Review article

The National Cholesterol Education Program's Adult Treatment Panel III (ATP III) identifies persons who have multiple metabolic risk factors or the “metabolic syndrome” as candidates for intensified therapeutic lifestyle changes (TLCs) ^[1] . This article focuses on both the theory and practice of such changes. In an era of increasingly potent cholesterol-lowering medication, some physicians may attach little importance to nondrug therapy. This article presents the case for TLC as a prime therapy for metabolic syndrome and its component features as defined by the ATP III, as follows:

Weight loss improves all of the previously listed components of the metabolic syndrome (and insulin resistance) and is central to any effective treatment regimen.

Weight gained after age 18 years carries a heavy metabolic price tag. In the Nurses' Health Study, a weight gain of 10 kg or more since the age of 18 was associated with increased mortality in middle adulthood ^[2] . Despite this statistic, there has been an alarming rate of growth in the incidence of overweight (body mass index [BMI], 25–29.9) and obesity (BMI, >30.0) in the United States ^[3] . BMI takes into account the effects of height and should be calculated in those individuals who have gained significant weight since age 18. The formula for BMI is weight/height² (kg/cm²) and this can be transformed if pounds and inches are the measurements available by using the following formula: BMI  =  703.1^* (weight  [lb]/height²  [in²])

Although measuring BMI is important, the addition of waist circumference (WC) helps clinicians identify those individuals at increased health risk within each BMI category. The robust Third National Health and Nutrition Examination Survey (NHANES III) database showed that, with few exceptions, within the three BMI categories, those individuals with high WC values were increasingly likely to have hypertension, diabetes, dyslipidemia, and the metabolic syndrome compared with those with normal WC values ^[4] . A large-scale autopsy study of young men who died of external causes, the Pathobiological Determinants of Atherosclerosis in Youth study, highlighted the effects of abdominal obesity on raised coronary lesions ^[5] . The authors noted that in those individuals with a BMI greater than 30 kg/m² the effect of obesity on raised lesions in the right coronary artery was greater in young men with a thick panniculus adiposus.

Yet once abdominal obesity is recognized, there is the more difficult problem of effectively treating it. As anyone who has considered weight loss will attest, there are many diets to choose from. A useful approach when considering nonpharmacologic treatment of obesity is to consider the following questions:

1. Is the diet successful in promoting weight loss in the short-term?
2. Is the diet successful in maintaining weight loss in the long-term?
3. Are there any health consequences to the diet?
4. Are there any clinical trial data to support this benefit?

It is instructive to apply these questions to the three kinds of dietary approaches that are available today, which include low-carbohydrate diets, very-low-fat diets, and reduced-fat diets.

The clinical trial data on each of these diets are also instructive. A meta-analysis of low-carbohydrate diets in the outpatient setting was not encouraging ^[6] . Only five studies that considered large numbers of patients (these studies were nonrandomized and without comparison groups) evaluated the patients' diets for more than 90 days. Among obese patients, weight loss was associated with longer diet duration (P  =  0.002) and restriction of caloric intake (P  =  0.03) but not with reduced carbohydrate content (P  =  0.90). The authors believed that there was insufficient evidence to make recommendations for or against the use of low-carbohydrate diets, particularly among participants older than 50 years, for use of these diets for longer than 90 days, or for diets of 20 g/day or less of carbohydrates.

Thus, clinical trial data are welcome. Samaha et al ^[7] randomized 132 severely obese subjects with a mean BMI of 43 and a high prevalence of diabetes (39%) or the metabolic syndrome (43%) to either a low-carbohydrate or low-fat diet and followed up these patients for 6 months. Subjects randomized to the low-carbohydrate group had greater weight loss than those assigned to the low-fat group in the short-term, but this benefit was attenuated by the drop-out rate because only 79 patients completed the study.

Nonetheless, the amount of weight lost (P < 0.001) and assignment to the low-carbohydrate diet (P  =  0.01) were independent predictors of improvement in TG levels and insulin sensitivity. Similar findings were reported by Foster et al ^[8] in their 1-year multicenter controlled trial involving 63 obese men and women who were randomly assigned to either a low-carbohydrate, high-protein, high-fat diet or a low-calorie, high-carbohydrate, low-fat (ie, conventional) diet. In the 63 obese subjects who were randomized to low-fat versus low-carbohydrate diets, those on the low-carbohydrate diet produced a greater weight loss (∼4%) than did those on the conventional diet for the first 6 months, but, as in the Samaha et al ^[7] trial, the differences were not significant at 1 year. The increase in HDL-C and the decrease in TG concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study. Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load. Adherence was poor and attrition was high in both groups. An editorial in the New England Journal of Medicine critically reviewed these diets and noted that maintenance of the marked initial weight loss is still not proven with low-carbohydrate diets and that there are potentially serious long-term consequences ^[9] . The authors listed hypercalciuria and the adverse effects of a high protein content on the kidney as potential problems. Perhaps most concerning is the use of a higher saturated fat intake, a well-known factor for atherogenic risk, especially in a population that is already at increased risk for cardiovascular disease.

Recently, a trial comparing an ad libitum low-carbohydrate diet versus a calorie-restricted low-fat diet was performed for 6 months in 53 obese (BMI, 30–35) women ^[10] . The very-low-carbohydrate diet group lost more weight (8.5 ± 1.0 kg versus 3.9 ± 1.0 kg; P < 0.001) and more body fat (4.8 ± 0.67 kg versus 2.0 ± 0.75 kg; P < 0.01) than the low-fatdiet group. Over the 6 months, however, there was no significant change in blood pressure, lipids, and glycemic parameters between the groups. Clearly, more studies, particularly long-term ones, are needed to determine the appropriate role for this dietary approach.

Another form of dietary control in those individuals at increased coronary risk is the very-low-fat diet. Ornish et al ^[11] studied 48 men and women to compare lifestyle management using a vegetarian diet of less than 10% fat, smoking cessation, stress management training, and moderate exercise versus an American Heart Association (AHA) step 1 diet. Although this was a small-scale study and randomization was apparently not impeccable, the intervention group lost 10 kg of weight and showed improvement in coronary angiographic appearance at 1 year. A larger scale experience with 440 subjects who had coronary heart disease (CHD) and multiple metabolic risk factors showed that both women and men lost weight and improved their risk-factor profiles with the Ornish program ^[12] .

The third approach is the modified-fat diet. One example is the diet used in the St. Thomas Atherosclerosis Regression Study. In this trial, overweight British men were randomized to a control group, a dietary group, and a drug group (resins). The dietary group had a 27% total-fat, 8% saturated-fat diet that was high in pectin-rich fruit. This diet was associated with weight reduction and a reduction in low-density lipoprotein cholesterol (LDL-C), which led to improvement on coronary angiography that rivaled the drug-treatment group ^[13] .

Such a diet is advocated by the ATP III panel ^[1] and the AHA ^[14] . The ATP III recommendations for TLC are described more fully in the section on lipids. The AHA espoused an overall healthy eating pattern that would include a variety of fruits, vegetables, grains, low-fat or nonfat dairy products, fish, legumes, and poultry or lean meats, and specific guidelines for attaining appropriate body weight, a desirable cholesterol profile, or a desirable blood pressure. For appropriate body weight, it recommended that individuals should match their energy intake to energy needs with appropriate changes to achieve weight loss when indicated. Furthermore, it suggested that persons “limit consumption of foods with a high caloric density or low nutritional quality, including those with a high content of sugars.” It noted that meal replacers, such as liquid formulas, can help people start a course of weight loss, but their short-term use doesn't substitute for development of a long-term, healthy eating pattern.

One study examined the effect of the kind of carbohydrate on weight loss in a controlled manner. Poppitt et al ^[15] randomized 46 obese subjects with metabolic syndrome to a control group, a low-fat complex carbohydrate diet, or a low-fat simple carbohydrate diet. Thirty-nine subjects completed the 6-month trial, which showed a significant decrease in BMI, waist circumference, and cholesterol in the complex versus simple carbohydrate group. As expected, TG levels were higher in the group assigned to the simple carbohydrate diet.

Although not a randomized trial, the National Weight Control Registry provides important insight into the ingredients of successful weight loss ^[16] . Wing and Hill ^[16] noted that those who lost on average 30 kg for an average of 5.5 years shared the following effective behaviors:

• Following a low-fat diet
• Frequent self-monitoring of body weight and food intake
• Maintaining high levels of regular physical activity

These successful dieters noted that weight-loss maintenance actually became easier over time. Moreover, when weight loss had been maintained for 2 to 5 years, the chances of long-term success greatly increased.

A team approach involving physicians, nurses, dietitians, and pharmacists also can be useful ^[1] . Three important weight-loss principles are as follows: (1) emphasize the importance of avoiding further weight gain; (2) reduce intake and increase physical activity in a regular fashion; and (3) aim for slow weight reduction, with the aim to lose 10% of body weight over a period of 1 year in an attempt to minimize the likelihood of weight regain.

For individuals with impaired glucose tolerance (IGT), the Da Qing trial ^[17] , the Diabetes Prevention Program (DPP) ^[18] , and the Finnish Diabetes Prevention Trial (FDPT) ^[19] provide convincing evidence for the benefits of lifestyle modification. The Da Qing trial examined 577 subjects with IGT and showed a large decrease in the development of type 2 diabetes mellitus (T2DM) in the exercise-only group, which was larger than that seen in the combined diet and exercise group. The results were significant even when adjusted for BMI. The DPP studied 3234 obese subjects with IGT, but not overt T2DM, who were randomized to metformin, lifestyle modifications, or placebo. Both treatment groups experienced results that were superior to placebo in preventing T2DM ^[18] . The lifestyle-modification program of the DPP, with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week, reduced the likelihood of T2DM by 58% and was actually more effective than metformin in this regard. The weight loss in the intervention group that was achieved in the first year was not sustained, but by the end of the trial, the intervention group had still lost 4 kg (or ∼4%, with a mean weight of 100 kg). An important observation was that the increase in physical activity was sustained during the trial.

In the FDPT, 522 men and women with IGT were randomized to an intervention group with individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat, and increasing intake of fiber and physical activity ^[19] . The mean follow-up period was 3.2 years. The striking findings were that the intervention group had lost significantly more weight than the control group and the risk of T2DM was reduced by 58% (P < 0.001). (This reduction in T2DM risk closely paralleled that seen in the DPP.) The reduction in the incidence of T2DM was directly associated with changes in lifestyle, with the subjects who exercised more deriving the most benefit. The DPP and FDPT had striking parallels (Table 1 ), although the definition of T2DM in both trials was not the same.

Exercise played a key role in a 24-month study among 64 Japanese American men and women with IGT who were randomized to a step 2 diet and aerobic exercise versus a step 1 diet with stretching exercises ^[20] . The former group had improved BMI, body composition, and body fat distribution. This result was also seen in the randomized Oslo Diet and Exercise Study, which compared the single and joint effect of diet and exercise on glycemic variables in 219 sedentary middle-aged men and women ^[21] . Exercise alone was not as beneficial as the combination of exercise and diet in improving glycemic variables in this 1-year study.

These trials all have in common the inclusion of exercise as part of the therapeutic regimen. Although some physicians may conclude that exercise is all that is needed, studies have shown that this is not so. This was seen in a controlled trial of 170 obese (average BMI, 30 ± 1), middle-aged men who were randomized to either a 9-month diet-induced weight-loss intervention, a 9-month aerobic exercise training program, or a weight-maintenance control group ^[22] . Weight loss decreased fasting glucose concentrations by 2%, insulin by 18%, and glucose and insulin areas during the oral glucose tolerance test (OGTT) by 8% and 26%, respectively (P < 0.01). By contrast, aerobic exercise did not improve fasting glucose or insulin concentrations or glucose responses during the OGTT but decreased insulin areas by 17% (P < 0.001). In multiple regression analyses, the improvement in lipid and glycemic parameters was related primarily to the reduction in obesity. Thus, taken together, the data support a combination of exercise, diet, and weight reduction to improve risk factors.

The lipid triad consists of elevated TGs, low HDL-C, and increased small, dense LDL-C. These are the lipid abnormalities characteristically associated with the metabolic syndrome. The ATP III offered the following advice for individuals with the metabolic syndrome. First, the panel suggested that there should be a maximum reduction of LDL-C. The level of LDL-C is decreased by reducing saturated fat and dietary cholesterol (high-fat dairy products and fatty cuts of meat) including more fiber in the diet. For some, plant stanol ester products may be an additional way to lower raised LDL-C levels. Second, once LDL-C has been reduced, emphasis shifts to management of the metabolic syndrome and its associated lipid components (Table 2 ). Although not measured routinely, the amount of small, dense LDL-C particles would be expected to decrease with the same measures that improve HDL-C and TG levels. Physicians should remember that in the Framingham Offspring Study, the higher the BMI, the greater the number of small LDL particles ^[23] . A high proportion of patients who have the metabolic syndrome have increased BMI and are sedentary. For these patients, weight-reduction therapy and regular physical activity is required to improve CHD risk factors.

The therapeutic diet in ATP III differs from the prior AHA and National Cholesterol Education Program diets in several ways. First, the limit for total calories from fat was set at 25% to 35% rather than at less than 30%. There were several important reasons for this change. First, the emphasis on total fat led to intakes of fat below 25%. In individuals with hypercholesterolemia, this low-fat, high-carbohydrate intake can actually increase TGs and lower HDL-C. The Dietary Alternatives Study ^[24] actually compared the lipid responses to varying amounts of total fat in individuals with hypercholesterolemia (HC) or combined elevations of cholesterol and triglycerides (combined hyperlipidemia [CH]). The authors of this study concluded that “more extreme restriction of fat intake offers little further advantage in HC or CH subjects and potentially undesirable effects in HC subjects.”

The ATP III also discussed the “glycemic index” of foods. This is an old concept that ranks carbohydrates according to their ability to increase glucose and insulin. A diet with a high glycemic index would have significant amounts of white potatoes and other white-flour baked goods along with sugars from juices and sodas. This diet would be in contrast to diets with whole grains, beans, nuts, and vegetables, which have a lower glycemic index. There are data from a cross-sectional study of 1420 British adults that show a significant negative relationship between HDL-C and the glycemic index in an adult diet ^[25] . In this study, the glycemic index was the only dietary variable significantly related to serum HDL-C concentration. Sacks and Katan ^[26] pointed out that a diet with high-fiber, low–glycemic-index foods would be preferable to a high–glycemic-index, low-fat diet because of more favorable effects on TG, serum glucose, and insulin levels. The ATP III recommended that carbohydrate intakes should be limited to 60% of total calories in persons who have metabolic syndrome. They suggested that lower intakes, perhaps as low as 50% of total calories, be considered for persons with elevated TGs or low HDL-C. Most important, they suggested that most of the carbohydrate intake should come from grain products, particularly whole grains, vegetables, fruits, and fat-free and low-fat dairy products.

Dreon et al ^[27] highlighted the undesirable effects of a diet that is too low in fat in children genetically inclined to small, dense LDL-C. The children given this low-fat diet experienced a decrease in the size of their LDL-C particles, resulting in atherogenic LDL or pattern B. Second, there was evidence to show that, among certain groups, such as those with T2DM, a diet higher in unsaturated fats and lower in carbohydrates could be beneficial. A meta-analysis of various approaches to diet therapy in patients with T2DM revealed that high–monounsaturated-fat diets improved TG and HDL-C levels and glycemic control without adversely affecting LDL-C concentrations ^[28] .

The ATP III also recommended enough moderate exercise to expend at least 200 kcal per day. Exercise can be expected to improve the TG/HDL abnormalities in most patients. In the Heritage Family Study, those subjects who had increased TG and low HDL-C levels at baseline had the greatest benefit from a 20-week endurance training program ^[29] . This improvement was not seen in those subjects with isolated, low HDL-C. The latter, however, were subjects whose HDL-C may have been very difficult to raise with any intervention. Recently, the Institute of Medicine of the National Academy of Science stated that 30 minutes per day of regular activity is insufficient to maintain body weight in adults ^[30] . They suggested 60 minutes of moderate-intensity physical activity per day to prevent weight gain. The need for increased activity to maintain body weight is also supported by the STRRIDE (Studies of Targeted Risk Reduction Interventions through Defined Exercise) trial ^[31] . The STRRIDE trial was an 8-month trial that randomized 120 middle-aged, overweight subjects with mild to moderate dyslipidemia into three exercise groups, stratified by amount and intensity, and a control group. There was a high-amount/vigorous-intensity group, a low-amount/vigorous-intensity group, and a low-amount/moderate-intensity group. The authors showed a significant dose-response relationship between the amount of exercise and the amount of weight loss and fat mass loss. The authors noted that most individuals can achieve the amount of exercise that proved so useful in this study by either doing brisk walking or an equivalent exercise for 30 minutes per day or a vigorous exercise such as jogging for 20 minutes per day.

In the United States, the increases in overweight and obesity have led to obesity-associated hypertension. NHANES III data showed that particularly up to age 60, the higher the BMI, the greater the prevalence of hypertension ^[32] . Certainly in the Framingham study, the age-adjusted relative risk for new-onset hypertension was highly associated with overweight status for men and women ^[33] . More than 20 years ago, Reisin et al ^[34] found that in a trial of weight reduction without salt restriction, there was a significant relation between weight loss and blood pressure at all ages and in both genders.

The association between obesity, hypertension, and insulin resistance should be noted. The Normative Aging Study demonstrated that diastolic blood pressure is a function of increasing abdominal girth ^[35] . Increases in abdominal circumference are particularly concerning in individuals with a BMI range of 25 to 30; in these individuals, the opportunity to improve blood pressure with small amounts of weight loss should not be missed. When weight loss occurs in obese adolescents ^[36] and adults ^[37] with hypertension, a significant relation between improvement in insulin sensitivity and a decreased blood pressure can be seen.

Although insulin resistance is at the core of many of the defects of the metabolic syndrome, hypertension is a less consistent predictor of insulin resistance compared with dyslipidemia ^[38] . It has been estimated that only approximately 50% of hypertensive patients are insulin resistant and hyperinsulinemic ^[39] . The Dietary Approaches to Stop Hypertension (DASH) trial has shown convincingly that a healthful dietary pattern can favorably influence elevated blood pressure even without sodium restriction ^[40] . The DASH diet is high in fruits, vegetables, low-fat dairy products, whole grains, poultry, fish, and nuts, which are good sources of potassium, calcium, and magnesium, and low in fats, red meat, and sweets. When this dietary pattern is followed in combination with a lower sodium intake, blood pressure is lowered further ^[41] .

Hypercoagulability and inflammation are not part of the ATP III definition but are clearly seen in individuals with metabolic syndrome. How does weight reduction and exercise help? Plasma tissue plasminogen activator inhibitor 1 (PAI-1) was predictive of coronary artery disease events in a prospective multicenter study of men with angina, although the associations disappeared after parameters reflecting insulin resistance were considered ^[42] . A study of obese subjects who underwent weight reduction with a hypocaloric diet showed that PAI-1 levels also decreased in these individuals ^[43] . Ridker et al ^[44] found that among 14,719 healthy women followed up prospectively, as the number of risk factors for metabolic syndrome increased, the levels of C-reactive protein (CRP) increased ^[44] . Moreover, among those individuals with the metabolic syndrome at study entry, age-adjusted incidence rate of future cardiovascular events was 3.4 per 1000 person-years if the baseline CRP level was less than 3.0 mg/L compared with 5.9 per 1000 person-years of exposure for those with baseline CRP levels greater than 3.0 mg/L. The effects of raised CRP were additive for those with four or five characteristics of the metabolic syndrome.

Exercise plays an important role in combating this unwanted aspect of the metabolic syndrome. A survey of 3800 British men showed that whether they had CHD or not, physical activity showed a significant and inverse dose-response relationship with fibrinogen, plasma and blood viscosity, platelet count, coagulation factors VIII and IX, von Willebrand factor, fibrin D-dimer, tissue plasminogen activator antigen, CRP, and white cell count, even after adjustment for possible confounders ^[45] . In addition, a study of obesity-related inflammatory markers and leisure-time activity indicated a beneficial effect of frequent physical activity ^[46] . The lower systemic inflammatory markers and improved insulin sensitivity were partially explained by a decrease in obesity in physically active subjects, however. Furthermore, when CRP and leptin were measured in ultramarathon runners, strikingly low CRP concentrations were found ^[47] . It seemed that circulating CRP was suppressed independent of total adiposity or fat mass. Lee and Lip ^[48] evaluated the effects of lifestyle habits (or lifestyle modifications) on blood coagulation, fibrinolysis, and platelet reactivity and found the data from intervention and randomized clinical trials to be “largely fragmented, rarely complete, and inconsistent.” Nonetheless, from their comprehensive review, they concluded that lifestyle change that incorporated exercise, weight reduction, smoking cessation, light to moderate alcohol consumption, fatty fish consumption, and relaxation should significantly lower coagulability, promote fibrinolysis, and reduce platelet reactivity.

The first practical step is to try to prevent weight gain in patients who have the metabolic syndrome. Although this step seems obvious, many patients are counseled to begin medications such as steroids, antidepressants, oral hypoglycemics, and even certain antipsychotic medications that are known to cause weight gain without a strategy in place to combat the weight gain that occurs. The ATP III also counsels on first implementing LDL-lowering measures (the exception would be patients with TG levels >800 mg/dL in whom attention to weight loss, diet, exercise, and medication to prevent very high TG levels and pancreatitis takes priority). Then, weight reduction for individuals who are overweight becomes a major focus of the TLC approach. The evidence-based report from the National Institutes of Health entitled “Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults” is a thorough review of this topic and provides many insights into this task ^[49] . The Obesity Guidelines panel reviewed 36 randomized clinical trial reports to determine important behavioral strategies. The key insights are summarized as follows:

• Multimodal strategies work better than a single approach.
• More frequent contact is associated with better adherence.
• Adherence declines with discontinued intervention or follow-up.
• Greater intensity of intervention, especially initially, is associated with faster and more sustained adherence.
• Motivation is enhanced when the patient sets achievable goals.

The panel further emphasized the importance of measurements that are not necessarily done by the physician. The baseline assessment of dietary intake can be obtained by the office nurse/assistant, and the patient can be taught self-monitoring to improve adherence. Physicians do need to use health messages that are matched to the level of the patient's readiness to change. Asking the patient if he or she has either thought about changing their diet/exercise/weight-reduction behavior or is ready to change these behaviors is an ideal way to begin counseling. As noted in ATP III, messages need to be culturally sensitive, address prior knowledge, and interactive. Patients often benefit by referral to a registered dietitian for medical nutrition therapy. Sometimes this expense can be mitigated by discontinuing the many unnecessary and expensive vitamin supplements that patients have purchased on their own.

The ATP III further emphasized regular physical activity to help accomplish the task of weight reduction and management of risk factors of the metabolic syndrome. The base of evidence for this recommendation is found in the US Surgeon General's report ^[50] . It is important for the physician to endorse physical activity at each visit. Helpful suggestions that can be given to patients include the following:

• Look for ways to incorporate more activity into the day.
• Aim for at least 30 minutes of activity at least 5 days per week.
• Buy a pedometer to monitor activity.
• Keep an activity log and bring it to the next visit.
• Involve family and friends in a healthy lifestyle.

A superb review of the deleterious effects of lifestyle and obesity with a useful section that the authors call a “blueprint for action” is recommended as essential reading for clinicians who confront patients with metabolic syndrome on a daily basis ^[51] .

This article has attempted to provide the groundwork for understanding the basis and nonpharmacologic management of the metabolic syndrome. Weight loss can greatly reduce insulin resistance and all of the manifestations of the metabolic syndrome. Physicians' endorsement of eating and exercise behaviors that lead to a healthier waistline and improved BMI, lower blood pressure, improved HDL-C and TGs, and lower blood sugars along with a reduced CRP carries the promise of improved long-term outcomes. While clinicians await further research into behavioral science, adipocytes, hormones, and the mechanistic link between insulin resistance and other important factors that will help them identify new targets for therapy, they can do much by promoting improved lifestyles for all individuals. The findings of the NHANES III (1988–1994) that perhaps 4% of adolescents and nearly 30% of overweight adolescents in the United States meet criteria for the metabolic syndrome suggest that a national focus on lifestyle change needs to start now ^[52] .