional strategy remains behavioral. Randomized placebo-controlled clinical trials are needed to determine whether these agents will delay, reverse, or prevent adverse outcomes (CVD, diabetes, and stroke) in patients with MS. Often the risk versus benefits of pharmacologic intervention must be discussed thoroughly with each patient (Table 2-7). The treating physician must remember that drugs such as TZDs, statins, incretin mimetics, and DPP-IV inhibitors are not inexpensive, costing patients up to $2,800 per year. These costs may be prohibitive to some and inappropriate for others, considering the lack of evidence-based outcome data supporting their use in MS.

Patients who meet the diagnostic criteria for MS are at increased risk for long-term CVD. The Atherosclerosis Risk in Communities (ARIC) study evaluated the risk of CVD and stroke among 12,089 black and white middle-aged individuals, 23% of whom met the criteria for MS yet did not have diabetes or CVD at baseline.⁴ Over an average of 11 years, men and women with MS were approximately 1.5 to 2 times more likely to develop CVD and stroke than individuals without MS. One may conclude from these findings that pharmacologic and lifestyle interventions may be complementary in reducing the likelihood of CVD and stroke in these high-risk patients. In the early 1950s, the higher level of HDL-C in women and the association of low HDL-C with CVD was first described in the Framingham Heart Study. Isolated low levels of HDL-C became a major potent lipid risk factor ⁶⁸ in 1977. Each 1 mg per dL decrease in HDL-C was associated with a 2% to 3% increase in CVD risk.⁶⁸ Although somewhat more controversial, elevated triglyceride levels were also thought to be associated with CVD. A meta-analysis of 17 population-based

P.64

Patients with MS should be characterized as to their 10-year risk for CVD as determined by the Framingham risk scoring tables (Tables 2-8 and 2-9). Patients having a 10% or higher chance of dying of CVD within the next

P.65

P.66

The Framingham Risk Assessment may be useful in assessing the likelihood of suffering a heart attack or stroke within 10 to 20 years, based on the presence of traditional risk factors. Equally important would be our ability to assess the

P.67

P.68

The Thrombolysis In Myocardial Infarction (TIMI) Trials⁷⁰ offers a 7-point risk score that can be used to predict the likelihood of experiencing an acute cardiac event within 30 days. These emergent CVD risk factors include age 65 years or older, a history of prior coronary stenosis of 50% or greater, three or more atherosclerosis risk factors, use of aspirin in the preceding week, two or more angina episodes in the preceding 24 hours, ST segment changes on electrocardiogram (ECG) of 1.0 mm or more, and increased levels of CRP. The TIMI score is a well-validated tool that can be assessed online at http://www.timi.org/files/riskscore/ua_calculator.htm.

Clinical trials of cholesterol-lowering drugs, primarily statins and fibrates, have consistently demonstrated their efficacy in primary and secondary prevention of cardiovascular morbidity and mortality.^{71,72,73,74,75,76} Major clinical trials

P.69

A series of clinical trials have also shown the importance of fibrate therapy in reducing cardiovascular risk. The Veterans Affairs HDL Infarction Trial (VA-HIT)⁷⁸ demonstrated that gemfibrozil reduced the risk for major cardiovascular events in high-risk patients such as those with diabetes and insulin resistance by 24%. In VA-HIT, mean baseline LDL-C was only about 112 mg per dL; HDL-C was also low at 32 mg per dL, and triglyceride levels were modest at 160 mg per dL. Gemfibrozil produced relatively little LDL-C change in either study. In VA-HIT, HDL-C was increased by about 6% and triglyceride was reduced by about 30%.

Combining statin and fibrate therapy in patients with MS can improve lipid profiles.⁷⁹ Simvastatin lowered triglycerides by 23%, total cholesterol by 27%, and non-HDL-C by 30%. The HDL-C increased by 6%. The addition of fenofibrate potentiated the effects of simvastatin on HDL-C, raising this parameter by 16% versus simvastatin alone while lowering triglycerides by a further 36%.

One important pharmacologic benefit of statin therapy was observed in 172 patients with severe coronary disease studied over 3 years.⁸⁰ Statins used in these high-risk patients reduced the mortality by 19%. This reduction in mortality was associated with a significant lowering of CRP levels from baseline.

Specific Metabolic Risk Factors as Targets for Therapy

Hypertension

The ATP III defines elevated blood pressure as a reading of 130/85 mm Hg or greater. This category includes patients taking antihypertensive medicines even if treatment achieves a blood pressure level that is within target range. Pharmacologic therapy is indicated in patients whose hypertension cannot be reduced to target using lifestyle intervention: weight loss, exercise, and dietary modification.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure⁸¹ established clinical guidelines for managing hypertension. Despite the concerns that thiazide diuretics and beta-blocking agents could have adverse effects on glucose tolerance,⁸² the safety and efficacy of these medications have been demonstrated in large randomized placebo-controlled clinical trials.⁸³ No single class of antihypertensive drugs has been identified as being uniquely efficacious for patients with MS. The weight of current evidence suggests that thiazide diuretics, angiotensin II receptor blockers, and angiotensin-converting enzyme

P.70

Insulin Resistance

Peroxisome Proliferator-Activated Receptors

TZDs are members of the PPAR- class. Whereas the metabolic effects of insulin are expressed primarily in skeletal muscles and the liver, PPAR- agents target adipose tissue. Insulin resistance is modified as TZDs lower levels of FFAs, redistribute visceral to subcutaneous fat, and raise plasma levels of adiponectin.^86,87,88 Although only approved for use in T2DM, their broad range of beneficial effects on improving metabolic parameters makes TZDs the leading candidates for potentially securing a major role in the future management of MS. Before TZDs can be recommended to patients with MS, randomized placebo controlled clinical trials are needed to assess their safety and efficacy in reducing cardiovascular risk in these high-risk patients.

Pharmacologic activation of PPAR- receptors favors lipid transport and oxidation, whereas PPAR- receptor activation favors lipid storage, insulin signaling, and reduced insulin resistance^89,90 (Table 2-10). The biologic role

P.71

A novel class of insulin sensitizers, possessing dual PPAR (PPAR- and PPAR- ) stimulating activities, improves both plasma glucose and lipid profiles. Dual PPAR activators (glitazars) have the ability to alter gene transcription within the PPAR receptor, thereby modifying metabolic pathways that influence MS. PPAR activation can have a positive effect on fatty acid oxidation, lipid metabolism, glucose metabolism, wound healing, carbohydrate metabolism, and endothelial cell inflammation.^47,48,49 Although the dual mechanisms of action offered by the glitazars are unique from a pharmacologic viewpoint, safety issues may prevent these drugs from reaching the market. In clinical trials, glitazars have been associated with a significant risk of carcinogenicity and cardiovascular mortality.⁹²

The use of bezafibrate, a / receptor agonist, has been shown in one long-term study to reduce the progression to T2DM in patients with IGT.⁹³

Metformin

Another insulin sensitizer, metformin, has been a cornerstone for the treatment of T2DM. Metformin appears to have beneficial metabolic effects that enhance the drug's attractive glucodynamic profile. In the United Kingdom Prospective Diabetes Study (UKPDS), metformin reduced new-onset coronary artery disease in obese patients with diabetes. Metformin prevented (or delayed) the onset of T2DM in subjects with IGT enrolled in the Diabetes Prevention Program.⁹⁴ To date, no CVD outcome data are available that place a positive spin on using metformin in patients with MS. Metformin should not, therefore, be recommended for the express purpose of reducing cardiovascular risk in patients with MS.

Rimonabant

Rimonabant is a selective CB1 receptor endocannabinoid blocker developed for reducing the cardiovascular risk factors associated with intra-abdominal obesity. Rimonabant is the first in a new class of drugs called selective CB1 blockers. The drug works by inhibiting the CB1 receptor, one of two receptors found in the endocannabinoid system (or EC system), located in the brain and adipose tissue (Fig. 2-5). The discovery of the EC system in the early 1990s allowed researchers to determine the site and mechanism of action of marijuana's psychoactive component tetrahydrocannabinol (THC). Activation of cannabinoid receptors is believed to affect central and peripheral action on lipid and glucose metabolism in adipose tissue while regulating food intake, energy balance, and nicotine desire.⁹⁵ Blocking the EC system with antagonist drugs, such as rimonabant, appears to help regulate behaviors such as feeding, fear, and anxiety.⁹⁶

The EC system is overactive in obese individuals. Blockade of the EC system by rimonabant reduces hunger, promotes weight loss, and improves

P.72

The RIO (Rimonabant in Obesity)-Diabetes Trial is one of four phase III studies comprising the RIO program, which assessed the efficacy and safety of rimonabant in cardiometabolic risk factor improvement and weight loss in more than 6,600 overweight and obese patients worldwide. RIO-Diabetes⁹⁷ was a multicenter, randomized, double-blind, placebo-controlled 12-month study enrolling 1,045 participants with a mean BMI of 34 kg per m², a mean waist circumference of 43.3 in., and a mean A1C of 7.5%. Study participants had T2DM and had been treated with metformin (60% of the patients) or one of several sulfonylureas for at least 6 months prior to randomization. Subjects continued

P.73

Only the rimonabant 20 mg was statistically more effective than placebo. The placebo group weight loss was 3.1 lb versus 11.7 lb for the rimonabant 20-mg group (n = 339). Forty-nine percent of the rimonabant patients lost at least 5% of their body weight over 12 months versus 14.5% of the placebo patients.

Improvement in waist circumference paralleled weight loss. Rimonabant patients averaged a 1.3-in. decrease in weight circumference when compared with placebo. Each 0.4-in. reduction in waist circumference was associated with a 1-kg weight loss.

During the RIO trial, the A1C rose 0.1% in the placebo group and dropped 0.6% in the rimonabant 20-mg group. The percentage of patients reaching the ADA-recommended treatment target of less than 7% during the study was 26.8% on placebo versus 52.7% on rimonabant. Both the metformin and sulfonylurea drug groups had similar improvement in A1C levels versus placebo.

Rimonabant also improved lipid profiles. HDL-C rose 8.4% higher in the rimonabant-treated patients versus placebo. Triglycerides levels decreased 16% greater in the rimonabant-treated patients than with placebo.

After 12 months in the RIO-Europe study, less than 20% of patients enrolled with MS continued to have diagnostic criteria for the disorder versus 31% of the baseline MS patients randomized to placebo. The most common side effects noted were nausea and vomiting, which led to the discontinuation of the drug in 1.5% of the rimonabant 20-mg group versus 0.3% of the placebo subjects.

Table 2-11 summarizes the highlights of the RIO-Diabetes Trial.

The benefits of rimonabant use in overweight patients with cardiovascular risk factors were also demonstrated in the RIO:North America Study. This study involved a 2-year evaluation of 3,045 patients at 64 American and 8 Canadian sites. All were adult patients who were obese (BMI >30 kg/m²) or overweight (BMI >27 kg/m²) and had untreated hypertension or hyperlipidemia. After 1 year, the patients using rimonabant 20 mg daily experienced significant reduction of their waist circumference and body weight as well as improvements in cardiometabolic risk factors such as HDL-C and triglycerides (Table 2-12). Improvement in metabolic parameters was maintained for 2 years if patients remained on rimonabant. However, patients who were re-randomized to placebo were unable to maintain their weight loss or metabolic stability.

Although the drug is well tolerated, 11% of patients using rimonabant 20 mg, as well as 6% of the placebo group, experienced nausea. One of the concerns of this trial was the high attrition rates of patients in the rimonabant 5- and 20-mg study groups as well as in the placebo cohort.

Prothrombotic State

No drugs are available that target PAI-1 or fibrinogen. An alternative approach to the prothrombotic state is antiplatelet therapy. Low-dose aspirin reduces

P.74

P.75

Proinflammatory State

By improving levels of CRP, statins can protect endothelial function and limit vascular inflammation. The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 study⁹⁹ (PROVE IT-TIMI 22), evaluated cardiac event rates in 3,745 patients who had acute coronary syndromes. LDL-C and CRP levels were evaluated 30 days after randomization in patients receiving 80 mg versus 40 mg of atorvastatin. Statin therapy reduced both LDL-C and CRP levels. Cardiac event rates correlated independently with both LDL-C and CRP. Patients with the greatest reduction in CRP levels had the lowest risk of cardiac events independent of the achieved lowering of LDL-C.

The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study examined atherosclerosis progression using intracoronary ultrasound in patients randomized to atorvastatin 80 mg versus pravastatin 40 mg. Coronary ultrasound was performed, and lipid and CRP levels were obtained at baseline and after 18 months of therapy. Atherosclerosis progression was independently correlated with changes in both LDL-C and CRP levels, findings similar to those of the PROVE IT-TIMI 22 trial.¹⁰⁰ The REVERSAL study suggests that aggressive statin therapy should be prescribed to achieve LDL-C levels below the current NCEP targets to reduce the incidence of CVD. The use of statins also was shown to have a significant effect on reducing inflammatory markers such as CRP.⁵⁰

Hyperglycemia

When patients with MS develop T2DM, their cardiac risk factor worsens (Fig. 2-6). A patient with T2DM is just as likely to die of a first MI as a patient without diabetes who has already had an MI.³³ In addition, a diabetic patient

P.76

The European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk) study¹⁰² was a European epidemiologic evaluation of cardiovascular mortality based on A1C levels. In this study, 4,662 men, ages 45 to 79, had an A1C obtained at baseline and after 3 years. Not all subjects had diabetes. Subjects with A1C levels at baseline between 5% and 6.9% had an increased risk of mortality from CVD two to four times greater than subjects with A1Cs lower than 5% at baseline. An increase of 1% in A1C was associated with a 28% increase in risk of death independent of age, blood pressure, serum cholesterol, BMI, and cigarette smoking habit. Thirteen percent of the deaths in the sample occurred in persons with clinically apparent diabetes (4% of the total sample). However, 72% of the cardiovascular-related deaths occurred in subjects with A1C concentrations averaging 5% to 6.9%. The study's authors concluded that mortality related to CVD was directly related to the A1C, even in patients who did not have diabetes. They also suggested that a 0.2% reduction in A1C reduced mortality in their study population by 10%. The population-based EPIC-Norfolk study may indicate that patients with diabetes should be treated toward the lowest and safest A1C possible to minimize cardiovascular mortality in these high-risk individuals.

The Final Word: Think Metabolic Syndrome Save a Life

Forty-seven million American adults have diagnostic criteria for MS. Patients diagnosed with at least three diagnostic components of the ATP III components for MS have a two to four times higher risk of dying of the disease than do their metabolically normal peers. Patients with MS are also likely to progress to develop T2DM.

MS is easily identified. Obesity anchors the pathophysiologic anomalies associated with this disorder. Obese individuals should be carefully screened for MS risk factors, including hypertension, hyperlipidemia, and IGT. Abnormalities in levels of nontraditional risk factors such as CRP should prompt more aggressive pharmacologic intervention in high-risk patients.

The diagnostic specifications regarding MS are not without controversy. Regardless of which diagnostic criteria are used (WHO, AACE, ATP III), lifestyle intervention (weight reduction and increased physical activity) is critical. Healthier food choices should be encouraged. Nicotine addiction and alcohol abuse should be addressed. Statins, antihypertensives, and aspirin therapy have good evidence-based studies supporting their use in reducing CVD in high-risk patients. Patients who are initiated on pharmacologic therapy should be treated to their safe and recommended metabolic targets. New medications are on the horizon that target obesity, insulin resistance, progression of prediabetes, hyperlipidemia, and CVD disease in high-risk patients.

P.77

Very few of our primary care based patients and their families would reject attempts at coaching them toward healthier lifestyle choices. Explaining to obese patients with hypertension and hyperlipidemia that exercise, healthy food choices, and a weight reduction targeting 7 pounds in the first year may reduce their chance of developing heart disease and diabetes is certainly time well spent. Recognizing MS within the primary care setting may encourage clinicians to apply their preventive medicine training when a patient presents for the annual physical or even for an evaluation of a sports-related injury.

The foundation of MS centers is based on recognizing the relationship between obesity and insulin resistance and cardiovascular mortality. Semantics aside, if the word syndrome helps us to focus aggressively on identifying and treating all metabolic risk factors that could result in CVD, why should the term not be used? Finally, the legitimacy of MS as a unique medical entity¹⁰³ has been recognized by the ICD-9 code 277.7 (dysmetabolic syndrome X). How can one bill for managing a disease that does not exist?

Managing Metabolic Syndrome in Children and Adolescents

As in adults, the precise definition of MS in children and adolescence is open to considerable debate. As children get older and pass through life's developmental stages, abnormal metabolic cut-off points change. Normal values of risk factors such as height, weight, blood pressure, and BMI also have gender- and age-specific differences.

Obesity in children is defined differently than in adults. Overweight children are defined as those with a BMI at the 95th percentile or higher for age and sex. Children who are at risk for being overweight are those with a BMI at the 85th percentile or higher but less than 95th percentile for age and sex. There are no cutpoints for waist circumference measurements in children.¹⁰⁴

Both boys and girls experience metabolic changes during puberty, making defining MS a work in progress. All children, for example, have increased insulin resistance and decreased insulin sensitivity during puberty because of elevations of growth hormone levels.¹⁰⁵ Body fat composition, blood pressure, and lipids are all affected by puberty. Lipid levels vary by pubertal stage. Total cholesterol drops in mid-puberty and begins to rise before adulthood.¹⁰⁶ The appearance of metabolic risk markers may be accompanied by a decrease in physical activity, poor dietary choices, and the possible start of nicotine use during the peer-driven, emotionally charged times of adolescence. Identifying MS in children and adolescence is difficult yet critical to prevent early CVD.

The prevalence of MS in children and adolescents is approximately 4.2% based on data from the NHANES III.¹⁰⁷ MS is more common in obese adolescent children. Among children with a BMI at the 95th percentile or higher,¹⁰⁸ the prevalence of MS is nearly 50%.

Obese children often have increased plasma insulin levels, which has been associated with hypertension and atherogenic dyslipidemia.¹⁰⁹ Definitions of MS

P.78

As in adults, clustering of MS risk factors in children may lead to premature CVD. Therefore, practitioners must thoroughly evaluate adolescent patients who have at least one risk factor for MS, especially if they are obese.

The components of MS and the levels that indicate higher risk are shown in Table 2-13.

The BMI is the most widely used and efficient measure of obesity in children. Age- and sex-specific norms are available for children from ages 2 to 20.⁷⁹ The BMI can also be charted over time so that children who are rapidly progressing toward the 95th percentile may be identified and counseled. All children should be screened yearly for obesity per the recommendations of the American Academy of Pediatrics.¹¹⁰ Patients who are obese will most likely

P.79

Screening Tests for Metabolic Syndrome in Children and Adolescents

The American Academy of Pediatrics Expert Committee on Evaluation and Treatment of Obesity in Children recommends measuring both fasting glucose and insulin levels in high-risk patients.¹¹² Because girls who have early menarche (< 11 years) tend to have higher insulin levels and excess body fat, these patients should be screened with fasting glucose and plasma insulin levels.¹¹⁰ Such patients are at risk for developing MS.

Children with a family history of either CVD or a parent with a total cholesterol of 240 mg per dL or higher should be screened for atherogenic dyslipidemia.¹¹³ Even in this high-risk population, less than 10% of all screened children have abnormal total cholesterol levels.¹¹⁴ Those patients with abnormal lipid values should have the test repeated at least once, as a single measure of serum cholesterol could vary as much as 14% under acceptable laboratory conditions.¹¹⁵ A third cholesterol measurement should be performed if the initial two tests values vary by more than 16%.¹¹⁵ The American Heart Association and the American Academy of Pediatrics also recommends screening lipid levels in children or adolescents with hypertension, smoking, sedentary lifestyle, obesity, and excessive alcohol intake.¹¹³

Obese children also need to be screened for hypertension. The National High Blood Pressure Education Program (NHBPEP) Working Group on High Blood Pressure in Children and Adolescents¹¹³ suggests screening each patient at every visit for hypertension beginning at 3 years of age. As in adults, an elevated blood pressure on three separate visits is necessary for the diagnosis of hypertension.

Management of Metabolic Syndrome in Children and Adolescents

Once a diagnosis of MS is made, behavioral and lifestyle interventions should take center stage at every appointment. Currently, there are no evidence-based guidelines for the management of MS in children and adolescents, although

P.80

P.81

The best approach to managing MS in children and adolescents is prevention. PCPs can encourage children, adolescents, and their parents to adopt healthy lifestyles, eat healthier foods, and increase their physical activity. Having a TV in the bedroom is associated with an increased risk of obesity.¹¹⁶ Children who eat while watching TV tend to consume foods with poor nutritional content.¹¹⁷ Physical education programs that promote noncompetitive instruction have been shown to improve fitness and cardiovascular risk profiles.¹¹⁸ Elimination of sugar-laden beverages from the home and school environment can result in weight reduction. The American Academy of Pediatrics guidelines for consumption of fruit juices is shown in Table 2-15.

Summary

Four percent to 7% of children and adolescents have criteria for the diagnosis of MS. Obese children are especially prone to having multiple risk factors associated with MS. These statistics are particularly disturbing because MS can progress to CVD and diabetes. Healthcare providers should screen all at-risk children and adolescents for components of MS, while promoting healthy lifestyle interventions with both the parents and the patient. Although guidelines for specific treatment of MS in younger patients are undetermined, treating the individual risk factors associated with the syndrome is strongly encouraged. The most prudent way to avoid cardiovascular risk and delay progression toward T2DM in younger patients is via preventive lifestyle interventions. Table 2-16 summarizes ways in which parents can assist in preventing MS in their children.

P.82

References

1. The metabolic syndrome. American Diabetes Association Web site. Available at: http://wwwdiabetes.org/weight-loss-and-exercise/weightloss/metabolicsyndrome.jsp. Accessed July 2005.

2. Unger J. Diagnosing and managing insulin resistance syndrome. Emerg Med. 2004;36:36 43.

3. Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM. Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease? Diabetes Care. 2004;27:2676 2681.

4. McNeill AM, Rosamond WD, Girman CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care. 2005;28:385 390.

5. Ellison RC, Zhang Y, Wagenknecht LE, et al. Relation of the metabolic syndrome to calcified atherosclerotic plaque in the coronary arteries and aorta. Am J Cardiol. 2005;95:1180 1186.

6. Boyd BD. Insulin and cancer. Integr Cancer Ther. 2003;2:315 329.

7. Vague J. Sexual differentiation, a factor affecting the forms of obesity. Presse Med. 1947;30:339 340.

8. Albrink MJ, Meigs JW. The relationship between serum triglycerides and skinfold thickness in obese subjects. Ann N Y Acad Sci. 1965;131:673 685.

9. Avagaro P, Crepaldi G, Enzi G, Tiengo A. Associazione di iperlidemia, diabete mellito e obesitia di medio gado. Acta Diabetol Lat. 1967;4:36 41.

10. Ohlson LO, Larsson B, Svardsudd K. The Influence of body fat distribution on the incidence of diabetes mellitus: 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes. 1985;34:1055 1058.

11. Ferrannini E, Buzzigoli G, Bonadonna R. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350 357.

12. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595 1607.

13. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Diabetes Care. 2005;28:2289 2304.

14. DeFronzo RA. Lilly Lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37:667 687.

P.83

15. Bajaj M, DeFronzo RA. Metabolic and molecular basis of insulin resistance. J Nucl Cardiol. 2003;10:311 323.

16. Despres JP, Lemieux I, Prud'homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ. 2001;322:716 720.

17. Matsuzawa Y. Pathophysiology and molecular mechanisms of visceral fat syndrome: the Japanese experience. Diabetes Metab Rev. 1997;13:3 13.

18. National Institutes of Health. Third Report on the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Executive Summary. Bethesda, MD: National Institutes of Health; 2001 (NIH publ. no. 01-3670).

19. The National Center for Health Statistics. National Health and Nutrition Examination Survey Web site. Available at: http://www.cdc.gov/nchs/about/major/nhanes/hlthprofess.htm. Accessed July 5, 2005.

20. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care. 2004;27:2444 2449.

21. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. JAMA. 2002;287: 356 359.

22. Zhou XH. Prevalence and trends of a metabolic syndrome phenotype among U.S. adolescents 1999 2000. Diabetes Care. 2004;27:2438 2443.

23. Ford ES, Giles WH. A comparison of the prevalence of the metabolic syndrome using two proposed definitions. Diabetes Care. 2003;26:575 581.

24. Meigs JB, Wilson PW, Nathan DM, et al. Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies. Diabetes. 2003;52:2160 2167.

25. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation. 2003;107:391 397.

26. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2003;108:414 419.

27. McLaughlin T, Abbasi F, Lamendola C, et al. Differentiation between obesity and insulin resistance in the association with C-reactive protein. Circulation. 2002;106:2908 2912.

28. Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care. 2003;26:2442 2450.

29. Kojima S, Funahashi T, Sakamoto T, et al. The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction. Heart. 2003;89:667 672.

30. Haffner SM, D'Agostino R Jr, Mykkanen L, et al. Insulin sensitivity in subjects with type 2 diabetes: relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study. Diabetes Care. 1999;22:562 568.

31. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35:595 601.

32. Pankow JS, Duncan BB, Schmidt MI, et al. Fasting plasma free fatty acids and risk of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes Care. 2004;27:77 82.

33. Arner P. Free fatty acids: do they play a central role in type 2 diabetes? Diabetes Obes Metab. 2001;3(Suppl 1):11 19.

34. Homko CJ, Cheung P, Boden G. Effects of free fatty acids on glucose uptake and utilization in healthy women. Diabetes. 2003;52:487 491.

35. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999;103:253 259.

36. Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001;50:1612 1617.

P.84

37. Bronfman M, Morales MN, Orellana A. Diacylglycerol activation of protein kinase C is modulated by long-chain acyl-CoA. Biochem Biophys Res Commun. 1988;152:987 992.

38. Boden G, Cheung P, Stein TP, Kresge K, Mozzoli M. FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol Endocrinol Metab. 2002;283: 12 19.

39. Boden G, Laakso M. Lipids and glucose in type 2 diabetes. Diabetes Care. 2004;27:2253 2259.

40. Joffe B, Zimmet P. The thrifty genotype in type 2 diabetes: an unfinished symphony moving to its finale? Endocrine. 1998;9:139 141.

41. Crespin SR, Greenough WB III, Steinberg D. Stimulation of insulin secretion by long-chain free fatty acids: a direct pancreatic effect. J Clin Invest. 1973;52:1979 1984.

42. Boden G, Chen X, Iqbal N. Acute lowering of plasma fatty acids lowers basal insulin secretion in diabetic and nondiabetic subjects. Diabetes. 1998;47:1609 1612.

43. Stefan N, Stumvoll M, Bogardus C, Tataranni PA. Elevated plasma nonesterified fatty acids are associated with deterioration of acute insulin response in IGT but not NGT. Am J Physiol Endocrinol Metab. 2003;284:E1156-E1161.

44. Cui Y, Blumenthal RS, Flaws JA, et al. Non high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med. 2001;161:1413 1419.

45. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients. JAMA. 2006;295:761 775.

46. Chen X, Iqbal N, Boden G. The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J Clin Invest. 1999:103:365 372.

47. Lohray BB, Lohray VB, Bajji AC, et al. ( )3-[4-[2-(phenoxazin-10-yl) ethoxyl]-2-ethoxypropanoic acid [( )DRF2725]: a dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. J Med Chem. 2001;44:2675 2678.

48. Sauerberg P, Pettersson I, Jeppesen L, et al. Novel tricyclic-alkyloxyphenylporpionic acid: dual PPAR/agonists with hypolipidemic and antidiabetic activity. J Med Chem. 2002;45:789 804.

49. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000;405: 421 424.

50. Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and the risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327 334.

51. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol in the prediction of first cardiovascular events. N Engl J Med. 2002;347: 1557 1565.

52. Yudkin JS, Stehouwer CDA, Emeis JJ, et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role of cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol. 1999;19:972 978.

53. Festa A, D'Agostino R, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102:42 47.

54. Frohlich M, Imhof A, Berg C, et al. Association between C-reactive protein and features of the metabolic syndrome: a population based study. Diabetes Care. 2000;23:1835 1839.

55. Festa A, D'Agostino R, Howard G, et al. Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the Insulin Resistance Atherosclerosis Study. Kidney Int. 2000;58:1703 1710.

56. Vega GL: Obesity, the metabolic syndrome, and cardiovascular disease. Am Heart J. 201; 142:1108 1116.

57. Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001; 89:763 771.

58. Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol. 2004;24:29 33.

59. Saltiel AR. You are what you secrete. Nat Med. 2001;7:887 859.

P.85

60. Purnell JQ, Kahn SE, Albers JJ, et al. Effect of weight loss with reduction of intra-abdominal fat on lipid metabolism in older men. J Clin Endocrinol Metab. 2000;85:977 982.

61. Franssila-Kallunki, Rissanen A, Ekstrand A, Ollus A, Groop L. Effects of weight loss on substrate oxidation, energy expenditure, and insulin sensitivity in obese individuals. Am J Clin Nutr. 1992;55:356 361.

62. Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56:320 328.

63. Bastard J-P, Jardel C, Bruckert E, et al. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab. 2000;85:3338 3342.

64. Schmaderer J, Unger J. Dietary Guidelines for Americans. The Female Patient. 2006;31: 31 40.

65. Harsha DW, Sacks FM, Obarzanek E, et al. Effect of dietary sodium intake on blood lipids: results from the DASH-sodium trial. Hypertension. 2004;43:393 398.

66. Azadbakht L, Mirmiran P, Esmaillzadeh A, Azizi T, Azizi F. Beneficial effects of a dietary approaches to stop hypertension eating plan on features of the metabolic syndrome. Diabetes Care. 2005;28:2823 2832.

67. United States Department of Agriculture Web Site. Available at: http://www.mypyramid.gov/. Accessed April 6, 2006.

68. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease: the Framingham Study. Am J Med. 1977; 62:707 714.

69. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213 219.

70. TIMI Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial. N Engl J Med. 1989;320:618 627.

71. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383 1389.

72. Shepherd J, Cobbe SM, Ford I, et al., for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301 1307.

73. Sacks FM, Pfeffer MA, Moye LA, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001 1009.

74. Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349 1357.

75. Ballantyne CM. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol. 1998;82:3Q 12Q.

76. Downs JR, Clearfield M, Weis S, et al. for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279:1615 1622.

77. Ballantyne CM, Stein EA, Paoletti R, Southworh H, Blasetto JW. The efficacy of rosuvastatin 10 mg in patients with metabolic syndrome. Am J Cardiol. 2003;91:25C-27C.

78. Rubins HB, Robins SJ, Collins D, et al. for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410 418.

79. Vega GL, Ma PT, Carter NB, et al. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol. 2003;91:956 960.

P.86

80. Horne BD, Muhlestein JB, Carlquist JF, et al. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol. 2000;36:1774 1780.

81. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC 7 report [erratum JAMA. 2003;290:197]. JAMA. 2003;289:2560 2572.

82. Langford HG, Cutter G, Oberman A, Kansal P, Russell G. The effect of thiazide therapy on glucose, insulin and cholesterol metabolism and of glucose on potassium: results of a cross-sectional study in patients from the Hypertension Detection and Follow-up Program. J Hum Hypertens. 1990;4:491 500.

83. Pasternak RC. The ALLHAT lipid lowering trial less is less. JAMA. 2002;288:3042 3044.

84. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703 713.

85. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755 1762.

86. Adams M, Montague CT, Prins JB, et al. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest. 1997;100:3149 3153.

87. de Souza CJ, Eckhardt M, Gagen K, et al. Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes. 2001;50:1863 1871.

88. Maeda N, Takahashi M, Funahashi T, et al. PPAR- ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094 2099.

89. Gulick T, Cresci S, Caira T, Moore DD, Kelly DP. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A. 1994;91:11012 11016.

90. Ye JM, Doyle PJ, Iglesias MA, et al. Peroxisome proliferator-activated receptor (PPAR)- activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR- activation. Diabetes. 2001;50:411 417.

91. Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci. 2005;26:244 251.

92. Brody JM. Selling safety lessons from muraglitazar. JAMA. 2005;494:2633 2635.

93. Tenenbaum A, Motro M, Fisman EZ, et al. Peroxisome proliferator-activated receptors ligand bezafibrate for prevention of type 2 diabetes mellitus in patients with coronary artery disease. Circulation. 2004;109:2197 2202.

94. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393 403.

95. Petrocellis L. The encannabinoid system: a general view and latest additions. Br J Pharmacol. 2004;141:765 774.

96. Alger B, Kim J. Endocannabinoids: getting the message across. PNAS. 2004;101:8512 8513.

97. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S; RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study [erratum Lancet. 2005;366:370]. Lancet. 2005;365:1389 1397.

98. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973 979.

99. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495 1504.

100. Nissen S. (REVERSAL) A prospective, randomized, double blind, multi-center study comparing the effects of atorvastatin vs. pravastatin on the progression of coronary atherosclerotic lesions as measured by intravascular ultrasound. American Heart Association Scientific Sessions 2003; Plenary Session XI: Late Breaking Clinical Trials. November 9 12, 2003; Orlando, Florida.

P.87

101. Khaw KT, Wareham N, Bingham S, et al. Association of hemoglobin A1C with cardiovascular disease and mortality in adults: the European Prospective Investigation into Cancer in Norfolk. Ann Intern Med. 2004;141:413 420.

102. Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). BMJ. 2001;322:15.

103. Online ICD9/ICD9CM codes. Available at: http://icd9cm.chrisendres.com/index.php?action=alphaletter&start=&mv=n. Accessed April 2, 2006.

104. Centers for Disease Control and Prevention. BMI for children and teens. 8 April 2003. Available at: http://www.cdc.gov/nccdphp/dnpa/bmi/bmi-for-age.htm. Accessed July 22, 2005.

105. Caprio S, Plewe G, Diamond MP, et al. Increased insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity. J Pediatr. 1989;114:963 967.

106. Berenson GS, Srinivasan SR, Cresanta JL, Foster TA, Webber LS. Dynamic changes of serum lipoproteins in children during adolescence and sexual maturation. Am J Epidemiol. 1981;113:157 170.

107. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988 1994. Arch Pediatr Adolesc Med. 2003;157:821 827.

108. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350:2362 2374.

109. Mo-Suwan L, Lebel L. Risk factors for cardiovascular disease in obese and normal children: Association of insulin with other cardiovascular risk factors. Biomed Environ Sci. 1996;9: 269 275.

110. American Academy of Pediatrics Committee on Nutrition. Prevention of pediatric overweight and obesity. Pediatrics. 2003;112:424 430.

111. American Diabetes Association. Clinical Practice Recommendations. Diabetes Care. 2006; 29(Suppl 1):S6.

112. Barlow SE, Dietz WH. Obesity evaluation and treatment: Expert Committee Recommendati-ons. The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services. Pediatrics. 1998;102:E29.

113. Williams CL, Hayman LL, Daniels SR, et al. Cardiovascular health in childhood: a statement for health professionals from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2002;106:143 160.

114. Steiner MH, Neinstein LS, Pennbridge J. Hypercholesterolemia in adolescents: effectiveness of screening strategies based on selected risk factors. Pediatrics. 1991;88:269 275.

115. Cooper GR, Myers GL, Smith SJ, et al. Blood lipid measurements. Variations and practical utility. JAMA. 1992;267:1652 1660.

116. Dennison BA, Erb TA, Jenkins PL. Television viewing and television in bedroom associated with overweight risk among low-income preschool children. Pediatrics. 2002;109:1028 1035.

117. Coon KA, Goldberg J, Rogers BL, Tucker KL. Relationships between use of television during meals and children's food consumption patterns. Pediatrics. 2001;107:E7.

118. Harrell JS, McMurray RG, Gansky SA, et al. A public health vs. a risk-based intervention to improve cardiovascular health in elementary school children: the Cardiovascular Health in Children (CHIC) study. Am J Public Health. 1999;89:1529 1535.