Management Of Obesity As A Chronic Disease: Nonpharmacologic, Pharmacologic, And

Management of Obesity as a Chronic Disease: Nonpharmacologic, Pharmacologic, and Surgical Options Ken Fujioka

Abstract FUJIOKA, KEN. Management of obesity as a chronic disease: nonpharmacologic, pharmacologic, and surgical options. Obes Res. 2002;10:116S–123S. The successful management of obesity requires a long-term approach that is tailored to an individual’s lifestyle and needs. Initial treatment should focus on lifestyle modifications— dietary interventions and increased physical activity—with behavioral modification strategies used adjunctively. Several antiobesity drugs are approved by the Food and Drug Administration for use in obese patients, as well as in overweight individuals with at least one obesityrelated comorbidity. Most are approved only for short-term weight loss, but sibutramine and orlistat are approved for long-term weight loss and maintenance. In addition to weight reduction, in clinical trials these drugs provided beneficial actions on several cardiovascular risk factors. Several other drugs currently approved for other uses show promise in their ability to cause weight loss. Surgical options should be reserved for severely obese patients with significant medical comorbidities or physical conditions. Key words: diet, physical activity, behavioral modification, antiobesity drug, gastric bypass

Introduction Obesity increases the risk of multiple medical conditions, many of which are associated with high morbidity and mortality, such as type 2 diabetes, hypertension, and coronary heart disease (1). The risks associated with many of these comorbid conditions may be reduced with modest weight loss. According to evidence-based guidelines from a

Nutrition and Metabolic Research Center, Scripps Clinic, San Diego, California. Address correspondence to Ken Fujioka, MD, Nutrition and Metabolic Research Center, Scripps Clinic, 12395 El Camino Real, Suite 317, San Diego, CA 92130. E-mail: [email protected] Copyright © 2002 NAASO

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National Institutes of Health (NIH) expert panel, treatment is indicated for obese patients with a body mass index (BMI) of 30 kg/m2 or higher as well as for overweight patients with a BMI of 25 to 29.9 kg/m2 (or a high waist circumference) plus two or more risk factors (1). The initial goal is to lose ⬃10% of body weight, and once this is achieved, further weight loss can be considered if indicated. To maintain weight loss, the individualized program should be continued indefinitely. This article describes the options that are available for the management of obesity.

Nonpharmacologic Treatment Options The initial treatment of obesity should focus on a diet and exercise program that has been individualized to the patient’s lifestyle and physical needs. Behavioral therapy should be implemented as an adjunct to this program. Nutrition and Diet Many different types of diets have been recommended for promoting weight loss, but regardless of which diet is selected, the total energy intake must be reduced in order for weight loss to occur. Moreover, once weight loss has occurred, the lower energy intake must be sustained to prevent weight regain. Conventional low-calorie diets are low in energy and fat content, with up to 30% of total calories derived from fat intake, and they are high in complex carbohydrate and fiber content through increased intake of whole grains, vegetables, and fruit (2). This dietary approach promotes a sustainable energy level that does not exceed energy expenditure, which is important for longterm maintenance of weight loss. Prepackaged foods may be useful in restricting caloric intake, because they help to control portion size, lead to more regular eating patterns, and may help promote adherence to the diet (3,4). Additionally, they prevent intake of calories from fat and sugar that patients may not recognize when they prepare foods themselves. Caloric restrictions of 500 to 600 kcal/d generally lead to weight loss of 0.5 kg per week and a 10% decrease in weight by 6 months (3).

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Very-low-calorie diets (VLCDs) consist of ⬍800 kcal/d and are designed to produce more rapid weight loss than conventional low-calorie diets (2). VLCDs have been reported to produce weekly weight loss of 1.5 to 2 kg in women and 2 to 2.5 kg in men (5). After 12 to 16 weeks, the average weight loss was 20 kg. In randomized controlled trials, greater weight loss was seen with VLCD than with a conventional low-calorie diet during the active phase of the study, but by 6 to 12 months, the advantage of VLCD was variable (1). VLCDs are available commercially in several formulations, including an all-liquid protein meal, a lowcarbohydrate, high-protein formulation, and a high-carbohydrate, moderate-protein formulation (2). VLCDs have been used successfully in patients with morbid obesity who were unable to undergo elective surgery because of their weight (6). As expected from the rapid weight loss, the use of VLCDs is associated with a high rate of weight regain (1). These diets should be administered under the close supervision of a physician. VLCDs are contraindicated in patients with moderate to severe liver or renal disease and should be used with special care and consideration in patients with cardiac or gallbladder disease (2). VLCDs may exacerbate osteoporosis, hyperuricemia, and gout. Low-fat diets contain ⬍20% fat and are high in carbohydrates and low to moderate in protein content (7). Obese subjects consuming these diets tend to ingest fewer calories and presumably lose weight because of the reduced energy intake. When obese subjects followed a low-calorie diet of 1200 kcal/d, the rate and amount of weight loss and the reduction in percentage of body fat did not differ significantly when dietary fat represented 10%, 20%, 30%, or 40% of the total caloric intake (8). However, several metaanalyses show that a reduction in dietary fat without restriction of energy intake produces a modest but clinically meaningful 2.5-kg weight loss in overweight subjects (9). This weight loss produces a corresponding beneficial effect on low-density lipoprotein (LDL)-cholesterol without adversely affecting other plasma lipids or cardiovascular risk factors. High-protein diets are generally higher in total fat, saturated fat, and cholesterol because of the increased protein from animal sources (10). Because these diets restrict carbohydrates, many healthful foods and nutrient sources may be eliminated. The initial weight loss with high-protein diets is because of a diuretic effect caused by the reduced carbohydrate intake. As the diet is continued, it causes metabolic ketosis, which in turn may suppress appetite and lead to lower caloric intake. Beneficial effects on plasma lipids and insulin resistance attributed to these diets are caused by weight loss and not the diet’s high protein composition. Because the added protein in these diets is not used efficiently by the body, it may impose an added burden on the kidneys and liver. High protein levels promote urinary calcium excretion; therefore, these diets may have potential for

exacerbating osteoporosis. According to a statement from the American Heart Association, high-protein diets are not harmful for most healthy individuals over the short term, but there have not been any scientific studies that document their long-term safety and effectiveness (10). Combination diets involve the use of both prepackaged foods and foods that are prepared by the patient. The prepackaged foods may be either liquid formulations or previously packaged whole food, which is purchased in a supermarket or supplied by a commercial weight-loss program. These diets aim to reduce caloric intake by 500 to 600 kcal/d. Prepackaged meals are widely available and can help patients eat a more appropriately portion-controlled meal. Physical Activity Obesity is associated closely with a sedentary lifestyle, as illustrated by the inverse relationship between body weight and the amount of physical activity (11). Exercise is a potent physiological stimulus of lipolysis, which results in the release of free fatty acids from triglycerides stored in fat for use as an energy source by muscle. Therefore, exercise increases energy expenditure, which results in a negative caloric balance. Although exercise alone may produce a 2% to 3% reduction in BMI, it is most effective when used as an adjunct to dietary therapy (1). A starting program for obese patients of 30 to 45 minutes of moderate physical activity should be encouraged at least 3 days per week, and if possible, it should be performed on most days (11). This level of physical activity will expend ⬃150 kcal daily (500 to 1000 calories per week). Unfortunately this may not be enough caloric expenditure, and 2000 or more calories burned per week may be needed to ensure weight maintenance (12). Appropriate physical activities can take any form that increases heart rate and energy expenditure. Walking is the most commonly prescribed and likely to be the most successful because of its safety and accessibility. A pedometer can be used to provide feedback concerning the number of steps or miles walked. Patients should start by walking for 10 minutes on 3 days per week and then increase the duration, frequency, and intensity of walking to the target level. The National Weight Control Registry recommends walking 4000 steps per day initially and increasing to 12,000 steps over 6 months. Regular physical activity should also be encouraged during long-term maintenance, because it is one of the most consistent traits of patients who keep their weight off. Behavioral Modification Behavioral strategies are designed to change the patient’s eating and activity habits to reinforce reductions in caloric intake and increases in physical activity (1,3). These strategies are an important component of a weight loss program because they target the barriers that often limit patient OBESITY RESEARCH Vol. 10 Suppl. 2 December 2002

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Table 1. Obesity-related comorbid disorders

Table 2. Agents used in the treatment of obesity

Coronary heart disease or other atherosclerotic disease Type 2 diabetes Sleep apnea Gynecologic abnormalities Osteoarthritis Gallbladder disease Stress incontinence Metabolic Syndrome (at least 3 of the following) Waist circumference, ⬎102 cm (men) or ⬎88 cm (women) Serum triglyceride, ⱖ150 mg/dL (106.9 mM) Blood pressure, ⱖ130/85 mm Hg Serum glucose, ⱖ110 mg/dL (6.1 mM)

Drug FDA approved for short-term use Benzphetamine hydrochloride Phendimetrazine tartrate Phentermine hydrochloride or tartrate Diethylpropion hydrochloride Mazindol FDA approved for long-term use* Sibutramine hydrochloride Ortistat Investigational agents† Bupropion Topiramate‡

Mechanism

Stimulates NE release Stimulates NE release Stimulates NE release Stimulates NE release Blocks NE reuptake Blocks NE and 5-HT reuptake Blocks gastric and pancreatic lipases Enhances NE activity Enhances GABA; blocks glutamate receptor subtypes

Adapted from Pi-Sunyer et al. (1) and Ford et al. (61).

adherence. Several behavioral strategies are commonly used: self-monitoring of eating habits and physical activity; stress management to diffuse situations that lead to overeating; stimulus control to avoid situations that lead to incidental eating; problem solving to identify weight-related problems and implement healthier alternatives; cognitive restructuring to correct unrealistic goals and inaccurate beliefs about weight loss and body image; social support from family, friends, and colleagues; and finally, relapse prevention after episodes of overeating or weight regain. Behavioral modification therapy is usually conducted in a group setting, which has the advantage of lower cost, but it can be done on a one-to-one basis with a health care practitioner. In addition, behavioral strategies can be implemented by the patient on his or her own either by recording food intake and activity in a diary or through use of selfdirected manual texts. Once behavioral therapy has ended, patients usually regain about one-third of their lost weight within the first year (3). However, regular biweekly contact with the behavioral therapy provider may help to maintain long-term weight loss (13). Cognitive-behavioral decisionmaking interventions have been shown to be more effective than traditional behavioral therapy in maintaining weight loss at 6 to 12 months, even though the initial rate of weight loss is slower (14,15).

Pharmacotherapy Antiobesity drug therapy is often useful as an adjunct for patients who cannot achieve sufficient weight loss through lifestyle and behavioral modification. These medications are approved by the Food and Drug Administration (FDA) for use in obese patients with a BMI of 30 kg/m2 or higher 118S

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* These agents are approved by the FDA for both weight loss and weight maintenance. † These agents are approved by the FDA for medical conditions other than weight loss. ‡ Exact mechanisms of action are unknown. FDA, Food and Drug Administration; NE, norepinephrine; 5-HT, serotonin; GABA, ␥-aminobutyric acid.

and in overweight patients with a BMI of 27 to 29.9 kg/m2 who have at least one obesity-related comorbidity (Table 1) (3). Most are approved only for short-term use, but sibutramine and orlistat are both approved for long-term use in weight loss and weight management (Table 2). Several investigational agents, such as bupropion and topiramate, may have beneficial effects on weight loss, but they are approved by the FDA only for medical conditions other than weight loss. Antiobesity drugs are classified on the basis of their mechanism of action—appetite suppression, altered nutrient absorption, or increased energy expenditure (16). Appetite Suppressants Currently available antiobesity drugs, with the exception of orlistat, reduce food intake through central mechanisms that suppress appetite (16,17). Most either stimulate norepinephrine release (e.g., phentermine, benzphetamine, phendimetrazine, diethylpropion) or block its reuptake into neurons (e.g., mazindol). The increased availability of norepinephrine stimulates ␤-adrenergic receptors in the hypothalamus to suppress appetite. With the exception of phentermine, these drugs are not widely used in clinical practice for weight loss (18). Phentermine is approved for use for 12 weeks in a 12-month period, but it is often used longer in clinical practice because of its relatively low cost. The only long-term randomized controlled study of phentermine in-

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volved 108 obese women who were treated with placebo or phentermine for 36 weeks in conjunction with instruction in a low-calorie diet (1000 kcal) (19). In this study, phentermine was administered at a daily dose of 30 mg either continuously or intermittently (4 weeks on followed by 4 weeks off therapy). Patients achieved significantly greater weight loss with continuous (12.2 kg) and intermittent (13.0 kg) phentermine than with placebo (4.8 kg; p ⬍ 0.01). Similar results have been seen in several shorter randomized trials (20,21). Phentermine is generally well tolerated, although some patients may experience stimulant-related symptoms, such as agitation and insomnia (17). Sibutramine is a norepinephrine and serotonin reuptake inhibitor that reduces food intake (22). Although sibutramine affects the same two neurotransmitters as phen-fen, it differs mechanistically in that it does not stimulate norepinephrine or serotonin release; rather it blocks the reuptake. Two studies have looked at the incidence of valvular heart disease and essentially did not see any difference between patients on sibutramine or placebo (23,24). Sibutramine 10 or 15 mg provided significantly greater weight loss than dietary advice alone in a 1-year study of 485 patients with BMI of 27 to 40 kg/m2 (25). Among those completing the study, weight loss averaged 4.4 kg and 6.4 kg with the 10and 15-mg doses, respectively, compared with 1.6 kg with placebo (p ⱕ 0.01). Only dry mouth occurred more frequently with sibutramine than with placebo. Withdrawal rates caused by adverse events or lack of efficacy were lower with sibutramine (14%) than placebo (21%). The efficacy of sibutramine in long-term maintenance of weight loss has also been shown in randomized controlled studies (26 –28). In one study, obese patients who lost at least 6 kg during a 4-week VLCD regimen were randomly assigned to sibutramine 10 mg or placebo for 1 year (26). Patients receiving sibutramine had a mean weight loss of 5.2 kg, whereas those in the placebo group gained 0.5 kg (p ⫽ 0.004). Three-quarters of the patients in the sibutramine group maintained all of their weight loss achieved after the VLCD compared with 42% of those in the placebo group (p ⬍ 0.01). In the Sibutramine Trial of Obesity Reduction and Maintenance (STORM), patients who had more than 5% weight loss after treatment with sibutramine 10 mg and an individualized 600 kcal/d dietary reduction for 6 months were randomly assigned to continue sibutramine or receive placebo for 18 additional months (27). Sibutramine was increased to 20 mg if weight regain occurred. Significantly more patients maintained at least 80% of their weight loss with sibutramine than with placebo (43% vs. 9%, p ⬍ 0.001). Bupropion is an antidepressant that enhances norepinephrine activity and weakly blocks dopamine reuptake. In an 8-week study of depressed patients, weight loss ⬎2.3 kg was observed in 9% and 15% of patients treated with 150-mg bupropion sustained-release (SR) tablets once and twice daily, respectively, compared with 7% of those treated

with placebo (29). It was noted subsequently that obese patients attending a weight-management program had greater success in losing weight when they were treated with bupropion (30). This prompted an 8-week study, in which 50 overweight and obese patients with BMI of 28 to 52.6 kg/m2 were randomly assigned to receive bupropion SR or placebo as an adjunct to a balanced 1600-kcal diet (31). Bupropion SR was started at 100 mg daily and then increased over 2 months to a maximal dose of 200 mg twice daily. Patients treated with bupropion SR achieved greater mean weight loss than those in the placebo group (5.0 vs. 1.2 kg; p ⫽ 0.0001). In a continuation phase, 14 patients who responded to bupropion SR continued treatment for 24 weeks and achieved mean weight loss of 12.5 kg, with nearly three-quarters of the loss coming from fat. In a classic placebo-controlled double-blind trial of bupropion SR in obese nondepressed patients, weight loss was also observed. Three hundred and twenty-seven patients were randomized to placebo, bupropion SR 300 mg, or bupropion SR 400 mg. Peak weight loss was seen at ⬃6 months; the 300-mg group lost an average of 7.2% of their weight, and the 400-mg group lost 10.1% vs. 5.15% for the placebo. At the end of 48 weeks the 300-mg group was able to maintain a 2.2% greater weight loss than the placebo group, and the 400 mg group maintained a weight loss 5.1% greater than the placebo group (31). Currently bupropion is approved for depression and smoking cessation and is not approved as a weight-loss agent. Topiramate is a structurally and pharmacologically novel anticonvulsant agent that was approved in 1996 for treatment of epilepsy. Unlike most antiepileptic agents, topiramate seems to have positive effects on weight (32). It may produce appetite suppression by blocking kainate/␣amino-3-hydroxy-5-methylisoxozole-4-propionicacid glutamate receptor subtypes, but it also has several other actions, including antagonist of voltage-gated sodium channels and modulation of ␥-aminobutyric acid-A activity (33,34). Animal pharmacology studies relevant to weight loss have demonstrated that topiramate can increase energy expenditure and reduce food intake, resulting in decreased energy deposition (35,36). These effects were associated with a selective loss of body fat and decreased levels of certain metabolic variables (e.g., leptin, insulin). At the 2002 American Diabetes Association Annual Meeting, Bray et al. (37) presented data on the dose-related effects of topiramate in obese patients. This was a 6-month randomized, placebo-controlled study of ascending doses of topiramate. In the intention-to-treat population, the greatest weight loss was seen in the patients taking the highest dose of topiramate (384 mg vs. placebo, 6.3% vs. 2.6%). Significant weight loss was also seen with lower doses of topiramate: 64 mg/d produced 5.0% weight loss, 96 mg produced 4.8%, and 192 mg produced 6.3% weight loss. For OBESITY RESEARCH Vol. 10 Suppl. 2 December 2002

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the completers, up to 8.5% weight loss was seen at the 384-mg dose of topiramate, and the weight loss was clearly dose-dependent. Topiramate has been evaluated in other obesity-related diseases, including binge-eating disorder; however, these studies were small and not randomized. Topiramate at doses ranging from 100 to 1400 mg was studied in 13 female patients with binge-eating disorder in an open-label study (33). The effect of topiramate was dose-related, with seven patients achieving weight loss in excess of 5 kg. Several case reports have also been published showing weight loss with topiramate in patients with binge-eating disorder (38); in patients gaining excessive weight on antipsychotic agents (34); and after mood stabilization in obese patients with major depression, bipolar disorder, or psychotic disorder (39 – 41). Although topiramate seems to have a positive effect on weight in the obese patient, it is currently only approved for the treatment of seizure disorders.

Increased Energy Expenditure None of the currently available prescription medications are believed to work primarily by increasing the metabolic use of calories. Ephedrine is an example of a drug that stimulates thermogenesis in humans, and it is the most common additive to over-the-counter (OTC) weight-loss products. At daily doses of 150 mg, it can cause blood pressure elevation, loss of glycemic control, and tremor (16). Since the early 1990s, it has been known that caffeine, which delays norepinephrine degradation, can work synergistically with ephedrine (46). In this study of 180 obese patients, the combination of caffeine 200 mg and ephedrine 20 mg taken three times a day produced weight loss that was 3.4% more than placebo, caffeine alone, or ephedrine alone. These compounds are OTC products and are not FDA regulated. Thus, they need to be used with extreme caution because of the sympathomimetic effects. Patients should always consult their physician before using these agents.

Altered Nutrient Absorption Orlistat potently and irreversibly inhibits gastric and pancreatic lipases to reduce systemic absorption of dietary fat (42). By blocking these enzymes, triglycerides in dietary fat cannot be metabolized into absorbable free fatty acids and monoglycerols. In a randomized controlled study, orlistat 120 mg three times daily or placebo was administered to 228 obese patients in conjunction with a low-calorie diet providing 30% of energy from fat (43). After 1 year of treatment, patients receiving orlistat lost 8.5% of their initial weight compared with 5.4% with placebo (p ⫽ 0.016). In 635 obese patients who received a nutritionally balanced diet, orlistat 60 mg three times daily and 120 mg three times daily produced significantly greater weight loss than placebo during the first year of treatment (7.1 and 7.9 kg, respectively, vs. 4.1 kg; p ⬍ 0.001) (44). Patients in each of the three groups gained weight during the second year, but those in the orlistat groups sustained more of their weight loss (p ⬍ 0.001). At the end of 2 years, patients treated with orlistat had lost ⬃5% of their initial weight. The effect of orlistat in weight maintenance was evaluated in 729 obese subjects who lost at least 8% of their body weight with a low-calorie diet during a 6-month lead-in phase (45). Successful patients were randomly assigned to receive placebo or orlistat 30, 60, or 120 mg three times daily in combination with a maintenance diet designed to prevent weight regain. After 1 year, patients receiving orlistat 120 mg three times daily regained significantly less weight than those in the placebo group (33% vs. 59%; p ⬍ 0.001). The lower doses did not differ significantly from placebo. In these studies, only gastrointestinal adverse events occurred more commonly with orlistat than placebo. These events, which were mostly related to loose stools and increased fecal urgency, were generally mild to moderate and resolved without intervention.

Beneficial Effects of Antiobesity Drugs on Other Risk Factors Weight loss has beneficial effects on other cardiovascular risk factors, including blood glucose, blood pressure, and lipid levels. Both sibutramine and orlistat have been shown to produce greater weight loss than placebo in obese patients with type 2 diabetes, and this was accompanied by a reduction in hemoglobin A1c and fasting blood glucose (47– 49). In a pooled analysis of three trials, treatment with orlistat 120 mg three times daily for 2 years significantly improved glucose tolerance and delayed progression from impaired glucose tolerance to type 2 diabetes (50). In clinical trials, orlistat produced small reductions in blood pressure in proportion to weight loss. Sibutramine also lowered blood pressure, but the magnitude was usually less than expected from weight loss because of its augmentation of norepinephrine action (51). Moreover, it is important to recognize that some patients may experience a rise in blood pressure at the start of sibutramine therapy. Because orlistat reduces fat absorption, an added benefit on lipid levels over and above that provided by weight loss may be expected. In clinical trials, orlistat lowered total and LDL cholesterol, relative to placebo, by 3% to 9% and 3% to 13%, respectively, but it had a variable effect on high-density lipoprotein (HDL)-cholesterol and triglyceride levels (50). In studies with sibutramine, total and LDL-cholesterol were essentially unchanged relative to placebo, but HDL-cholesterol increased, and in some studies, triglycerides declined relative to placebo (26,27,52).

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Treatment Considerations Most antiobesity medications produced 5% to 10% weight loss in clinical trials, which is likely to be of significant medical benefit even if the patient has not reached his or her desirable body weight (16). Obesity is a chronic

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disease, as evidenced by the high likelihood of weight regain, and consequently a long-term approach to treatment is needed. Only sibutramine and orlistat are approved by the FDA for long-term use in weight loss and maintenance. Both were more effective than placebo in sustaining weight loss in clinical trials lasting 1 year or longer (26,27,45). In comparison, the evidence supporting the use of investigational agents, such as bupropion and topiramate, is limited to short-term studies or case reports. If an investigational agent is prescribed, clinicians should adequately inform their patients from a liability perspective that the drug has not been approved as a weight-loss medication. Reimbursement should also be considered, because it may vary from 10% to 30% depending on the type of insurance. Clinicians must learn to recognize treatment failure and alter the drug therapy regimen. Patients who do not lose at least 4 lbs during the first 4 to 8 weeks of therapy should be considered nonresponders to that medication (16). In this situation, the medication should be stopped and another antiobesity drug should be considered. Once a patient has lost a significant amount of weight, it becomes important to sustain the weight loss. Even if the patient does not lose additional weight, it is appropriate to continue the medication as part of a weight-maintenance program. Nonprescription Products for Weight Loss Over-the-counter weight-loss products are more widely used than prescription drugs. In the Behavioral Risk Factor Surveillance System, a population-based telephone survey of more than 14,000 adults conducted in 1998, 7% reported use of nonprescription weight-loss products, with 2% reporting use of phenylpropanolamine products and 1% reporting use of ephedrine products (53). Use of nonprescription products was particularly high among young obese women (28.4%) and among those receiving prescription antiobesity medications (33.8%). Clinicians must be aware that many of their patients may be using OTC products concomitantly with prescription antiobesity drugs. The safety of phenylpropanolamine and ephedrine is of concern, and this concern led to withdrawal of phenylpropanolamine from the OTC market. Several herbal dietary supplements that contain ephedrine and caffeine have recently been evaluated in randomized clinical trials. Ma Huang-Guarana at a daily dose of 72 mg ephedrine alkaloids and 240 mg caffeine produced significantly greater loss of weight (4.0 vs. 0.8 kg; p ⬍ 0.001) and fat (2.1 vs. 0.2%; p ⫽ 0.006) than placebo in an 8-week study of 67 subjects with BMI of 29 to 35 kg/m2 (54). However, mean systolic blood pressure increased above baseline by 4 mm Hg at weeks 2 to 6 and returned to baseline at the final assessment. Moreover, heart rate increased significantly relative to placebo (⫹6.9 vs. ⫺17 bpm; p ⬍ 0.001). Eight subjects discontinued the dietary supplement within the first 2 weeks because of adverse

events—two for elevated blood pressure, four for palpitations, one for palpitations with chest pain, and one for extreme irritability. Ma Huang (active ingredient ephedra) also has been evaluated in combination with a Kola nut supplement providing a daily dose of 90 mg of ephedrine alkaloids and 192 mg of caffeine in a 6-month randomized controlled study of 167 subjects (55). The supplement was significantly better than placebo in weight loss (5.3 vs. 2.6 kg; p ⬍ 0.001) and fat loss (4.3 vs. 2.7 kg; p ⫽ 0.02). It lowered LDL-cholesterol by 8 mg/dL and increased HDL-cholesterol by 2.7 mg/dL, but significant increases in blood pressure (3 mm Hg) and heart rate (4 bpm) were again seen. Thus, the ephedrine-based supplements seem effective in promoting short-term weight loss, although the cardiovascular safety of these products remains a concern.

Surgery According to the NIH Consensus Statement for Severe Obesity, patients with BMI ⱖ 40 kg/m2 and those with BMI of 35 to 40 kg/m2 who have high-risk comorbid conditions or significant obesity-related physical conditions that interfere with their lifestyle may be considered as candidates for surgery (56). Weight-loss surgery should be reserved for patients in whom other methods have failed (57). Two surgical procedures may be considered: vertical banded gastroplasty, in which a small pouch with a restricted outlet is constructed along the lesser curvature of the stomach (58), and gastric bypass, in which a proximal gastric pouch is constructed whose outlet is a Y-shaped limb of the small intestine (59). A meta-analysis of surgical interventions demonstrated a reduction in BMI of 16.4 kg/m2 at 12 months and an overall reduction of 13.3 kg/m2 at the latest follow-up assessment (60). Gastric bypass is performed more often than vertical banded gastroplasty because it provides greater weight loss (59). In general, gastric bypass is associated with 35% weight loss during the first 18 to 24 months, but most patients regain 10% of their lost weight by the third or fourth year after surgery (59). However, weight loss is generally well maintained.

Summary Once a proper evaluation and risk assessment is complete, a weight-loss program tailored to the patient’s weightloss goals and level of motivation should be implemented. Any successful weight-loss program should include dietary guidelines to create an energy deficit during active weight loss and an exercise regimen to help during weight maintenance. Behavioral therapy is effective when used in combination with lifestyle modifications. For patients who cannot achieve or maintain the desired weight loss, antiobesity drug therapy should be considered. When choosing a drug therapy, risks of the medication should be weighed against OBESITY RESEARCH Vol. 10 Suppl. 2 December 2002

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the benefits that may result from the expected weight loss. Appropriate patient selection is an important factor in determining which patients should receive antiobesity drug therapy. Surgery should be reserved for severely obese patients with significant medical comorbidities or physical conditions that have failed nonsurgical attempts.

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