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Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
I. Introduction II. Using the Currently Available Drugs III. Drugs Approved by the U.S. Food and Drug Administration or the European Medicinal Evaluation Agency for Treatment of Overweight Patients A. Drugs Approved for Long-Term Use 1. Orlistat. a. Mechanism of action. b. Long-term studies. c. Studies in special populations. d. Meta-analysis of orlistat studies. e. Safety considerations. 2. Sibutramine. a. Mechanism of action. b. Long-term studies. c. Studies in special populations. d. Meta-analysis of sibutramine studies. e. Combining sibutramine and orlistat. f. Dosage and safety considerations. 3. Rimonabant. a. Mechanism of action. b. Long-term studies. c. Studies in special populations. d. Safety considerations. e. Other cannabinoid antagonists. B. Drugs Approved by the U.S. Food and Drug Administration for Short-Term Treatment of Overweight Patients 1. Sympathomimetic Drugs. a. Mechanism of action. b. Clinical studies. IV. Antidepressant and Antiepileptic Drugs That Produce Weight Loss but Are Not Approved by the U.S. Food and Drug Administration for Weight Loss A. Fluoxetine and Sertraline 1. Mechanism of Action. 2. Clinical Studies. B. Bupropion 1. Mechanism of Action. 2. Clinical Studies for Weight Loss. C. Topiramate 1. Mechanism of Action. 2. Clinical Studies for Weight Loss. 3. Special Situations. D. Zonisamide 1. Mechanism of Action. 2. Clinical Studies for Weight Loss. E. Lamotrigine 1. Mechanism of Action. 2. Clinical Studies. V. Drugs Approved by the U.S. Food and Drug Administration for Uses Other Than Overweight A. Metformin 1. Mechanism of Action. 2. Clinical Studies. B. Pramlintide 1. Mechanism of Action. 2. Clinical Studies. C. Exenatide 1. Mechanism of Action. 2. Clinical Studies with Weight Loss as a Component. D. Somatostatin 1. Mechanism of Action. 2. Clinical Studies for Weight Loss. E. Atomoxetine 1. Mechanism of Action. 2. Clinical Study for Weight Loss. F. Growth Hormone and Growth Hormone Fragment 1. Mechanism of Action. 2. Clinical Studies on Body Composition. VI. Drugs with Clinical Data or in Clinical Studies A. Leptin 1. Mechanism of Action. 2. Clinical Studies. B. Neuropeptide Y Receptor Antagonists 1. Mechanism of Action. 2. Clinical Studies. C. Serotonin 2C Receptor Agonists 1. Mechanism of Action. 2. Clinical Studies. D. Peptide YY3-36 1. Mechanism of Action. 2. Clinical Studies. E. Oxyntomodulin 1. Mechanism of Action. 2. Clinical Studies. F. Pancreatic Lipase Inhibitor 1. Mechanism of Action. 2. Clinical Studies. G. Cholecystokinin H. Combination of Bupropion and Naltrexone (Contrave) I. Combination of Bupropion and Zonisamide (Empatic) J. Combination of Topiramate and Phentermine (Qnexa) VII. Drugs in the Early Phases of Development A. Melanin-Concentrating Hormone Receptor-1 Antagonist B. Histamine-3 Receptor Antagonists C. Ghrelin Antagonists D. Angiogenesis Antagonists and Fat Cell Antibodies VIII. Drugs and Herbal Medications No Longer under Investigation or Withdrawn A. Ephedra B. beta3-Adrenergic Agonists C. Bromocriptine D. Ecopipam E. Axokine IX. Over-the-Counter Medications A. Orlistat B. Phenylpropanolamine X. Herbal Products, Functional Foods, and Nutriceuticals A. Interventions Requiring Special Training 1. Acupuncture/Acupressure. 2. Homeopathy. 3. Hypnotherapy. B. Minerals and Metabolites 1. Chromium Picolinate. 2. Hydroxymethyl Butyrate. 3. Pyruvate. 4. Conjugated Linoleic Acid. 5. Calcium. C. Herbal Dietary Supplements 1. Ephedra sinica. 2. Green Tea Extract. 3. Garcinia cambogia. 4. Yohimbine from Pausinystalia yohimbe. 5. Hoodia. 6. Citrus aurantium (Bitter Orange). 7. Ayurvedic Preparations. D. Fibers 1. Chitosan. 2. Glucomannan. 3. Guar Gum. 4. Plantago psyllium. XI. Conclusions
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I. Introduction |
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Physicians have several strategies for confronting the problems of the overweight patient. The physician can counsel the patient that he or she is concerned about the patient's current level of body weight and can initiate treatment if the patient is interested. Alternatively, if a physician feels uncomfortable with addressing overweight in patients, he or she can ignore the problem and hope that the patient will not raise the issue. Or, finally the physician can wait until the complications of excess weight manifest themselves as diabetes, dyslipidemia, hypertension, or other disorders and then institute appropriate therapy for each of these medical problems. With the current high-quality therapies available to treat diabetes mellitus, dyslipidemia, and hypertension, many physicians would prefer this latter strategy.
However, if medical treatment of the overweight patient were more effective, physicians might prefer to treat the excess weight and thus delay the onset of the problems related to overweight. This strategy was the basis for the long-term Diabetes Prevention Program (DPP)1 and the Swedish Obese Subjects Study. In the DPP, the onset of new cases of diabetes among individuals with impaired glucose tolerance was reduced 55% during an average follow-up of 3.2 years in the group who lost weight compared with the control group who did not lose weight (Knowler et al., 2002
). In the Swedish Obese Subjects Study, the incidence of new cases of diabetes was reduced to zero over 2 years in patients who lost weight and maintained a weight loss of 
12%, compared with an incidence of 8.5% for new cases of diabetes in those who did not lose weight (Sjostrom et al., 2004). Thus, effective treatment of the overweight patient at risk for diabetes or hypertension can reduce the risk of developing these serious diseases in the future.
One reason most physicians are reluctant to treat overweight patients is that the treatments are limited in number and effectiveness. At the time this article was written, there were only two drugs approved by the U.S. Food and Drug Administration for long-term use. As monotherapy, these agents can produce an overall weight loss of 8 to 10% among patients who continue to take the medication for >6 months. However, to achieve the elimination of new cases of diabetes as noted above, the weight loss needs to exceed 12%, a goal that is not usually achieved with current monotherapy. Thus, there is a great need for new drugs to be used as monotherapy and probably in combinations when prevention fails.
Both physicians and patients know that overweight is a stigmatized disease (Puhl and Brownell, 2003). One commonly held view is that overweight people are lazy and weak-willed. If fat people just had willpower, they would push themselves away from the table and not be overweight. This widely held view is shared by the public and by health professionals alike. The clamoring of women to be lean and well proportioned supports this view. The declining relative weight of centerfold models in Playboy magazine and of women who are winners of the Miss America contest in the latter part of the 20th century also supports this view. Many physicians just do not like to see overweight patients come into their offices. This attitude poses a major challenge to any efforts to improve the lot of people who are overweight.
There can be both medical and cosmetic (self-image) benefits to weight loss. However, they do not necessarily occur together. For example, a 10% weight loss, which would be clinically significant for a 300-pound (145-kg) person, would only reduce body weight by 30 to 270 pounds, a weight change that many people might not notice and would not be considered a cosmetic success. At the other extreme, a 10% weight loss for an individual weighing 150 pounds would lower his or her weight to 135 pounds, which would have a very positive impact on self-image. We also know that cosmetically significant weight losses may not produce clinically significant effects. After liposuction that removed 
7% of body weight, there were no improvements in health-related risk factors. These distinctions are shown in Table 1.
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Three other issues aggravate the problem of treating overweight patients. The first is the "negative halo" that surrounds the use of appetite suppressants because amphetamine is addictive. There was never any evidence that dexfenfluramine was addictive. Nonetheless, the drug was scheduled by the U.S. Drug Enforcement Agency as a Schedule IV drug because, on paper, it had chemical similarities to amphetamine.
The second issue is the concern about the plateau of body weight that is reached when homeostatic mechanisms in the body come into play and stop further weight loss. There is an analogy with treatment of hypertension. When an antihypertensive drug is given, blood pressure drops and then stops falling within a few weeks to reach a plateau at a new lower level. The antihypertensive drug has not lost its effect when the plateau occurs, but its effect is being counteracted by physiological mechanisms designed to maintain blood pressure. In the treatment of overweight patients, a similar plateau in body weight is often viewed as a therapeutic failure for the weight loss drug. This is particularly so when weight is regained after the drug is stopped. These attitudes and biases need to change before any effective new therapy will become widely accepted.
The final issue is the toxicity associated with many antiobesity drugs. The disaster that occurred for some of the patients who took the combination of fenfluramine and phentermine is one example (others are listed in Table 2). Aortic regurgitation occurred in up to 25% of the patients treated with this combination of drugs and led many physicians to say, "I told you so" and "I'm certainly glad I didn't use those drugs." This issue has largely subsided with time, but there will always remain a residue of concern among some physicians and among regulators about the potential problems that might surface when new treatments for overweight are made available to the public. Although the drug treatment of overweight patients has at least a century-long history (Colman, 2005), progress in drug discovery was given a new impetus by the discovery of leptin in 1994 (Zhang et al., 1994). This peptide demonstrated that overweight can be caused by a hormone deficiency and be reversed by replacement of that hormone (Halaas et al., 1995; Maffei et al., 1995; Farooqi et al., 2002). Even before the discovery of leptin, overweight had been declared to be a chronic disease by a National Institutes of Health Consensus Conference in 1985 (Bray, 2004). In the 20th century, bad eating habits were considered a primary cause for overweight. Because some bad habits can be behaviorally extinguished over a 12-week period of time, overweight medications approved before 1985 were approved for periods up to 12 weeks as an adjunct to a lifestyle change program. Equating overweight with bad habits and the stigmatization of obesity slowed the use of overweight medications chronically, as is done with medications for other chronic diseases (Puhl and Brownell, 2003). With the recognition that longer-term therapy was needed, clinical trials have been extended in length. Since 1990, only three medications have been approved for the chronic treatment of overweight, and one of them, dexfenfluramine, was withdrawn 2 years later (Anonymous, 1996).
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II. Using the Currently Available Drugs |
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; National Heart, Lung, and Blood Institute and North American Association for the Study of Obesity, 2000; Haddock et al., 2002; Yanovski and Yanovski, 2002; Kim et al., 2003; Padwal et al., 2004, 2005; Colman, 2005; Li et al., 2005; Snow et al., 2005; Vettor et al., 2005).
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As a guide for the use of medications, we will use an algorithm that was described by the National Heart, Lung, and Blood Institute. The first step in this algorithm is to measure height, weight, and waist circumference to establish the body mass index (BMI) and the degree of central adiposity. If the BMI, ([weight in kilograms divided by the square of the height in meters] or [weight in pounds divided by square of the height (inches)] x 703] is >30 kg/m2 the patient is by definition obese and can be considered for medications. Overweight individuals with a BMI between 27 and 30 kg/m2 may also be considered if they have diabetes, hypertension, sleep apnea, or another medical condition that would benefit from weight loss.
Waist circumference is also an important indicator of risk from excess fat. The currently recommended upper limit for waist circumference in the United States is 102 cm (40 inches) for a man and 88 cm (35 inches) for a woman. A recent proposal from the International Diabetes Federation requires the presence of central adiposity to diagnose the metabolic syndrome and uses values for waist circumference >80 cm for females and >94 cm for males. Another important initial step in evaluating the overweight patient is to assess associated (comorbid) conditions by measuring blood pressure, glucose, lipids and, when indicated, by performing other tests. With results from this laboratory panel and waist circumference, the metabolic syndrome can be diagnosed. This is best done with the criteria from the National Cholesterol Education Panel Adult Treatment III Guidelines (Table 4).
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Once the patient has been established as an appropriate candidate to lose weight and he or she is motivated to do so, the next step is to set a weight loss goal. Most patients have an unrealistic view of how much weight they can lose. For them, a weight loss of <15% is often viewed as a failure. In contrast, weight loss using monotherapy with the drugs that are currently available is not usually >10%. It is, thus, important for physician and patient alike to set a weight loss goal for initial therapy that is not >10% and to set a lower limit for weight loss of <5%, which will suggest that an alternative strategy is needed.
The next step is to be certain that the patient is "ready" to lose weight. With use of ideas from psychology, the patient must be ready to work on weight loss as opposed to not yet thinking about the problem. Once the weight goal is established and patients are prepared to take charge of their weight loss program, the next steps are to help them develop lifestyle changes that will benefit their program. The most important of these is monitoring what they eat, where they eat it, and under what circumstances they eat. A second element is to provide advice on diet and physical activity. Replacing voluntary choices with "portion-controlled" choices at one or more meals can be helpful. There are frozen foods, ready-to-make food items, and canned meal replacements that can be used for this purpose. Patients also need more exercise. One strategy is to have them get a step-counter and record the number of steps they take with the goal of gradually increasing this number to 10,000 steps/day. In a review of lifestyle treatment used with pharmacotherapy in randomized clinical trials Poston et al. (2001) found that balanced-deficit diets were used in 40.7%, low-calorie diets in 25% and self-monitoring behavioral strategies in 23.1% of patients (Poston et al., 2001). When a patient returns to you, establish whether he or she has met the goals. If so, the patient continues as is, but if after 3 months he or she fails to meet the goals, then medications may be considered. The next step is to discuss the pros and cons of medication with the patient. An algorithm from the American College of Physicians (Snow et al., 2005) recommends six medications: orlistat, sibutramine, phentermine, diethylpropion, fluoxetine, and bupropion. The first four have been approved by the U.S. Food and Drug Administration for treatment of overweight patients, but fluoxetine and bupropion have not, and they should not be used primarily for this purpose. In our view, fluoxetine and bupropion should only be used for weight loss in special situations. Fluoxetine is appropriate for the overweight patient who is depressed. Bupropion may also be helpful in reducing or preventing weight gain when people try to stop smoking and when they are depressed.
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III. Drugs Approved by the U.S. Food and Drug Administration or the European Medicinal Evaluation Agency for Treatment of Overweight Patients |
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1. Orlistat.
a. Mechanism of action.
Orlistat is a lipase inhibitor. In pharmacological studies, it was shown to be a potent selective inhibitor of pancreatic lipase and to thus reduce the intestinal digestion of fat. The drug has a dose-dependent effect on fecal fat loss, increasing it to 30%. Thus, orlistat is recommended to be used with a diet that has 30% of its energy as fat. Orlistat has little effect in subjects eating a low-fat diet, as might be anticipated from its mechanism of action. In single-dose randomized and placebo-controlled studies, 120 mg of orlistat was shown to increase glucagon-like peptide-1 (GLP-1) and C-peptide more than placebo (Damci et al., 2004), to increase fecal fat loss but decrease the acute increase in cholecystokinin (O'Donovan et al., 2003), but not to influence the behavioral measures of satiety (Goedecke et al., 2003).
b. Long-term studies.
Results of a number of 1- to 2-year long-term clinical trials with orlistat have been published. The results of a 2-year trial are shown in Fig. 1 (Sjostrom et al., 1998). The trial consisted of two parts. In the 1st year, patients received a hypocaloric diet calculated to be 500 kcal/day less than the patient's requirements. During the 2nd year, the diet was calculated to maintain body weight. By the end of year 1, the placebo-treated patients lost -6.1% of their initial body weight and the drug-treated patients lost -10.2%. The patients were randomized again at the end of year 1. Those switched from orlistat to placebo gained weight from -10 to -6% below baseline. Those switched from placebo to orlistat lost weight from -6 to -8.1% below baseline, which was essentially identical to the -7.9% weight loss in the patients treated with orlistat for the full 2 years.
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). One group received placebo throughout the 2 years (97 patients), and a second group received orlistat (120 mg three times per day) for 2 years (109 patients). At the end of 1 year, the dose for two-thirds of the group treated with orlistat for 1 year was changed to 60 mg three times per day (102 patients), and the others were switched to placebo (95 patients) (Davidson et al., 1999). After 1 year, the weight loss was -8.67 kg in the orlistat-treated group and -5.81 kg in the placebo group (P < 0.001). During the 2nd year, those switched to placebo after 1 year reached the same weight as those treated with placebo for 2 years (-4.5% in those treated with placebo for 2 years and -4.2% in those switched to placebo during year 2).
In a third 2-year study, 783 patients remained in the placebo or orlistat-treated groups at 60 or 120 mg three times per day for the entire 2 years (Rossner et al., 2000). After 1 year with a weight-loss diet, the placebo group lost -7 kg, which was significantly less than the -9.6 kg lost by the group treated with orlistat 60 mg three times daily or the -9.8 kg lost by the group treated with 120 mg of orlistat three times daily. During the 2nd year, when the diet was liberalized to a "weight maintenance" diet, all three groups regained some weight. At the end of 2 years, the patients in the placebo group were -4.3 kg below baseline, the patients treated with 60 mg of orlistat three times per day were -6.8 kg below baseline, and the patients who took 120 mg of orlistat three times per day were -7.6 kg below baseline.
The final 2-year trial evaluated 796 subjects in a general-practice setting (Hauptman, 2000). After 1 year of treatment with 120 mg of orlistat three times per day, the orlistat-treated patients (n = 117) lost -8.8 kg, compared with -4.3 kg in the placebo group (n = 91). During the 2nd year, when the diet was liberalized to "maintain body weight," both groups regained some weight. At the end of 2 years, the orlistat group was -5.2 kg below their baseline weight compared with -1.5 kg below baseline for the group treated with placebo.
The pooled 2-year data from these four studies are shown in Fig. 2. This figure contains information on both the 120- and 60-mg-three-times-a-day doses. It is clear that there is a dose response. The maximal weight loss was achieved between 6 and 9 months, and then there was a slow regain in all of the groups during the rest of the study.
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). A total of 3304 overweight patients, 21% of whom had impaired glucose tolerance, were included in this Swedish trial (Fig. 3). The lowest body weight was achieved during the 1st year: >-11% below baseline in the orlistat-treated group and 6% below baseline in the placebo-treated group. Over the remaining 3 years of the trial, there was a small regain in weight, such that by the end of 4 years, the orlistat-treated patients were -6.9% below baseline compared with -4.1% for those receiving placebo. The trial also showed a 37% reduction in the conversion of patients from impaired glucose tolerance to diabetes; essentially all of this benefit occurred in the patients with impaired glucose tolerance when they were enrolled into the trial.
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). Patients were enrolled if they had lost >8% of their body weight over 6 months while eating a 1000 kcal/day (4180 kJ/day) diet. The 729 patients were randomized to receive placebo or orlistat at 30, 60, or 120 mg three times per day for 12 months. At the end of this time, the placebo-treated patients regained 56% of their body weight, compared with 32.4% in the group treated with 120 mg of orlistat three times per day. The other two doses of orlistat were no different from placebo in preventing the regain of weight.
c. Studies in special populations.
i. Diabetic patients.
Patients with diabetes treated with orlistat, 120 mg three times daily for 1 year, lost more weight than the placebo-treated group (Hollander et al., 1998; Kelley et al., 2002; Miles et al., 2002). The subjects with diabetes also showed a significantly greater decrease in hemoglobin A1c levels. In another study of orlistat and weight loss, investigators pooled data on 675 subjects from three of the 2-year studies described previously in which glucose tolerance tests were available (Heymsfield et al., 2000). During treatment, 6.6% of the patients taking orlistat converted from a normal to an impaired glucose tolerance test, compared with 10.8% in the placebo-treated group. None of the orlistat-treated patients who originally had normal glucose tolerance developed diabetes, compared with 1.2% in the placebo-treated group. Of those who initially had normal glucose tolerance, 7.6% in the placebo group but only 3% in the orlistat-treated group developed diabetes.
The effect of orlistat in preventing diabetes has been assessed in a 4-year study (Torgerson et al., 2004). In this trial weight was reduced by 2.8 kg (95% CI 1.1–4.5 kg) compared with placebo, and the conversion rate to diabetes was reduced from 9 to 6% for a relative risk reduction of 0.63 (95% CI 0.46–0.86) (Padwal et al., 2005).
ii. Metabolic syndrome and lipids.
In a further analysis, patients who participated in the studies described above were divided into the highest and lowest quintiles for triglycerides and HDL cholesterol levels (Reaven et al., 2001). Those with high triglyceride and low HDL cholesterol levels were labeled "syndrome X," and those with the lowest triglyceride levels and highest HDL cholesterol levels were the "nonsyndrome X" controls. With this classification, there were almost no men in the nonsyndrome X group, compared with an equal sex breakdown in the syndrome X group. In addition, the syndrome X group had slightly higher systolic and diastolic blood pressure levels and a nearly 2-fold higher level of fasting insulin. Besides weight loss, the only difference between the placebo and orlistat-treated patients was the decrease in LDL cholesterol levels in the patients treated with orlistat. However, the syndrome X subgroup showed a significantly greater decrease in triglyceride and insulin levels than those without syndrome X. Levels of HDL cholesterol increased more in the syndrome X group, but LDL cholesterol levels showed a smaller decrease than that in the nonsyndrome X group. All of the clinical studies with orlistat have shown significant decreases in serum cholesterol and LDL cholesterol levels that usually are greater than decreases that can be accounted for by weight loss alone (Bray and Greenway, 1999). One study showed that orlistat reduces the absorption of cholesterol from the GI tract, thus providing a mechanism for the clinical observations (Mittendorfer et al., 2001).
iii. Studies in children.
A multicenter trial tested the effect of orlistat in 539 obese adolescents (Chanoine et al., 2005). Subjects were randomized to placebo or 120 mg of orlistat three times a day and a mildly hypocaloric diet containing 30% fat. By the end of the study BMI decreased -0.55 kg/m2 in the drug-treated group but increased +0.31 kg/m2 in the placebo group. By the end of the study, weight increased by only +0.51 kg in the orlistat-treated group, compared with +3.14 kg in the placebo-treated group (Fig. 4). This difference was due to differences in body fat. The side effects were gastrointestinal in origin, as expected from the mode of action of orlistat. A second small 6-month randomized clinical trial from a single site failed to show a difference resulting from treatment with orlistat in a population of 40 adolescents (Maahs et al., 2006).
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; Avenell et al., 2004; Li et al., 2005). By pooling six studies Haddock et al. (2002) estimated the weight loss in patients treated with orlistat to be -7.1 kg (range -4.0 to -10.3 kg) compared with -5.02 kg (range -3.0 to -6.1 kg) for the placebo-treated groups. In the meta-analysis of Li et al. (2005), the overall mean difference between orlistat and placebo after 12 months of therapy in 22 studies was -2.70 kg (95% CI -3.79 to -1.61 kg). Because this analysis included diabetic and nondiabetic subjects, we have summarized the data from the five 2-year studies in Table 5.
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In another meta-analysis of orlistat, 8-year-long studies, only one of which was in diabetic subjects, examined the effects of weight loss at 1 and 2 years and on the various laboratory and clinical responses. The overall effect of orlistat on weight loss at 12 months using the weighted mean difference was -3.01 kg (95% CI -3.48 to -2.54 kg) (Table 6). After 24 months, the overall effect of orlistat on weight loss was -3.26 kg (95% CI -4.15 to -2.37 kg). In terms of weight maintenance, the overall effect of orlistat after 12 months was -0.85 kg (95% CI -1.50 to -0.19 kg) (Davidson et al., 1999; Hill et al., 1999; Hauptman, 2000; Rossner et al., 2000). The pooled data show significant overall effects after 1 year of treatment on the change in cholesterol [-0.34 mM (95% CI -0.41 to -0.027)] (n = 7 studies), the change in LDL cholesterol [-0.29 mM (95% CI -0.34 to -0.24)] (n = 7 studies), the change in HDL cholesterol [-0.03 mM (95% CI -0.05 to -0.01)] (n = 6 studies), the change in triglycerides [0.03 mM (95% CI -0.04 to 0.10)] (n = 6 studies), the change in hemoglobin A1c [-0.17% (95% CI -0.24 to -0.10] (n = 3 studies) (Hollander et al., 1998; Lindgarde, 2000; Broom et al., 2002), the change in systolic blood pressure [-2.02 mm Hg (95% CI -2.87 to -1.17)] (n = 7 studies), and the change in diastolic blood pressure [-1.64 mm Hg (95% CI -2.20 to -1.09)] (n = 7 studies)]. In a meta-analysis focused on the use of orlistat in diabetics Norris et al. (2004) reported a weighted mean difference in favor of orlistat of -2.6 kg (95% CI -3.2 to -2.1) after 52 to 57 weeks of treatment.
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e. Safety considerations.
Orlistat is not absorbed to any significant degree from the gastrointestinal tract, and its side effects are thus related to the blockade of triglyceride digestion in the intestine (Zhi et al., 1999). Fecal fat loss and related GI symptoms are common initially, but they subside as patients learn to use the drug (Bray and Greenway, 1999). The quality of life in patients treated with orlistat may improve despite concerns about GI symptoms. Orlistat can cause small but significant decreases in fat-soluble vitamins. Levels usually remain within the normal range, but a few patients may need vitamin supplementation. Because it is impossible to tell which patients need vitamins, it is wise to provide a multivitamin routinely with instructions to take it before bedtime. Orlistat does not seem to affect the absorption of other drugs, except cyclosporin.
2. Sibutramine.
a. Mechanism of action.
Sibutramine is a highly selective inhibitor for the reuptake at nerve endings of norepinephrine and serotonin and, to a lesser degree, dopamine. In preclinical experimental and clinical studies, it reduced food intake. In a double-blind placebo-controlled 2-week trial, a 30-mg/day dose of sibutramine reduced food intake by 23% on day 7 and 26% on day 14 relative to placebo and also decreased the percentage of fat eaten. A smaller dose of 10 mg also significantly reduced food intake at 14 days (Rolls et al., 1998). The effect of sibutramine on food intake has also been examined over a longer period of time (Barkeling et al., 2003). The first 2 weeks of this 10-month trial were conducted in a double-blind, randomized, placebo-controlled, crossover design. Participants then entered a 10-month open-label trial with repeat food intake at the end. There was a 16% reduction in energy intake at the test lunch in the first part of the study (after 2 weeks). Ten months later, there was still a 27% reduction compared with participants' preweight loss placebo-treatment food intake. In animals, sibutramine also stimulates thermogenesis, but there are conflicting data in humans (Hansen et al., 1998; Seagle et al., 1998). Mechanistic studies have shown that the effect of sibutramine can be mimicked by combining a selective serotonin reuptake inhibitor (fluoxetine) with a selective norepinephrine reuptake inhibitor (nisoxetine). When injected alone these specific reuptake inhibitors do not replicate the reduction of food intake produced by sibutramine (Jackson et al., 1997). Sibutramine treatment of experimental animals increased the activity of the sympathetic nervous system and attenuated the rise in NPY and fall in POMC in the arcuate nucleus in energy-restricted rats indicating that this drug influences both monoamine and peptidergic pathways involved in food intake (Levin and Dunn-Meynell, 2000).
b. Long-term studies.
Sibutramine has been approved by the U.S. Food and Drug Administration for long-term use in the treatment of overweight patients. Sibutramine has been evaluated extensively in several multicenter trials lasting 6 to 24 months. In a 6-month dose-ranging study of 1047 patients, 67% treated with sibutramine achieved a 5% weight loss from baseline, and 35% lost 10% (Bray and Greenway, 1999). There was a clear dose-response effect in this 24-week trial, and patients regained weight when the drug was stopped, indicating that the drug remained effective when used. Data from this multicenter trial are shown in Fig. 5 (Bray et al., 1999). In a 1-year trial of 456 patients who received sibutramine (10 or 15 mg/day) or placebo, 56% of those who stayed in the trial for 12 months lost at least 5% of their initial body weight, and 30% of the patients lost 10% of their initial body weight while taking the 10-mg dose (Smith and Goulder, 2001).
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; James et al., 2000; Mathus-Vliegen, 2005). In a multicenter trial, participants were initially given a very low-calorie diet (VLCD) for 6 weeks to induce weight loss (Apfelbaum et al., 1999). Of the initial 181 subjects enrolled, 142 were randomized to either 10 mg/day of sibutramine or placebo after losing -6 kg or more with the VLCD. After another 12 months, those receiving the drug lost an additional 6.4 kg compared with a small weight gain of +0.2 kg for those receiving placebo. The authors concluded that sibutramine had effectively enhanced the initial weight loss and maintained it for an additional 12 months.
This was followed by the Sibutramine Trial of Obesity Reduction and Maintenance (STORM) Trial that lasted 2 years and provided evidence for weight maintenance (James et al., 2000) (Fig. 6). Seven centers participated in this study, in which patients were initially enrolled in an open-label phase and treated with 10 mg/day of sibutramine for 6 months. Of the patients who lost >8 kg, two-thirds were then randomized to sibutramine and one-third to placebo. During the 18-month double-blind phase of this trial, the placebo-treated patients steadily regained weight, maintaining only 20% of their weight loss at the end of the trial. In contrast, the subjects treated with sibutramine maintained their weight for 12 months and then regained an average of only 2 kg, thus maintaining 80% of their initial weight loss after 2 years (James et al., 2000). Despite the higher weight loss with sibutramine at the end of the 18 months of controlled observation, the blood pressure levels of the sibutramine-treated patients were still higher than those of the patients treated with placebo.
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10 kg during 3 months and were randomized to 10 mg/day of sibutramine or placebo for the remaining 15 months. Mean weight loss during the VLCD period for the successful subjects was 14.5% from baseline. After 2 additional months of treatment in the hospital clinic, the final 13 months were conducted in the general practitioner's offices. At 18 months, the odds ratio was 1.76 (95% CI 1.06–2.93) favoring weight loss with sibutramine (P = 0.03). With use of the intent-to-treat analysis, >80% of the weight loss at the end of the VLCD was maintained by 70, 51, and 30% of those receiving sibutramine at 6, 12, and 18 months compared with 48, 31, and 20% of those receiving placebo, and these differences were significant at all time points (P 
0.03) (Mathus-Vliegen, 2005).
The possibility of using sibutramine as intermittent therapy has been tested in a randomized, placebo-controlled trial lasting 52 weeks (Wirth and Krause, 2001) (Fig. 7). The patients randomized to sibutramine received one of two regimens. One group received continuous treatment with 15 mg/day for 1 year, and the other group had two 6-week periods when sibutramine was withdrawn. During the periods when the drug was replaced by placebo, there was a small regain in weight that was lost when the drug was resumed. At the end of the trial, the continuous-therapy and intermittent-therapy groups lost the same amount of weight.
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). In this study, hemoglobin A1c levels decreased 0.3% in the drug-treated group and remained stable in the placebo group. Fasting glucose values decreased 0.3 mg/dl in the drug-treated patients and increased 1.4 mg/dl in the placebo-treated group. In a 24-week trial, the dose of sibutramine was increased from 5 to 20 mg/day over 6 weeks (Fujioka et al., 2000). Among those who completed the treatment, weight loss was -4.3 kg (4.3%) in the sibutramine-treated patients, compared with -0.3 kg (0.3%) in placebo-treated patients. Hemoglobin A1c levels decreased 1.67% in the drug-treated group, compared with 0.53% in the placebo-treated group. These changes in glucose and hemoglobin A1c levels were expected from the amount of weight loss associated with drug treatment.
In a 12-month multicenter, randomized, placebo-controlled study (McNulty et al., 2003), 194 diabetics receiving metformin were assigned to placebo (n = 64), 15 mg/day of sibutramine (n = 68), or 20 mg/day of sibutramine (n = 62). At 12 months, weight loss in the 15 mg/day group was 5.5 ± 0.6 kg and in the 20 mg/day group it was 8.0 ± 0.9 kg compared with 0.2 ± 0.5 kg in the placebo group. Glycemic control improved in parallel with weight loss. Sibutramine raised sitting diastolic blood pressure by >5 mm Hg in 43% of those receiving 15 mg/day of sibutramine compared with 25% for the placebo group (P < 0.05). Pulse rate increased >10 beats/min in 42% of those receiving sibutramine, compared with 17% for those receiving placebo.
The 2-year trial by Redmon et al. (2005) was a double-blind, randomized, placebo-controlled trial that had a crossover for the control group after the 1st year. The treatment group received 10 mg/day of sibutramine for the entire 2 years. In addition, they had a portion-controlled diet used for 7 days at the end of each 2 months. There was a significantly greater weight loss in the drug-treated group that reached -9.7 kg at 12 months, compared with -1.6 kg in the placebo-treated group. During the 2nd year, those receiving sibutramine continuously regained weight slowly, rising to a maximal loss of -6.3 kg at 24 months. In contrast, the group that got sibutramine only during the 2nd year weighed less at 24 months than those receiving sibutramine continuously for 2 years (-6.3 kg in the continuous treatment group versus -9.7 kg for the crossover group). There was an improvement in diabetic control associated with the weight loss.
A meta-analysis has been done of eight studies in diabetic patients receiving sibutramine (Vettor et al., 2005). In this meta-analysis, the changes in body weight, waist circumference, glucose, hemoglobin A1c, triglycerides, and HDL cholesterol favored sibutramine. The mean weight loss was 5.53 ± 2.2 kg for those treated with sibutramine and 0.90 ± 0.17 kg for the placebo-treated patients. There was no significant change in systolic blood pressure, but diastolic blood pressure was significantly higher in the sibutramine-treated patients (Vettor et al., 2005). In the meta-analysis by Norris et al. (2004) the net weight loss over 12 to 26 weeks in 4 trials, including 391 diabetic patients, was 4.5 kg (95% CI 7.2–1.8 kg).
ii. Hypertensive patients.
Some trials have reported the use of sibutramine to treat overweight patients with hypertension. In a 3-month trial, where all patients received 
-blockers, with or without thiazides, for their hypertension McMahon et al. (2000) reported that sibutramine-treated patients lost 4.2 kg (4.5%), compared with a loss of 0.3 kg (0.3%) in the placebo-treated group. Mean supine and standing diastolic and systolic blood pressure levels were not significantly different between drug-treated and placebo-treated patients. Heart rate, however, increased by 5.6 ± 8.25 beats/min (mean ± S.D.) in the sibutramine-treated patients, compared with an increase of 2.2 ± 6.43 beats/min in the placebo group. In another 52-week trial, patients with hypertension whose blood pressure levels were controlled with calcium channel blockers with or without -blockers or thiazides (McMahon et al., 2000) received sibutramine in doses that were increased from 5 to 20 mg/day during the first 6 weeks. Weight loss was significantly greater in the sibutramine-treated patients, averaging -4.4 kg (4.7%), compared with -0.5 kg (0.7%) in the placebo-treated group. Diastolic blood pressure levels decreased 1.3 mm Hg in the placebo-treated group and increased +2 mm Hg in the sibutramine-treated group. Systolic blood pressure levels increased +1.5 mm Hg in the placebo-treated group and +2.7 mm Hg in the sibutramine-treated group. Heart rate was unchanged in the placebo-treated patients, but increased by +4.9 beats/min in the sibutramine-treated patients.
The effects of sibutramine on blood pressure have been evaluated in a meta-analysis of 21 studies by Kim et al. (2003). Sibutramine produced a significant overall weight loss and a significant increase in both systolic and diastolic blood pressures. In a subgroup analysis, they found the effect on systolic blood pressure to be greater with higher doses of sibutramine, in individuals weighing 92 kg and in younger individuals (<44 years of age). Older individuals with body weights of 92 kg also showed a greater rise in diastolic blood pressure. In another analysis of two studies with use of sibutramine for 48 weeks Jordan et al. (2005) reported that sibutramine significantly reduced body weight but did not lead to a difference in systolic blood pressure after 48 weeks (-0.1 ± 15.5 mm Hg for placebo versus -0.2 ± 1.52 mm Hg for the sibutramine group). However, the change in diastolic blood pressure was statistically significant with a small rise of +0.3 ± 9.5 mm Hg in the sibutramine group and a decrease of -0.8 ± 9.2 mm Hg in the placebo group (P = 0.049).
iii. Sibutramine plus behavioral weight loss.
Sibutramine has been studied as part of a behavioral weight-loss program in two reports (Wadden et al., 2005). With sibutramine alone, the weight loss over 12 months was 5.0 ± 7.4 kg (5%). Behavior modification alone produced a weight loss of 6.7 ± 7.9 kg. Adding a brief behavioral therpy session to a group that also received sibutramine produced a slightly larger weight loss of 7.5 ± 8.0 kg. When the intensive lifestyle intervention was combined with sibutramine, the weight loss increased to 12.1 ± 9.8 kg. When a structured meal plan was added to the medication and behavioral modification in one of these studies (Wadden et al., 2005), the weight loss increased further to 15 kg (Wadden et al., 2001). Completing the food intake records was a strong predictor of success (Wadden et al., 2005). Those in the combined therapy group receiving an intensive lifestyle program and sibutramine who were in the highest third for record keeping lost 18.1 ± 9.8 kg compared with 7.7 ± 7.5 kg in the lowest third for record-keeping (Fig. 8).
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iv. Studies in children.
Sibutramine has also been used in children and adolescents (Berkowitz et al., 2003, 2006; Godoy-Matos et al., 2005). In a single center, 85 adolescents aged 13 to 17 years with a BMI of 32 to 44 kg/m2 were randomized to treatment for 6 months with placebo or sibutramine. Weight loss in the drug-treated group was 7.8 kg, for an 8.5% reduction in BMI, compared with 3.2 kg in the placebo group, for a 4.0% reduction in BMI. When the placebo group was switched to sibutramine after 6 months, there was an additional significant weight loss in this group. In a 12-month, multicenter, randomized, placebo-controlled trial, 498 adolescents aged 12 to 16 were treated with sibutramine or placebo (Berkowitz et al., 2006). The dose of sibutramine was 10 mg/day for 6 months and then increased to 15 mg/day in those who had not lost >10% of their baseline BMI. After 12 months, the mean absolute change in BMI was -2.9 kg/m2 (-8.2%) in the sibutramine group compared with -0.3 kg/m2 (-0.8%) in the placebo group (P < 0.001). Triglycerides HDL cholesterol, and insulin sensitivity improved, and there was no significant difference in either systolic or diastolic blood pressure.
d. Meta-analysis of sibutramine studies.
Several meta-analyses of sibutramine have been published (Haddock et al., 2002; Avenell et al., 2004; Li et al., 2005). By pooling four studies Haddock et al. (2002) estimated the weight loss in patients treated with sibutramine as -5.3 kg (range 4.0–7.3 kg) compared with -1.8 kg (range 0.8–3.3 kg) for the placebo-treated groups. In the meta-analysis of Li et al. (2005), the overall mean difference after 12 months of therapy in five studies was -4.45 kg (95% CI -5.29 to -3.62 kg) (Table 7).
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In the meta-analysis by Avenell et al. (2004), the overall placebo-subtracted effect of sibutramine at 12 months was -4.12 kg (95% CI -4.97 to -3.26 kg). Table 8 shows a summary for each of the trials that had data for sibutramine out to 12 months (Avenell et al., 2004). After an additional interval in the weight maintenance studies, the data showed a loss at 15 months of -3.70 kg (95% CI -5.71 to -1.69 kg) (Apfelbaum et al., 1999) and at 18 months of -3.40 kg (95% CI -4.45 to -2.35 kg) (James et al., 2000).
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e. Combining sibutramine and orlistat.
Because sibutramine works on noradrenergic and serotonergic reuptake mechanisms in the brain and orlistat works peripherally to reduce triglyceride digestion in the GI tract, their mechanisms of action do not overlap and combining them might provide additive weight loss (Wadden et al., 2000). To test this possibility, researchers randomly assigned patients to orlistat or placebo after 1 year of treatment with sibutramine (Wadden et al., 2000). During the additional 4 months of treatment, the two groups lost no significant amount of weight and adding orlistat had no detectable effect.
In an open-label randomized 12-week study, 86 overweight patients were assigned to treatment with 120 mg of orlistat three times a day, to treatment with 10 mg/day of sibutramine, the combination of orlistat and sibutramine, or to a diet group. During the 12 weeks, sibutramine produced more weight loss than orlistat alone. In another study, 150 obese subjects were randomized to 850 mg of metformin b.i.d., 120 mg of orlistat t.i.d., or 10 mg of sibutramine b.i.d. treatment for 6 months. The BMI decreased by -9.1, -9.9, and -13.6%, respectively. Weight loss was greater in the sibutramine group than in either the metformin or orlistat groups (P < 0.001) (Gokcel et al., 2002). A third study, also of 6 months' duration, randomized 89 obese women to orlistat, sibutramine, or the combination and showed weight losses of 5.5, 10.1, and 10.8 kg, respectively. The combination was superior to orlistat but not to sibutramine alone (Sari et al., 2004). A fourth study randomized 86 obese subjects to 10 mg/day of sibutramine, 360 mg/day of orlistat, the combination, or diet alone. In this stud
