St. Luke's-Roosevelt Hospital Center, 1111 Amsterdam Avenue, Room 1020, New York, NY 10025. E-mail: email@example.com
Intervention in weight management should begin before the onset of the metabolic syndrome. Therapeutic lifestyle changes (e.g., diet and physical activity) comprise the cornerstone of care for overweight and obese patients. Behavior modification approaches are useful in facilitating adherence to specific dietary regimens. Pharmacotherapy is an option for patients with a BMI >30 kg/m2 or for those with a BMI of 27 to 30 kg/m2 and two or more risk factors, who have failed on diet and exercise alone. To date, the U.S. Food and Drug Administration has approved three weight loss agents: sibutramine, orlistat, and phentermine.
Obesity is the precipitating factor for the majority of patients who develop the metabolic syndrome. Obesity is not only associated with traditional risk factors (e.g., hypertension, dyslipidemia, and insulin resistance) (1), but also with non-traditional risk factors [e.g., C-reactive protein (CRP)1 and interleukin-6] levels that promote an inflammatory and procoagulatory state conducive to clotting, ischemic heart disease, and stroke (2, 3). The combination of these risk factors in various clusters leads to serious chronic disease, including type 2 diabetes and cardiovascular disease (CVD) and, therefore, constitutes the secondary target of risk-reduction therapy under current National Cholesterol Education Program Adult Treatment Panel III guidelines (1, 4).
The issue for clinicians is when and how to intervene in the cascade of events that progresses from obesity to chronic disease—before or after the development of chronic disease and risk factors. Both common sense and evidence-based medicine dictate that, optimally, non-pharmacologic intervention in weight control should begin before the onset of metabolic risk for diabetes and CVD.
Unfortunately, no single specific treatment exists for the individual with the metabolic syndrome. Instead, the goal of treatment is directed toward reducing the risk factors found in a given patient (4). Therapeutic lifestyle changes comprise the cornerstone of care for overweight and obese patients. For the past three decades, behavior modification aimed at helping individuals identify the problems and barriers interfering with their ability to achieve lifestyle change, lose weight, and maintain that loss long-term has been the primary treatment for obesity and reducing metabolic risk factors.
Cornerstone of Care: Lifestyle Changes Treatment Plan
Lifestyle change through behavior modification approaches is difficult and requires a comprehensive treatment program that incorporates diet and exercise and, if necessary, adjunctive pharmacotherapy. The goal of weight loss therapy, to reduce body weight by ∼10%, is achievable and effective, and realizing that goal can significantly decrease the severity of obesity-associated risk factors (5).
Extensive evidence suggests that moderate weight loss of 5% to 10% of initial body weight significantly improves the health of obese patients (6, 7, 8). Indeed, weight loss modulates the risk of diabetes (i.e., reducing hyperglycemia and hemoglobin A1C level), hypertension (i.e., reducing systolic and diastolic blood pressure), and dyslipidemia [i.e., reducing triglyceride and low-density lipoprotein-cholesterol (LDL-C) levels and increasing high-density lipoprotein cholesterol (HDL-C)].
Weight loss has been shown to improve traditional markers of CVD risk. Data from the Framingham Heart Study indicate that even small changes in weight translate into significant changes in long-term risk (1). For example, weight loss of 10 lb was associated with decreases in cholesterol (7.5 and 5.8 mg/dL), blood pressure (4.4 and 4.2 mm Hg), and glucose (0.6 and 1.2 mg/dL) in men and women, respectively (1).
Weight loss also has a positive effect on non-traditional risk factors such as CRP. A study by Tchernof et al. (9) showed that significant weight loss (∼10% of initial body weight) decreased CRP levels (an inflammatory marker associated with insulin resistance, endothelial dysfunction, and CVD) in a cohort of 61 obese (BMI > 35.6 ± 5.0 kg/m2) postmenopausal women (Figure 1). After weight loss, reduction in CRP levels averaged −32.3%, from 3.06 (+0.69, −1.29) to 1.63 (+0.70, −0.75) μg/mL (p < 0.0001, medians and interquartile differences).
Weight loss is a cardioprotective intervention that seems to reduce both traditional and non-traditional markers for diabetes and CVD.
Therapeutic Lifestyle Changes Treatment Plan: Diet and Physical Activity
Weight loss is difficult to achieve and even more difficult to maintain. It is often compromised by the unrealistic expectations of patients who desire to lose 25% of their total body weight despite the fact that none of the existing treatments, except gastric bypass, achieve this level of efficacy (10).
Successful weight loss and maintenance requires therapeutic lifestyle changes, and, to achieve this, many patients find specific behavioral modification techniques helpful. According to Poston and Foreyt (11), behavior modification is “a systematic method for modifying eating, exercise, or other behaviors that may contribute to or maintain obesity.” Behavior modification techniques include self-monitoring, stimulus control, cognitive restructuring, stress management, and social support (5).
Of these techniques, self-monitoring is the most important. Its goal is to enhance awareness of behaviors and other factors that influence eating (11). Self-monitoring tools include the following:
•A food diary to record total caloric intake, total fat grams consumed, food groups used, and situations where overeating is common;
•An activity log to record frequency, duration, and intensity of exercise; and
•A weight record to document changes in weight, body fat, or lean body mass (11).
Weight loss may be achieved with various hypocaloric diets that emphasize a non-atherogenic regimen coupled with physical activity. Current NIH/National Heart, Lung, and Blood Institute guidelines suggest that weight loss (defined as a 7% to 10% decrease in weight and waist circumference) can be achieved with a reduction in calories of 500 to 1000 kcal/d, which will reduce weight at the rate of 0.45 to 0.91 kg (1 to 2 lb) per week (5).
Therapeutic Lifestyle Changes Diet: A Low-Fat Approach
The nutrient composition of the therapeutic lifestyle changes (TLC) diet, a diet appropriate for long-term adherence, stresses reduced saturated fat (<7% of total calories), reduced trans fat, reduced dietary cholesterol (<200 mg/d), and a total fat intake of 25% to 35% of calories (Table 1) (4). Most dietary fat should be unsaturated, and simple sugars should be limited. Carbohydrates should comprise 50% to 60% of total calories and be derived from complex sources such as fruits, vegetables, and grains. The fiber content should rise to 20 to 30 g/d; the average American currently consumes only 15 grams of fiber daily.
Table 1. TLC: nutrient composition of the TLC diet (4)
Reprinted with permission. TLC, Therapeutic Lifestyle Changes.
Balance energy intake and expenditure to maintain healthy body weight/prevent weight gain
The dietary factors that affect energy intake include nutrient composition, energy density, and portion size. In 12 studies included in a meta-analysis of ad libitum dietary intervention studies, Astrup et al. (12) clearly showed that low-fat diets decrease daily energy intake and result in greater weight reduction. Subjects with the heaviest initial body weight lost the greatest amount of weight on low-fat diets (12). In general, the majority of overweight individuals respond favorably to diets based on lowering the percentage of fat.
Many patients find it easier to adhere to a Mediterranean-type diet in which monounsaturated fat is substituted for saturated and trans fats, and intake of fruits, vegetables, fiber, and whole grains is high. The Lyon Diet Heart Study was a randomized secondary-prevention trial that evaluated whether a Mediterranean-type diet, compared with a prudent Western-type diet, reduced the rate of recurrence after a first myocardial infarction (MI) (13).
Clinically stable patients (age < 70 years) were followed for 46 months. Patients in the Mediterranean-type diet group had a reduced rate of cardiac death and non-fatal MI compared with those in the Western-type diet group—14 vs. 44 events, respectively (p = 0.0001) (13). Although the cardioprotective effect of the Mediterranean-type diet was maintained for up to 4 years, major traditional risk factors, such as high blood cholesterol and high blood pressure, were shown to be independent and joint predictors of recurrence.
Low Energy Density Diets
Numerous studies have shown that the energy density of the diet influences body weight over the short term. In a short-term (14-day) study, Stubbs et al. (14) evaluated the effect of a high, medium, and low energy density diet given ad libitum on body weight in six healthy, normal weight men. Subjects on the low energy density diet lost weight, whereas weight remained unchanged on the medium energy density diet and increased on the high energy density diet (14). The cumulative weight changes recorded with the low, medium, and high energy density diets were −1.20, 0.02, and 0.91 kg, respectively (14).
Numerous long-term studies have confirmed the efficacy of low energy density diets in promoting weight loss. Most notably, Weinsier et al. (15) showed that individuals were able to achieve and sustain weight loss for >1 year on a low energy density diet.
Portion size is an important variable influencing caloric intake and weight control. As individuals consume larger portions than required for sustenance, they gain increasing amounts of weight. Apparently, most people take the admonition “clean your plate” seriously, no matter what the size of the portion on the plate. A recent study showed that portion size significantly influenced caloric intake (16). The greater the portion of macaroni and cheese served (500, 625, 750, or 100 grams), the more people ate. Subjects consumed ∼30% more energy (150 kcal) when they were served the largest compared with the smallest portion.
The consumption of sucrose-sweetened drinks with meals has also been shown to contribute a significant number of extra calories. In 42 non-dieting men, sucrose-laden lemonade (16 oz) taken with lunch significantly increased caloric intake compared with no beverage or water (16 oz) (17).
Nutrient-dense meal replacements, or formula diets, are a safe and effective alternative to pharmacological therapy. At St. Luke's-Roosevelt Hospital, formula diets are used extensively. Many patients find that substituting one or two meals daily with a specifically prescribed volume of meal replacement helps them lose weight initially and maintain their weight loss over time.
Notably, a German study showed that meal replacements provide an effective approach toward sustained weight loss and improvements in cardiovascular and metabolic risk factors (18). Patients (n = 100) were randomized into two groups to receive an energy-restricted diet consisting of conventional foods or a meal replacement (two meals, two snacks) consisting of a vitamin- and mineral-rich formula. During the first 3 months, the weight loss phase of the study, patients who received the meal-replacement diet lost considerably more weight compared with those on the calorie-restricted diet—7.1 ± 3.5 vs. 1.3 ± 2.2 kg, respectively (Figure 2) (18). In addition, patients on the formula diet had significant reductions in plasma concentrations of triacylglycerol and glucose and insulin resistance, whereas those on the conventional diet had no improvements in these biomarkers of cardiovascular and metabolic risk.
During the second 24-month phase of this 27-month study, both groups were prescribed the same diet of one meal replacement and one nutrition bar as a snack (18). On this regimen, both groups were able to maintain their weight loss throughout the 2-year follow-up period. Although patients in the meal-replacement group lost more weight during the initial 3 months of the study, both groups lost weight at similar rates thereafter. Over the long term, both groups experienced significant reductions in systolic blood pressure and insulin resistance and plasma concentrations of triacylglycerol and glucose. This study supports the use of formula diets as an intervention that helps patients meet both their weight loss and weight maintenance goals.
Weight Loss Maintenance and Diabetes Prevention
Skeptics contend that the therapeutic lifestyle changes approach is doomed, because inevitably patients will “fall off the wagon” and fail to sustain their weight loss. However, data from the Diabetes Prevention Program show that lifestyle intervention not only results in sustained weight loss but also prevents type 2 diabetes in obese individuals with impaired glucose tolerance to a greater extent than pharmacological intervention (7, 8). In the largest of these studies, investigators from 27 centers randomized 3234 middle-aged (mean age, 51 years), overweight (BMI > 24 kg/m2), non-diabetic individuals with elevated fasting and postload plasma glucose concentrations to three groups to receive metformin (850 mg twice daily), a lifestyle modification program, or placebo.
The goals for the subjects assigned to the intensive lifestyle intervention group were a weight reduction of 7% and >150 minutes of moderate exercise a week (7). Both the placebo and metformin groups received standard written and oral information about diet and exercise, but without specific goals. Fifty percent of the participants in the lifestyle intervention group achieved the goal of weight loss >7% of initial body weight at 24 weeks, and 38% sustained a weight loss of at least 7% at the time of the most recent visit (Figure 3A) (7). Participants in the lifestyle intervention group also increased their physical activity 6-fold over the placebo group, an increase they sustained throughout the study period (Figure 3B) (7).
The overall effect of these positive lifestyle changes in the lifestyle intervention group was a greatly reduced incidence of conversion to diabetes. Lifestyle intervention reduced the incidence of diabetes by 58% and metformin reduced it by 31% compared with placebo (Figure 3C) (7). The benefits of lifestyle intervention in preventing diabetes were apparent at 6 months. Overall, lifestyle intervention was more effective than pharmacological treatment in preventing diabetes (7).
Physical activity also plays a major role in long-term weight management. A direct correlation exists between the amount, rather than the intensity, of physical activity and weight loss maintenance. A randomized 18-month study showed that mean weight loss for women exercising >200 min/wk was significantly greater than that associated with 150 to 200 or <150 min/wk (19).
Similarly, the National Weight Control Registry, the largest study of individuals successful at long-term weight loss maintenance, reported that registry members adhered to a low-fat, low-calorie diet and were extremely active, walking, on average, 28 mi and expending 2500 to 3000 kcal weekly (20). Moderate physical activity on most days of the week, coupled with adherence to a low-calorie, low-fat diet, seems to be the key to successful long-term weight loss maintenance.
According to National Weight Control Registry data, effective long-term weight management hinges on implementing three behaviors: self-monitoring; consuming a diet low in fat and calories; and engaging in regular physical activity (Table 2) (21). Studies have shown that participation in a therapeutic lifestyle changes program (i.e., diet and physical activity) can lower weight, reduce the conversion rate to diabetes, and improve risk factors for CVD.
Table 2. Cardinal behaviors of successful long-term weight management: National Weight Control Registry Data (21)
Diet: record food intake daily, limit certain foods or food quantity
Weight: check body weight ≥1 time/wk
2. Low-calorie, low-fat diet
Total energy intake: 1693 kcal/d
Energy intake from fat: 24%
3. Regular physical activity
2500 to 3000 kcal/weekly (e.g., walk 4 mi/d)
The image of drug therapy for obesity has been blemished by the past use of “diet drugs,” such as amphetamine, with harmful or addictive potential (10). Because amphetamine is addictive, it was presumed that the entire class of B-phenylethylamine compounds shared this trait. However, other drugs in this class, namely phentermine and sibutramine, have no abuse potential (10). Another alleged drawback of diet pharmacotherapy is the perception that it does not work, because patients regain weight once they finish therapy (10).
Obesity is a chronic and relapsing disease for which there is no foolproof cure. Therefore, pharmacological therapy should be viewed as a useful adjunct to lifestyle modification interventions. For patients with a BMI ≥30 kg/m2 or for those with a BMI of 27 to 30 kg/m2 and two or more risk factors, who have failed on diet and exercise alone, pharmacotherapy is an option (11). To date, the U.S. Food and Drug Administration has approved three weight-loss agents: sibutramine, orlistat, and phentermine (10). Of these three agents, sibutramine and orlistat have been approved for long-term use. The mechanisms of action of these three drugs are reduction of energy intake (sibutramine and phentermine) and reduction of dietary fat absorption (orlistat) (10).
Sibutramine is a serotonin and a norepinephrine reuptake inhibitor, originally developed as an antidepressant, which reduces food intake by curbing hunger and enhancing satiety (22). Several multicenter trials of 6 to 18 months of duration have evaluated the efficacy and safety of sibutramine (10). Depending on the dose, sibutramine produces an average 10- to 15-lb weight loss.
The seven-center Sibutramine Trial of Obesity Reduction and Maintenance showed that over the first 6 months (the managed weight-reduction phase), patients lost 5% of their initial weight with little or no weight regain and were eligible for randomization to sibutramine (n = 352) or placebo (n = 115) (22). Of the 204 sibutramine-treated patients who completed the 18-month trial, 89 (43%) maintained 80% or more of their weight loss compared with 9 (16%) of the 57 patients in the placebo group (p < 0.001) (22). At the end of the study, 142 (69%) maintained at least a 5% weight loss, 94 (46%) maintained a 10% weight loss, and 55 (27%) maintained their full initial weight loss.
In a 1-year randomized trial, sibutramine was shown to augment the benefits of lifestyle modification (23). Fifty-three women were randomized to receive sibutramine alone or sibutramine in conjunction with behavior modification or behavior modification plus a structured meal plan. At study end, significantly (p < 0.05) greater weight losses were experienced by patients in the drug plus lifestyle group (10.8 ± 10.3%) and the combined drug plus structured meal plan plus lifestyle group (16.5 ± 8.0%) compared with patients in the drug-alone group (4.1 ± 6.3%). The investigators concluded that the addition of intensively structured lifestyle modification to the pharmacological management of obesity significantly improved weight loss and patients’ satisfaction with treatment outcome.
In a recently published study, Wadden et al. (24) showed that patients who took sibutramine in conjunction with diet (1500 kcal daily) and physical activity (daily 0.5-hour walks) lost 27 lb, whereas those who took sibutramine alone lost 11 lb.
Adverse effects of sympathomimetic drugs, such as sibutramine, are increased blood pressure and increased heart rate, and patients taking the drug need to be monitored for these effects (10, 22). The drug is contraindicated in patients with coronary artery disease. Milder side effects include dry mouth, constipation, insomnia, dizziness, and nausea (22).
Orlistat, a gastrointestinal lipase inhibitor, reduces dietary fat absorption by ∼30% (25). Four 2-year trials showed the efficacy and safety of orlistat. Two multicenter, double-blind, 2-year studies, an 18-center U.S. study (25), and a 15-center European study (26) randomized patients to receive orlistat (120 mg three times per day) in conjunction with a hypocaloric diet for 1 year and orlistat in conjunction with a eucaloric weight maintenance diet for the second year. Both studies showed that orlistat-treated patients lost more weight than placebo-treated patients during the first year (9% to 10% vs. 6%, respectively, of initial body weight) (25, 26).
In the European trial, patients who switched from orlistat to placebo gained weight, whereas those who switched from placebo to orlistat lost weight during the second year of treatment (26). The U.S. study compared two dose regimens of orlistat (60 vs. 120 mg) in the weight maintenance phase of the trial (25). Patients treated with 120 mg orlistat throughout the 2-year study period regained less weight during the second year (3.2 kg; 35.2% regain) than did those treated with 60 mg orlistat (4.26; 51.3% regain) or placebo (5.63 kg; 63.4% regain). Improvements in risk factors for diabetes and CVD (e.g., LDL-C and insulin levels) were associated with 120 mg orlistat treatment in these two trials (25, 26), as well as in other studies (27, 28).
Two multicenter randomized controlled trials, the Orlistat Primary Care Study (6) and the European Orlistat Obesity Study (29), compared orlistat in 120 mg and 60 mg three times per day regimens vs. placebo over a 2-year period. At the end of the first year, the percentage of body weight lost from initial body weight was greatest among patients treated with the higher orlistat dose in the U.S. and European trials: 7.9% and 9.7%, respectively. During the second year maintenance period, orlistat, particularly the 120-mg dose, was associated with less weight gain in both trials. In the second year of the U.S. study, 6.6% of patients in the placebo group compared with 18.6% of those in the 120 mg orlistat group (p = 0.001) and 14.6% of those in the 60 mg orlistat group (p = 0.008) sustained a weight loss of ≥10% of initial body weight (6). Thus, four multicenter trials showed that orlistat in conjunction with diet promoted sustained weight loss over a 2-year period.
The only side effect of orlistat observed in clinical trials was a small decline in fat-soluble vitamins (within the normal range). Gastrointestinal side effects, such as steatorrhea, or soft and frequent stools, have also been reported.
Widely prescribed in the United States, phentermine is an adrenergic agent that, like sibutramine, curbs appetite and enhances satiety. Although phentermine has been used as a weight loss agent for decades, it has never been tested in long-term clinical trials (10). In a meta-analysis of nine randomized, controlled trials of phentermine, patients treated with the drug lost an average of 3.6 kg of additional weight compared with 3.0 kg in diethylpropion-treated patients (30).
Because phentermine acts on the catecholamine system, it can increase blood pressure and heart rate; therefore, patients need to be monitored for these effects. Other potential side effects of the drug include dry mouth, headache, insomnia, and constipation.
In summary, all three of the Food and Drug Administration–approved agents are effective weight loss adjuncts. Orlistat has been shown to provide about the same effectiveness as sibutramine over a 1-year period. In addition to weight loss, orlistat seems to have an independent effect on decreasing total cholesterol and LDL-C levels.
Control of cardiovascular and metabolic risk factors requires a multimodal approach. Numerous studies have shown that weight loss (10% of initial body weight) and increased physical activity provide significant risk factor reduction. Whether this translates into lower morbidity and mortality from type 2 diabetes and CVD has been clearly shown for traditional risk factors but is less certain for non-traditional ones. If therapeutic lifestyle changes are unsuccessful in reducing risk factors to guideline levels, it is incumbent on the physician to add specific pharmacotherapy for each abnormal risk factor (e.g., fibrates, statins, and niacin for dyslipidemia and metformin for hyperglycemia).
Q: Since reducing carbohydrate intake raises HDL-C, lowers triglycerides, reduces waist circumference and blood pressure, and improves insulin sensitivity, is a low-carbohydrate diet recommended for patients with the metabolic syndrome? If not, what diet is best?
Dr. Pi-Sunyer: The best long-term diet is one that is low in saturated fat and cholesterol, as has been documented in numerous clinical trials over the years. However, patients can lose weight with just about any diet that works for them. A high-protein, low-carbohydrate diet is a fine short-term weight-loss approach; many individuals have successfully lost weight on an Atkins-type diet, which is high in protein, high in fat, and low in carbohydrates. Although such diets are acceptable in the short term for acute weight loss, a diet that is high in cholesterol and saturated fat is probably not beneficial over the long term. For long-term weight maintenance, I would suggest either a Mediterranean-type diet or the therapeutic lifestyle changes (TLC) diet.
Dr. Haffner: During acute weight loss, the most important determination is the amount of caloric deficit. It is relatively much more important than the actual type of diet. Although it is relatively unimportant in acute weight loss, increased physical activity is important in weight maintenance. I tend to agree that the problem with high-fat, low-carbohydrate diets is that you have to teach patients two different diets: one for weight loss and another for weight stabilization. That is a difficult concept to explain to patients.
Q: What is the outcome in terms of sustained risk factor reduction for individuals who lose 10% of their body weight and maintain weight loss over a long time period?
Dr. Pi-Sunyer: We do not have a definitive answer to that question, because it has been very difficult to follow a cohort of patients who have lost weight over a long period of time. The only cohort that I know of in which patients have been followed is the SOS (Swedish Obese Subjects) study in Sweden, a surgical study that compared a surgical intervention vs. a medical intervention and subsequently followed patients for over 10 years (1, 2, 3). The investigators found that patients who maintained a 17% weight loss from baseline were able to maintain low lipids and low blood pressure. Although their blood pressure initially decreased and remained down for ∼4 years, it began to creep up again and is now back to baseline or above. However, systolic blood pressure rises with age, and since these patients are 10 years older now than they were when they had their intervention, part of this effect could be attributable to aging rather than to a lack of sustained weight loss.