Drug Treatment of the Overweight Patient

GASTROENTEROLOGY 2007;132:2239 –2252

Drug Treatment of the Overweight Patient GEORGE A. BRAY and DONNA H. RYAN Pennington Biomedical Research Center, Baton Rouge, Louisiana

George A. Bray, MD

Three medications with approval for long-term use in the treatment of obesity are currently available in the United States. Sibutramine (U.S. Food and Drug Administration [FDA] approved in 1997), orlistat (FDA approved in 1999), and rimonabant (available in Europe and given FDA approvable status in 2006 and expected to be marketed in 2007) represent modern approaches to medications used adjunctively for weight management. As demonstrated in large clinical trials of 2 to 4 years’ duration, these medications significantly increase weight loss compared with placebo; weight loss with these drugs reaches a nadir between 20 and 28 weeks; weight loss, averaged 8%– 10%, with the placebo contributing 4%– 6% of that. Weight maintenance is demonstrated as long as adherence to medication continues. All medications have side effects that need to be considered. For sibutramine, there is a rise in blood pressure and heart rate that may require discontinuation of the drug in a small percent of patients. For orlistat, steatorrhea produces the principal gastrointestinal side effects. Rimonabant appears to have a favorable safety and tolerability profile. Nausea and gastrointestinal symptoms are the chief tolerability issue, but they are usually self-limited. In addition there are several drugs and drug combinations in phase 2 or phase 2 trials that will be reported on in the coming years.

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n this paper we will review the field of drug therapy for the overweight patient. Table 1 lists the drugs that are available and whether they are approved for a weight loss indication or some other indication by the U.S. Food and Drug Administration (FDA). For individuals desiring more detail or additional guidance in the use of medications to treat overweight, information can be found in a variety of sources.1–13 Our guidance on appropriate selection of patients for the use of medications for weight management is that health improvement be the goal of therapy. The prescribing guide-

lines for weight loss medications that have been approved by the FDA for long-term use indicate that the body mass index (BMI) should be 30 kg/m2 or greater, or, if there is a comorbid condition such as hypertension, diabetes, or hyperlipidemia, that the BMI be 27 kg/m2 or greater. Our recommendation would also include metabolic syndrome as a comorbid condition. If an individual with a BMI ⬎27 meets NCEP ATPIII criteria for metabolic syndrome, then obesity pharmacotherapy may be indicated. We are supportive of the concept of using this metabolic syndrome diagnosis for determining eligibility for pharmacotherapy, because the criteria identify individuals who have levels of lipids, blood pressure, and fasting glucose that are somewhat lower than the traditional values that identify risk, and weight loss is likely to benefit in terms of risk reduction for diabetes and cardiovascular disease. The presence of an elevated waist circumference, specific to ethnic group, is an important criterion to consider. The currently recommended upper limit for waist circumference in the NCEP ATPIII definition of metabolic syndrome14 is 102 cm (40 inches) for a man and 88 cm (35 inches) for a woman, but ethnic-specific definitions are helpful. The recent proposal from the International Diabetes Federation for metabolic syndrome is useful, because it provides ethnic-specific waist circumference definitions and also because it uses values for waist circumference ⬎80 cm for females and 94 cm for males.15 We would support the use of the International Diabetes Federation criteria for metabolic syndrome as an alternate approach for minorities. Once it is established that the patient is an appropriate candidate for medically supervised weight loss, an assessAbbreviations used in this paper: BMI, body mass index; CI, confidence interval; FDA, U.S. Food and Drug Administration; GLP-1, Glucagon-like peptide-1; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NPY, neuropeptide Y; RIO, Rimonabant in Obesity. © 2007 by the AGA Institute 0016-5085/07/$32.00 doi:10.1053/j.gastro.2007.03.053

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Table 1. Drugs Approved by the U.S. Food and Drug Administration That Produce Weight Loss Generic name

Trade names

Status

Usual dose

Comments

Drugs approved by the U.S. FDA for long-term treatment of overweight patients Orlistat Xenical 120 3 times a day Sibutramine Meridia; Reductil 5–15 mg/day Rimonabant Accomplia in Europe Under review 20 mg/day Drugs approved by the U.S. FDA for short-term Benzphetamine Bontril Diethylpropion Tenuate; Tepanil Phendimetrazine Phentermine Fastin

treatment of overweight patients DEA-III DEA-II DEA-III DEA-II

Drugs approved by the U.S. FDA for purposes other than weight loss Metformin Glucophage Bupropion Wellbutrin Zonisamide Topiramate

May have GI side effects Raises blood pressure GI side effects, mood effects

Zonegran Topamax

Antidiabetic Antidepressant and prevention of weight gain after cessation of smoking Antiepileptic Antiepileptic

GI, gastrointestinal.

ment of the patient’s motivation must be made. Weight loss is hard work, and patients must be highly motivated to be successful. Then, 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% would often be viewed as a failure. In contrast, weight loss using monotherapy with the drugs that are currently available is usually not ⬎10%, even with a lifestyle intervention in addition to medication. 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 key to effective pharmacotherapy is to link the behavioral approach to the drug’s mechanism of action. Patients must be fully informed of the drug’s mechanism of action and side effects. Thus, the next step is to fully discuss the medication with the patient and then ask them to sign a consent form indicating their knowledge of the required behavioral approaches, potential side effects, and responsibility for follow-up. We advise that physicians stay with prescribing medications approved by the FDA for long-term use. To our surprise, an algorithm sponsored by the American College of Physicians6 recommends 6 medications: orlistat, sibutramine, phentermine, diethylpropion, fluoxetine, and bupropion. The first 4 have been approved by the FDA for treatment of overweight patients, and may have some application, but fluoxetine, sertraline, and bupropion have not received an FDA approval for weight loss indication, and they should not be used primarily for this purpose. In our view, fluoxetine and bupropion should not be used for weight loss, but may be appropriate choices for management of depression in overweight patients. Bupropion may also be helpful in reducing or preventing the weight gain when people try to stop smoking.

Drugs Approved by the FDA for Treatment of Overweight Drugs Approved for Long-Term Use Orlistat: mechanism of action. Orlistat is a lipase inhibitor. The drug has a dose-dependent effect on fecal fat loss; with diets with 30% fat, about 1/3 will not be absorbed. Orlistat has little effect in subjects eating a low-fat diet. Long-term studies. A number of 1- to 4-year longterm clinical trials with orlistat have been published. We will focus on those of 2 or more years’ duration,16 –19 because it is our belief that obesity pharmacotherapy is a long-term paradigm. The pooled 2-year data from these 4 studies is shown in Figure 1, which demonstrates the weight-loss trajectory with orlistat and placebo over 2 years. It contains information on both the 120-mg 3 times a day and the 60-mg 3 times a day dose. 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.

Figure 1. Percent change from initial body weight over 2 years— integrated database.

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Table 2. Net Mean Weight Loss With 2-Year Use of Orlistat Compared With Placebo Author (year)

Mean change compared with placebo (95% CI)

Davidson (1999) Hauptman (2000) Rossner (2000) Sjostrom (1998) Torgerson (2004)

⫺2.95 (95% CI ⫺4.45 to –1.45) ⫺3.80 (95% CI ⫺5.37 to –2.23) ⫺3.00 (95% CI ⫺4.17 to –1.83) ⫺4.20 (95% CI ⫺5.26 to –3.14) ⫺4.17 (95% CI ⫺4.60 to –3.74)

Adapted from Li et al. Ann Intern Med 2005;142:532–546.

The results of a 4-year double-blind, randomized, placebo-controlled trial with orlistat have also been reported.20 A total of 3304 overweight patients, 21% of whom had impaired glucose tolerance, were included in this Swedish trial. The lowest body weight was achieved during the first year: more than ⫺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, from 9% to 6% for a relative risk reduction of 0.63 (95% confidence interval [CI] 0.46 to 0.86);7 essentially all of this benefit occurred in the patients with impaired glucose tolerance at enrollment into the trial. Weight maintenance with orlistat was evaluated in a 1-year study.21 Patients were enrolled if they had lost ⬎8% of their body weight over 6 months while eating a 1000-kcal per day diet. The 729 patients were randomized to receive placebo or orlistat at 30 mg, 60 mg, or 120 mg 3 times per day for 12 months. At the end of this time, the placebo-treated patients had regained 56% of their body weight compared with 32.4% in the group treated with orlistat, 120 mg 3 times per day. The other 2 doses of orlistat were no different from placebo in preventing the regain of weight. Studies in special populations: studies in diabetics. Patients with diabetes treated with orlistat, 120 mg 3 times daily for 1 year, lost more weight than the placebotreated group.22–24 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 3 of the 2-year studies described previously in which glucose tolerance tests were available.25 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 placebotreated 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.

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Orlistat and lipid effects. All of the clinical studies with orlistat have shown significant decreases in serum cholesterol and low-density lipoprotein (LDL) cholesterol levels that usually are greater than can be accounted for by weight loss alone.5 One study showed that orlistat reduces the absorption of cholesterol from the gastrointestinal tract, thus providing a mechanism for the clinical observations.26 Studies in children. A multicenter trial tested the effect of orlistat in 539 obese adolescents.27 Subjects were randomized to placebo or orlistat 120 mg 3 times a day and a mildly hypocaloric diet containing 30% fat. By the end of the study, BMI had decreased ⫺0.55 kg/m2 in the drug-treated group but had increased 0.31 kg/m2 in the placebo group. By the end of the study, weight had increased by only 0.51 kg in the orlistat-treated group, compared with 3.14 kg in the placebo-treated group (Figure 2). 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 find a difference resulting from treatment with orlistat in a population of 40 adolescents.28 Meta-analyses of orlistat studies. Several meta-analyses of orlistat have been published.10,11,29 By pooling 6 studies, Haddock et al10 estimated the weight loss in patients treated with orlistat as ⫺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 another metaanalysis by Li et al11 the overall mean difference after 24 months of therapy in 22 studies was ⫺2.70 kg (95% CI ⫺3.79 to ⫺1.61 kg). Because this analysis included data sets with diabetic and nondiabetic subjects we have summarized the data from the five 2-year studies that did not include diabetic subjects in Table 2. Another meta-analysis30 examined the effects in 8 1-year long studies— only 1 of which was in diabetic patients— on weight loss at 1 and 2 years and on the various laboratory and clinical

Figure 2. Effect of orlistat on BMI of adolescents. Reprinted with permission.27

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Table 3. Net Mean Weight Loss Using 1 Year of Orlistat Compared With Placebo Treatment

Placebo

Author

Yr

n

Mean SD

n

Sjostrom Hollander Davidson Rossner Hauptman Lindegarde Finer Broom

1998 1998 1999 2000 2000 2000 2000 2001

343 156 657 241 210 190 110 259

⫺8.10 ⫾ 8.21 ⫺3.84 ⫾ 5.00 ⫺8.76 ⫾ 9.48 –8.13 ⫾ 8.22 ⫺5.40 ⫾ 7.44 ⫺4.20 ⫾ 7.03 ⫺3.29 ⫾ 6.85 ⫺5.80 ⫾ 8.50

340 151 223 236 212 186 108 163

Mean SD ⫺3.90 ⫾ 7.02 ⫺1.43 ⫾ 5.10 ⫺5.81 ⫾ 10.01 ⫺5.23 ⫾ 7.40 ⫺1.41 ⫾ 6.31 ⫺2.90 ⫾ 6.74 ⫺1.31 ⫾ 6.29 ⫺2.30 ⫾ 6.40

WMD (95% CI) ⫺4.20 (⫺5.35 to ⫺3.05) ⫺2.41 (⫺3.54 to ⫺1.29) ⫺2.95 (⫺4.45 to ⫺1.45) ⫺2.90 (⫺4.30 to ⫺1.50) ⫺3.99 (⫺5.31 to ⫺2.67) ⫺1.30 (⫺2.69 to ⫺0.09) ⫺1.98 (⫺3.73 to ⫺0.23) ⫺3.50 (⫺4.79 to ⫺2.21)

Adapted from Avenell et al.30 WMD, weighted mean difference.

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 2). 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).17⫺19,21 We include only studies in nondiabetic populations in our summary of 1-year studies illustrated in Table 3. In a meta-analysis focused on the use of orlistat in diabetics, Norris et al31 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. Safety considerations. Orlistat is not absorbed to any significant degree, and its side effects are thus related to the blockade of triglyceride digestion in the intestine.32 Fecal fat loss and related gastrointestinal symptoms are common initially, but they subside as patients learn to use the drug.5 The quality of life in patients treated with orlistat may improve despite concerns about gastrointestinal 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. It is anticipated that orlistat will be available over the counter in 2007. Physicians should be aware of the need for vitamin supplementation when this medication is used over the long term and assess their patients for this use.

intake by 23% on day 7 and 26% on day 14 relative to placebo. A smaller dose of 10 mg also significantly reduced food intake at 14 days.33 In animals, sibutramine also stimulates thermogenesis, but there are conflicting data in human beings.34 If sibutramine increases energy expenditure, it is on the order of 100 kcal/day.35 Long-term studies. Sibutramine has been evaluated extensively in several multicenter trials lasting 6 –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% or more. 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 Figure 3.36 Three trials have assessed the value of using sibutramine to prevent regain of body weight.37–39 We will discuss the Sibutramine Trial of Obesity Reduction and Maintenance Trial that lasted 2 years and provided evidence for weight maintenance.38 Of the patients who lost more than ⫺8 kg, during 6 months taking sibutramine 10 mg/day, 2/3 were then randomized to sibutramine and 1/3 to placebo. During the 18-month double-blind phase, the placebo-treated patients steadily regained

Sibutramine 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. It is a so-called selective serotonin norepinephrine reuptake inhibitor. In clinical studies it reduces food intake. In a double-blind placebo-controlled 2 week trial, a 30-mg/day dose of sibutramine reduced food

Figure 3. Effect of sibutramine on body weight. Reprinted with permission.36

May 2007

weight, maintaining only 20% of their weight loss at 2 years. 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.38 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 in the patients treated with placebo. The possibility of using sibutramine as intermittent therapy has been tested in a randomized, placebo-controlled trial lasting 52 weeks.40 The patients randomized to sibutramine received 1 of 2 regimens. One group received continuous treatment with 15 mg/day for 1 year, and the other had 2 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 had lost the same amount of weight. Sibutramine plus behavioral weight loss. The intensity of the behavioral component of the weight loss program influences the amount of weight loss with sibutramine. Because sibutramine enhances satiety, a dietary program that takes advantage of this mechanism is likely to produce greater weight loss. Wadden et al41 illustrate the advantage of a structured behavioral intervention in combination with sibutramine. With minimal behavioral intervention, the weight loss was ⫺6.7 ⫾ 7.9 kg over 12 months and the effect of sibutramine alone was ⫺5.0 ⫾ 7.4 kg. When a brief behavior modification was added, the weight loss increased. When a 30-week behavioral plan was added to the medication group the weight loss increased further to 12.1 ⫾ 9.8 kg. Also of interest was that those participants who recorded their food intake more frequently lost more than twice as much weight as those who did not (18.1 ⫾ 9.8 vs 7.7 ⫾ 7.5 kg) (Figure 4). Studies in special populations: diabetic patients. A number of studies have examined the effect of sibutramine in diabetic patients. A meta-analysis of 8 studies in diabetic patients receiving sibutramine8 showed that changes in body weight, waist circumference, glucose, hemoglobin A1c, triglycerides, and high-density lipoprotein (HDL)-cholesterol favored sibutramine. The mean weight loss was ⫺5.53 ⫾ 2.2 for those treated with sibutramine and ⫺0.90 ⫾ 0.17 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.8 In the meta-analysis by Norris et al31 the net weight loss over 12–26 weeks in 4 trials including 391 diabetics was ⫺4.5 kg (95% CI ⫺7.2 to ⫺1.8 kg). Hypertensive patients. Sibutramine has been used to treat overweight in patients with hypertension. One 52week trial involved patients with hypertension whose blood pressure levels were controlled with calcium chan-

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Figure 4. Effect of additional therapy on weight loss with sibutramine. Reprinted with permission.41

nel blockers with or without beta-blockers or thiazides.42 Sibutramine doses were increased from 5 mg 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 placebotreated 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. The systolic blood pressure levels increased ⫹0.5 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 per minute in the sibutramine-treated patients. The effects of sibutramine on blood pressure have been evaluated in a meta-analysis of 21 studies.12 Sibutramine produced a significant overall weight loss and significant increase in both systolic and diastolic blood pressure. In a subgroup analysis, Kim et al12 found the effect on systolic blood pressure to be greater with higher doses of sibutramine, in individuals weighing 92 kg or more and in younger individuals ⬍44 years of age. Diastolic blood pressure also increased in older individuals with body weights of 92 kg. In another analysis of 2 studies using sibutramine for 48 weeks, Jordan et al43 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 and ⫺0.2 ⫾ 1.52 mm Hg for the sibutramine group). However, the change in diastolic blood pressure was statistically significant with a small increase of ⫹0.3 ⫾ 9.5 mm Hg in the sibutramine group and ⫺0.8 ⫾ 9.2 mm Hg in the placebo group (P ⫽ .049). Studies in children. Overweight adolescents have been treated with sibutramine.44 – 46 In a 12-month, mul-

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Figure 5. Clinical trial of sibutramine in adolescents.

ticenter randomized placebo-controlled trial, 498 adolescents aged 12–16 were treated with sibutramine or placebo.46 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 ⬍ .001). Triglycerides, HDL-cholesterol, and insulin sensitivity improved, and there was no significant difference in the changes in either systolic or diastolic blood pressure (Figure 5). Meta-analysis. Several meta-analyses of sibutramine have been published.10,11,30 By pooling 4 studies, Haddock et al10 estimated the weight loss in patients treated with sibutramine as ⫺5.3 kg (range: 4.0 to 7.3 kg) compared with ⫺1.8 kg (range: 0.8 to 3.3 kg) for the placebotreated groups. In the meta-analysis of Li et al,11 the overall mean difference after 12 months of therapy in 5 studies was ⫺4.45 kg (95% CI ⫺5.29 to ⫺3.62 kg). In the study by Avenell et al,30 the overall effect of sibutramine at 12 months was ⫺4.12 kg (95% CI ⫺4.97 to ⫺3.26 kg). Table 4 is a summary for each of the trials that had data out to 12 months with sibutramine.30 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)37 and at 18 months of ⫺3.40 kg (95% CI ⫺4.45 to ⫺2.35 kg).38 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 gastrointestinal tract, their mechanisms of action do not overlap, and combining them might provide additive weight loss. To test this possibility, researchers randomly assigned patients to orlistat or placebo after 1 year of treatment with sibutramine.47 During the additional 4 months of treatment the 2 groups lost no significant amount of weight and adding orlistat had no detectable effect. Safety considerations. Sibutramine is available in 5-mg, 10-mg, and 15-mg doses; 10 mg/day as a single dose is the recommended starting level, with titration up or down, depending on response. Doses ⬎15 mg/day are not recommended. Of the patients who lost 2 kg (4.4 lb) in the first 4 weeks of treatment, 60% achieved a weight loss of ⬎5%, compared with ⬍10% of those who did not lose 2 kg (4 lb) in 4 weeks. Combining data from the 11 studies on sibutramine showed a reduction in triglyceride, total cholesterol, and LDL-cholesterol levels and an increase in HDL-cholesterol levels that were related to the magnitude of the weight loss.

Rimonabant Mechanism of action. There are 2 cannabinoid receptors, CB-1 (470 amino acids in length) and CB-2 (360 amino acids in length). The CB-1 receptor has almost all the amino acids that comprise the CB-2 receptor and additional amino acids at both ends. CB-1 receptors are distributed widely throughout the body, including through the brain in the areas related to feeding, on fat cells, and in the gastrointestinal tract. Marijuana and tetrahydrocannabinol, which stimulate the CB-1 receptor, increase high fat and high sweet food intake, and fasting increases the levels of endocannabinoids. Rimonabant is a specific antagonist of the CB-1 receptor, and inhibits sweet food intake in marmosets as well as high-fat food intake in rats but not in rats fed standard chow. CB-1 knockout mice are lean and resistant to diet-induced overweight.48 –51

Table 4. Effect of Sibutramine vs Placebo and Diet at 12 Months Treatment

Control

Author

Yr

n

Mean SD

n

Mean SD

Apfelbaum McMahon Smith Smith

1999 2000 2001a 2001b

81 142 154 153

⫺5.20 ⫾ 7.50 ⫺4.40 ⫾ 7.16 ⫺4.40 ⫾ 7.16 ⫺6.40 ⫾ 7.73

78 69 157 157

0.50 ⫾ 5.70 ⫺0.50 ⫾ 6.06 ⫺1.60 ⫾ 6.37 ⫺1.60 ⫾ 6.37

Adapted from Avenell et al.30 WMD, weighted mean difference.

WMD (95% CI) ⫺5.70 (⫺7.77 to ⫺3.63) ⫺3.90 (⫺5.75 to ⫺2.05) ⫺2.80 (⫺4.31 to ⫺1.29) ⫺4.32 (⫺6.38 to ⫺3.22)

May 2007

Long-term clinical studies. The results of 4 phase III trials of rimonabant for the treatment of overweight have been presented, and 3 of these are now published. The first trial, called the Rimonabant in Obesity [RIO]-Europe trial was reported in 2005.52 A total of 1057 patients with a BMI ⬎30 kg/m2 without comorbidities or ⬎27 kg/m2 with hypertension or dyslipidemia were stratified on whether they lost ⬎2 kg or ⬍2 kg during run-in and then randomized in a ratio of 1:2:2 to receive placebo, rimonabant 5 mg/day, or rimonabant 20 mg/day. The energy content of the diet was calculated by subtracting 600 kcal/day from the energy requirements calculated from the Harris-Benedict equation. The trial consisted of a 4 week run-in period followed by 52 weeks of treatment. Of those who started, 61% (920) completed the first year. Weight loss was 2% in the placebo group and 8.5% in the 20 mg rimonabant group. Baseline weight was between 98.5 kg (placebo group) and 102.0 kg (for the rimonabant 20 mg dose). During run-in there was a mean ⫺1.9 kg weight loss. From baseline at the end of run-in the placebo the group that completed the trial lost an additional ⫺2.3 kg, the low-dose rimonabant group lost ⫺3.6 kg, and the high-dose group lost ⫺8.6 kg. On an intent-to-treat basis, these numbers were a weight loss of ⫺1.8 kg for the placebo group, ⫺3.4 kg for the 5 mg/day, and ⫺6.6 kg for the 20 mg/day group. Expressing the data as a responder analysis, the authors reported that 30.5% of the placebo group lost 5% or more, compared with 44.2% for the 5 mg/day and 67.4% for the 20 mg/day dose of rimonabant. When a weight loss of 10% or more was considered, the numbers were 12.4% for the placebo group, 15.3% for the 5 mg/day group, and 39% for the 20 mg/day dose of rimonabant. Waist circumference was also reduced by treatment. Triglycerides were reduced by 6.8% in the 20 mg/day group compared with a rise of 8.3% in the placebo group. HDL cholesterol increased by 22.3% in the high-dose group compared with 13.4% in the placebo group. These changes in metabolic parameters were reflected in a change in the prevalence of the metabolic syndrome, which decreased by 33.9% in the placebo group compared with 34.8% in the 5 mg/day dose group and 64.8% in the 20 mg/day rimonabant dose group. In the 20 mg/day group the low density lipoprotein particle size increased, adiponectin increased, glucose decreased, insulin decreased, C-reactive protein decreased, and the metabolic syndrome prevalence was cut in half. There was no significant change in blood pressure or pulse between groups. The number of patients withdrawing for drug-related adverse events was slightly higher in the 5 mg/day dose and even higher with the 20 mg/day dose. The major reasons for withdrawal were psychiatric, nervous system, and gastrointestinal tract symptoms. The complaints that occurred with more than 5% frequency in the drug-treated patients included upper respiratory tract infection, nasopharyngitis, nausea, influenza, diarrhea, arthralgia, anxiety, insomnia,

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viral gastroenteritis, dizziness, depressed mood, and fatigue in the 20 mg/day dose.53 The second study was in dyslipidemic patients and is called the RIO-lipids (Rimonabant in Obesity-Lipids) study.54 This was a 12-month randomized double-blind placebo-controlled trial of rimonabant at 2 doses vs placebo in overweight subjects eating a 600 kcal/day deficit diet. The inclusion criteria were a BMI of 27 to 40 kg/m2, elevated fasting triglycerides (150 –700 mg/dL), ratio of cholesterol to HDL-cholesterol ⬎5 in men and ⬎4.5 in women, and no more than 5 kg variation in body weight in the previous 3 months. Subjects were stratified at run-in by triglycerides below or above 400 mg/dL and at the end of run-in by a weight loss of ⬎2 kg or ⬍2 kg. Randomization was on a 1:1:1 basis of placebo:5 mg/day rimonabant:20 mg/day rimonabant. The drop-out rate was about 40% by the end of 12 months. Weight losses in this trial were almost identical to those in the RIO-Europe trial. After an approximate 2-kg weight loss during run-in, the placebo patients in the completers group lost an addition ⫺2.3 kg, compared with ⫺4.2 kg in the 5 mg/day dose group and ⫺8.8 kg in the 20 mg/day dose group of rimonabant. Waist circumference also decreased in a dose-dependent way. Triglycerides, HDLcholesterol, in the peak size of LDL-cholesterol particles, adiponectin, fasting insulin, leptin, and C-reactive protein all improved with weight loss. Several liver enzymes fell with treatment suggesting improvement in nonalcoholic steatosis. Blood pressure decreased significantly in RIO-Lipids in contrast with RIO-Europe. As might be expected from these metabolic changes, the prevalence of the metabolic syndrome in those who met the ATP-III criteria at randomization decreased to 25.8% in the placebo group, 40.0% in the 5 mg/day group, and 41.0% in the 20 mg/day group. The third randomized, double-blind, placebo-controlled study called RIO-North America was also a 2-year study that randomized 3045 overweight subjects with a BMI ⬎30 kg/m2 or with a BMI ⬎27 kg/m2 with treated or untreated hypertension or dyslipidemia and without diabetes to placebo, 5 mg rimonabant, or 20 mg rimonabant. Participants were instructed in a 600 kcal/day deficit diet. Randomization and baseline occurred after a 4 week run-in period when subjects had lost an average of 1.9 kg (Figure 6). They were thus stratified by whether they lost ⬎2 kg or ⬍2 kg during run-in. At 1 year half of the patients in each drug group were switched to placebo. At 1 year completion rates were 51% to 55% for the 3 arms. During the first year weight loss was ⫺2.8 kg in the placebo group and ⫺8.6 kg in the 20-mg rimonabant group. Weight loss declined steadily until week 36, after which it plateaued. For the second year, those individuals who were switched from rimonabant to placebo regained weight at almost the mirror image of the rate at which they lost it during the first year. At the end of the study they were still slightly lighter, but no different from the group treated with placebo for the full 2 years. Waist circumference decreased, and the percentage with the

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Figure 6. Effect of rimonabant on body weight over 2 years. Reprinted with permission.53

metabolic syndrome decreased from 34.8% to 21.2% compared with a change from 31.7% to 29.2% in the placebotreated group. HDL-cholesterol and triglycerides improved on the higher dose of rimonabant. Patients with depression were not included in this study. Adverse events leading to discontinuation of the study were higher in the rimonabant-treated than in the placebotreated participants. This said, the profile and effectiveness of this agent appear very promising for treatment of obesity and the physical and laboratory findings that make up the metabolic syndrome. Studies in special populations: diabetic patients. The fourth study, RIO-Diabetes, randomized 1045 subjects in 151 centers in 11 countries to treatment who already had diabetes treated with diet, metformin, or sulfonylurea drugs to 1 year of treatment with rimonabant 5 or 20 mg/day. Weight loss in the placebo group was ⫺1.4 kg, compared with ⫺2.3 kg in the 5-mg group and ⫺5.3 kg in the 20-mg group. Triglycerides and blood pressure declined more in the subjects treated with 20 mg/day of rimonabant. During treatment with 20 mg/ day of rimonabant 55.9% of completers lost ⬎5% of body weight compared with 19.5% in the placebo-treated group. Safety considerations. Because this drug “dampens” the feedback systems for pleasurable responses, there is concern about its behavioral effects.

Drugs Approved by the FDA for ShortTerm Treatment of Overweight Patients Phentermine and Diethylpropion: Sympathomimetic Drugs Approved for ShortTerm Use Mechanism of action. Phentermine and diethylpropion behave in many ways like the adrenergic neurotransmitters and are thus called “sympathomimetic amines.” They were originally thought to “release” nor-

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epinephrine from vesicular stores, but more recent data would suggest that they act primarily to inhibit reuptake of norepinephrine and dopamine at nerve endings. Clinical studies. Most of the data on phentermine, diethylpropion, benzphetamine, and phendimetrazine come from short-term trials.5 One of the longest of these clinical trials lasted 36 weeks and compared placebo treatment with continuous phentermine or intermittent phentermine.55 Both continuous and intermittent phentermine therapy produced more weight loss than placebo. In the drug-free periods, the patients treated intermittently lost weight more slowly, only to lose more rapidly when the drug was reinstituted. Phentermine and diethylpropion are classified by the U.S. Drug Enforcement Agency as schedule IV drugs; benzphetamine and phendimetrazine are schedule III drugs. This regulatory classification indicates the government’s belief that they have the potential for abuse, although this potential appears to be very low. Phentermine and diethylpropion are approved for only a “few weeks,” which usually is interpreted as up to 12 weeks. Weight loss with phentermine and diethylpropion persists for the duration of treatment, suggesting that tolerance does not develop to these drugs. If tolerance were to develop, the drugs would be expected to lose their effectiveness, and patients would require increased amounts of the drug to maintain weight loss. This does not appear to occur.

Drugs Approved for Purposes Other Than Obesity Exenatide Glucagon-like peptide-1 (GLP-1) is derived from the processing of the proglucagon peptide, which is secreted by L-cells in the terminal ileum in response to a meal. Increased GLP-1 inhibits glucagon secretion, stimulates insulin secretion, stimulates gluconeogenesis, and delays gastric emptying.56 It has been postulated to be responsible for the superior weight loss and superior improvement in diabetes seen after gastric bypass surgery for overweight.57,58 GLP-1 is rapidly degraded by dipeptidyl peptidase-4, an enzyme that is elevated in the obese. Bypass operations for overweight increase GLP-1, but do not change the levels of dipeptidyl peptidase-4.59,60 Exenatide (Exendin-4) is a 39-amino acid peptide that is produced in the salivary gland of the gila monster lizard. It has 53% homology with GLP-1, but it has a much longer half-life. Exenatide decreases food intake and body weight gain in Zucker rats while lowering HgbA1c.61 It also increases beta-cell mass to a greater extent than would be expected for the degree of insulin resistance.62 Exendin-4 induces satiety and weight loss in Zucker rats with peripheral administration and crosses the blood– brain barrier to act in the central nervous system.63,64 Exenatide has been approved by the FDA for treatment of type 2 diabetics who are inadequately con-

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trolled while being treated with either metformin or sulfonylureas. In humans, exenatide reduces fasting and postprandial glucose levels, slows gastric emptying, and decreases food intake by 19%.65 The side effects of exenatide in humans are headache, nausea, and vomiting that are lessened by gradual dose escalation.66 Several clinical trials of 30 weeks’ duration have been reported using exenatide at 10 ␮g subcutaneously per day or a placebo.67– 69 In 1 trial with 377 type 2 diabetic subjects who were failing maximal sulfonylurea therapy, exenatide produced a fall of 0.74% more in HgbA1c than placebo. Fasting glucose also decreased, and there was a progressive weight loss of 1.6 kg.69 The interesting feature of this weight loss is that it occurred without adding lifestyle, diet, or exercise. Weight loss was as much in those with nausea as in those without, suggesting that this is not the primary mechanism for the weight loss. In a 26-week randomized control trial, exenatide produced a 2.3-kg weight loss compared with a gain of 1.8 kg in the group receiving insulin glargine.70

Metformin Metformin is approved for use in persons with type 2 diabetes. Metformin has also been shown to be effective in producing mild weight loss, perhaps best illustrated by the results of the Diabetes Prevention Program. In that study, at an average follow-up of 2.8 years, individuals who received metformin lost ⫺2.1 kg compared with ⫺0.1 kg for the placebo group.71 These effects of metformin may be the result of effects of fatty acid oxidation or on AMP-activated protein kinase, but the final evidence is not in.

Drugs on the Horizon Drugs in Phase 2 and Phase 3 Clinical Trials There are many pharmaceutical products targeting overweight in various stages of development. Some notable investments have been made in evaluating leptin, topiramate, and, recently, axokine (ciliary neurotrophic factor) as obesity pharmacotherapy. These products are no longer being pursued for the general obesity market, although there is interest in developing leptin for lipodystrophy. We chose to review medications that are actively being pursued in phase 2 and phase 3 studies at the time of this writing, so as to provide readers with an idea of potential products that might be seen in the marketplace.

Other CB-1 Antagonists There are a number of pharmaceutical companies who have agents in development targeting the CB-1 receptor. We expect other agents to follow the rimonabant path to approval for an indication in obesity.

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Neuropeptide-Y Receptor Antagonists Neuropeptide Y (NPY) is a widely distributed neuropeptide that has 5 receptors, Y-1, Y-2, Y-4, Y-5, and Y-6. NPY stimulates food intake, inhibits energy expenditure, and increases body weight by activating Y-1 and Y-5 receptors in the hypothalamus.72 Levels of NPY in the hypothalamus are temporally related to food intake and are elevated with energy depletion. Surprisingly, NPY knockout mice have no phenotype. NPY-5 receptor antagonists fall into 2 categories—those that reduce food intake and those that do not— but of those that do, they seem to do so through a mechanism separate from Y-5. Thus, Y-5 receptor antagonists do not appear promising as antioverweight agents.73 Y-1 receptor antagonists appear to have greater potential as antioverweight agents. A dihydropyridine neuropeptide Y-1 antagonist inhibited NPY-induced feeding in satiated rats.74 Another Y-1 receptor antagonist, J-104870, suppressed food intake when given orally to Zucker rats.75 A study measuring NPY in obese humans casts doubt on the importance of the NPY antagonists in the treatment of overweight in humans. Obese women had lower NPY levels than lean women and weight loss with a 400 kcal/day diet and adrenergic agonists (caffeine and ephedrine or caffeine, ephedrine, and yohimbine) did not change NPY levels at rest or after exercise.76 Several clinical trials with a selective Y-5 receptor antagonist have been completed. The first was a 2-year randomized, placebo-controlled trial. It included 2 doses. There was a small but significantly greater response to the drug. The findings supported the hypothesis that NPY5R is a component of energy homeostatic pathways in human beings, although pharmacologic antagonism of the NPY5R was not sufficient to obtain clinically meaningful weight loss in overweight and obese adults.77 Another company has reported in abstract format a trial designed to test the effect of an NPY-5 antagonist on the prevention of weight regain after weight loss induced by providing patients with a very low calorie diet prior to randomization. This agent remains under investigation.

Serotonin 2C Receptor Agonists Mice lacking the serotonin 2C receptor have increased food intake because they take longer to be satiated. These mice also are resistant to fenfluramine, a serotonin agonist that causes weight loss. A human mutation of the serotonin 2C receptor has been identified that is associated with early-onset human overweight.78,79 The precursor of serotonin, 5-hydroxytryptophan, reduces food intake and body weight in clinical studies.80,81 Fenfluramine82,83 and dexfenfluramine,84 2 drugs that act on the serotonin system but were withdrawn from the market in 1997 due to cardiovascular side effects, also reduce food intake in human studies. Meta-chlorophenylpiperazine, a direct serotonin agonist, reduces food intake by 28% in women and 20% in men.85 Another

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serotoninergic drug, sumatriptan, which acts on the 5-HT1B/1D receptor, also reduced food intake in human subjects.86 Because of the robust effects of agonists toward the serotonin 2C receptors in suppressing food intake, a number of new agents are now under development. Only 1 of these, described below, has advanced to formal clinical trials. The results of a phase II dose-ranging study for APD356 (now named locaserin) were announced by the company in a press release on December 13, 2005. A total of 459 male and female subjects with a BMI between 29 and 46 kg/m2 with an average weight of 100 kg were enrolled in a randomized, double-blind controlled trial comparing placebo against 10 and 15 mg given once daily and 10 mg given twice daily (20 mg/day). Over the 12 weeks of the trial the placebo group lost ⫺0.32 kg (n ⫽ 88 completers) compared with ⫺1.8 kg in the 10 mg/day dose given twice daily (n ⫽ 86), ⫺2.6 kg in the 15 mg/day dose (n ⫽ 82 completers), and ⫺3.6 kg in the 10 mg twice daily (20 mg total) (n ⫽ 77 completers). Side effects that were higher in the active treatment groups than the placebo group were headache, nausea, dizziness, vomiting, and dry mouth. No cardiac valvular changes were noted.87 Additional clinical trials are being planned.

PYY 3–36 PYY 3–36 is a hormone produced by the L-cells in the gastrointestinal tract and is secreted in proportion to the caloric content of a meal. PYY 3–36 levels are lower fasting and after a meal in the overweight subjects compared with lean subjects. Development of a nasal spray formulation for PYY 3–36 has undergone a phase I clinical trial. Based on the review of this trial, Merck and Company severed its commercial relationship with Nastech on March 1, 2006. Nastech, the developer of the nasal formulation, plans to continue developing this product. Caloric intake at a lunch buffet was reduced by 30% in 12 obese subjects and by 29% in 12 lean subjects after 2 hours of PYY 3–36 infused intravenously.88 Thrice daily nasal administration over 6 days was well tolerated and reduced caloric intake by about 30% while giving 0.6 kg weight loss.89

Oxyntomodulin Oxyntomodulin is a gastrointestinal peptide produced in the L-cells of the intestine and is released in response to food. Animals injected with oxyntomodulin have a reduction in body fat and food intake. In a short-term clinical study, it was reported to reduce food intake by 19.3% compared with a placebo infusion. In a 4-week randomized, double-blind, placebo-controlled trial, overweight volunteers injected oxyntomodulin subcutaneously 3 times a day 30 minutes before meals. Body weight was reduced ⫺2.3 ⫾ 0.4 kg in the group receiving oxyntomodulin compared with ⫺0.5 ⫾

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0.5 kg in the placebo group. Leptin decreased and adiponectin increased in the group receiving oxyntomodulin. Energy intake in the treated group decreased by 170 ⫾ 37 kcal (25% ⫾ 5%) at the beginning study meal and by 250 ⫾ 63 kcal (35% ⫾ 9%) at the final meal.90 Further studies on this intriguing peptide are awaited.

Pancreatic Lipase Inhibitor Although orlistat, a lipase inhibitor, is already approved for the treatment of overweight, another lipase inhibitor, cetilistat, is under development. In a 5-day trial of cetilistat (ATL-962) in 90 normal volunteers housed on an inpatient unit, there was a 3–7-fold increase in fecal fat that was dose dependent. Only 11% of subjects had more than 1 oily stool, leading to the suggestion that this lipase inhibitor may have fewer gastrointestinal adverse events compared with orlistat.91 A 12-week clinical trial randomized 612 obese diabetic subjects to cetilistat 40 mg, 80 mg, 120 mg, orlistat 120 mg, or placebo given 3 times a day. Weight loss was ⫺2.9 kg, ⫺3.9 kg, ⫺4.3 kg, ⫺3.8 kg, and ⫺2.9 kg, respectively. The prevalence of gastrointestinal side effects was 11.6%, 1.7%, and 4% in the orlistat, cetilistat 120 mg, and placebo groups, respectively.92

Growth Hormone Fragment A group working in Australia has identified a fragment of growth hormone that is lipolytic. This compound, called AOD9604, is a modified fragment of the amino acids in growth hormone from 177–191, and is orally active. It is said to bind to the fat cell stimulating lipolysis and inhibiting reesterification without stimulating growth. A 12-week multicenter trial randomized 300 obese subjects to 1 of 5 daily doses (1, 5, 10, 20, and 30 mg) of AOD9604 or placebo. The 1-mg dose was the most effective for weight loss. Subjects on the 1 mg dose lost 2.6 kg compared with 0.8 kg in the placebo group, and the rate of weight loss was constant throughout the trial.93 Phase III trials are evidently in the planning stages.

Combinations Vivus and Orexigen are companies that have a business plan for obesity treatment, based on the use of multiple medications to improve the amount of weight loss. They have identified medications approved by the FDA for other indications that are associated with weight loss, and are investigating, in clinical trials, the use of combinations of these medications. Three combinations have been patented and are under study— bupropion and naltrexone, bupropion and zonisamide, and topiramate and phentermine. The concept is to use medications with different mechanisms of action to maximize weight loss and, thus, be more appealing to the general public than the current approved medications, which are associated with ⬃5% weight loss as a medication effect. The medications under study will have to be carefully evaluated for

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safety because of the long-term nature of medication use and the inherent risk-benefit issues when treating obesity. Tolerability will also be an issue to be carefully assessed.

Conclusions Although the drugs presently available for the treatment of overweight are few in number and limited in efficacy, the pipeline for development of drugs for overweight is very rich. Because drug development is more sophisticated today than in the past, we anticipate that the development of safe and effective drugs for the treatment of overweight will proceed at a more rapid pace than was the case for other chronic diseases, like hypertension and diabetes, that presently have safe and effective medications. Our view is that we are entering an era where obesity will be managed like type 2 diabetes. Multiple medications with different mechanisms of action will be FDA approved for long-term management of obesity. Physicians of the future will be able to choose among many drugs, targeting multiple mechanisms of action, and combination pharmacotherapy will be common. We predict that advances in therapeutic approaches to lifestyle change will make addition of medication to these programs the routine, with the emphasis on prevention of obesity comorbidities. References 1. National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases (U.S.). Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. Washington, DC: National Institutes of Health, National Heart, Lung, and Blood Institute, 1998. 2. North American Association for the Study of Obesity. National Heart, Lung, and Blood Institute. The practical guide: identification, evaluation, and treatment for overweight and obesity in adults. Washington, DC: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 2000. 3. United States. Public Health Service. Office of the Surgeon General, United States. Office of Disease Prevention and Health Promotion, Centers for Disease Control and Prevention (U.S.), National Institutes of Health (U.S.). The Surgeon General’s call to action to prevent and decrease overweight and obesity. Washington, DC: U.S. Dept. of Health and Human Services, Public Health Service. For sale by the Supt. of Docs., U.S. G.P.O., 2001. 4. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002;346:591– 602. 5. Bray GA, Greenway FL. Current and potential drugs for treatment of obesity. Endocr Rev 1999;20:805– 875. 6. Snow V, Barry P, Fitterman N, Qaseem A, Weiss K. Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2005;142:525–531. 7. Padwal R, Majumdar SR, Johnson JA, Varney J, McAlister FA. A systematic review of drug therapy to delay or prevent type 2 diabetes. Diabetes Care 2005;28:736 –744.

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8. Vettor R, Serra R, Fabris R, Pagano C, Federspil G. Effect of sibutramine on weight management and metabolic control in type 2 diabetes: a meta-analysis of clinical studies. Diabetes Care 2005;28:942–949. 9. Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev 2004: CD004094. 10. Haddock CK, Poston WS, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes Relat Metab Disord 2002;26:262–273. 11. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC. Metaanalysis: pharmacologic treatment of obesity. Ann Intern Med 2005;142:532–546. 12. Kim SH, Lee YM, Jee SH, Nam CM. Effect of sibutramine on weight loss and blood pressure: a meta-analysis of controlled trials. Obes Res 2003;11:1116 –1123. 13. Colman E. Anorectics on trial: a half century of federal regulation of prescription appetite suppressants. Ann Intern Med 2005; 143:380 –385. 14. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 15. IDF Worldwide Definition of the Metabolic Syndrome. Volume 2006; Brussels, Belgium: International Diabetes Federation, 2006. 16. Sjostrom L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Krempf M. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998;352:167–172. 17. Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, Heimburger DC, Lucas CP, Robbins DC, Chung J, Heymsfield SB. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999;281:235–242. 18. Rossner S, Sjostrom L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res 2000; 8:49 – 61. 19. Hauptman J. Orlistat: selective inhibition of caloric absorption can affect long-term body weight. Endocrine 2000;13:201– 206. 20. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27:155–161. 21. Hill JO, Hauptman J, Anderson JW, Fujioka K, O’Neil PM, Smith DK, Zavoral JH, Aronne LJ. Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study. Am J Clin Nutr 1999;69:1108 –1116. 22. Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR, Crockett SE, Kaplan RA, Comstock J, Lucas CP, Lodewick PA, Canovatchel W, Chung J, Hauptman J. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care 1998;21: 1288 –1294. 23. Kelley DE, Bray GA, Pi-Sunyer FX, Klein S, Hill J, Miles J, Hollander P. Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 2002;25: 1033–1041.

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for the management of obese type 2 diabetic patients. Diabetes Metab 2006;55:A395.

Received November 22, 2006. Accepted December 6, 2006. Address requests for reprints to: George A. Bray, MD, 6400 Perkins Road, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808. e-mail: [email protected]; fax: (225) 7633045.