Medications For Obesity Treatment Approved Medications

Sibutramine

Sibutramine is approved by the Food and Drug Administration for long-term use in the treatment of obesity. Sibutramine has been evaluated extensively in several multicenter trials lasting 6 to 24 mo; a meta-analysis of some of these trials is shown in Table 2 (10-13). In a 6-mo dose-ranging study of 1047 patients, 67% treated with sibutramine achieved a 5% weight loss from baseline, and 35% lost 10% or more (14).

Table 2

Meta-Analysis of Net Weight Loss With Sibutramine (Placebo Drug)

Table 2

Meta-Analysis of Net Weight Loss With Sibutramine (Placebo Drug)

Apfelbaum (10)

-5.70( 95%

CI

-7.77

to

-3.63)

Davis (13)

-3.00 (95%

CI

-4.55

to

-1.45)

Hauner (11)

-5.30 (95%

CI

-6.83

to

-3.77)

McNulty (12)

-4.80 (95%

CI

-6.02

to

-3.58)

Wirth (16)

-4.00 (95%

CI

-5.01

to

-2.99)

Adapted from ref. 5.

Adapted from ref. 5.

There was a clear dose-response effect in this 24-wk 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. 2 (14).

In a 1-yr trial of456 patients who received sibutramine (10 mg or 15 mg/d) or placebo, 56% of those who stayed in the trial for 12 mo 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 (8). In a third trial in patients who initially lost weight eating a very-low-calorie diet before being randomized to sibutramine (10 mg/d) or placebo, sibutramine produced additional weight loss, whereas the placebo-treated patients regained weight (8). The Sibutramine Trial of Obesity Reduction and Maintenance lasted 2 yr and provided evidence for weight maintenance (15). Seven centers participated in this trial, in which patients were initially enrolled in an open-label phase and treated with 10 mg/d of sibutramine for 6 mo. Of the patients who lost more than 8 kg, two-thirds were then randomized to sibutramine and one-third to placebo. During the 18-mo double-blind phase of this trial, the placebo-treated patients steadily regained weight, maintaining only 20% of their initial weight loss at the end of the trial. In contrast, the subjects treated with sibutramine maintained their weight for 12 mo and then regained an average of only 2 kg, thus maintaining 80% of their initial weight loss after 2 yr (16). Despite the higher weight loss with sibutramine at the end of the 18 mo 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 wk (15). The patients randomized to sibutramine received one of two regimens. One group received continuous treatment with 15 mg/d for 1 yr, and the other had two 6-wk 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.

Some trials have reported the use of sibutramine to treat patients with hypertension. In a 3-mo trial, all patients were receiving ^-blockers with or without thiazides for their hypertension (17). The 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

End of Treatment

End of Treatment

Bray, Obes Res, 1999 Treatment Week

Fig. 2. Effect of sibutramine on body weight. (From ref. 14)

(mean ┬▒standard deviation) beats per minute in the sibutramine-treated patients, as compared with an increase of 2.2 ┬▒6.43 beats per minute in the placebo group. One 52-wk trial involved patients with hypertension whose blood pressure levels were controlled with calcium channel blockers with or without ^-blockers or thiazides (18). Sibutramine doses were increased from 5 to 20 mg/d during the first 6 wk. Weight loss was significantly greater in the sibutramine-treated patients, averaging 4.4 kg (4.7%), as compared with 0.5 kg (0.7%) in the placebo-treated group. Diastolic blood pressure levels decreased by 1.3 mmHg in the placebo-treated group and increased by 2 mmHg in the sibutramine-treated group. The systolic blood pressure levels increased by 1.5 mmHg in the placebo-treated group and by 2.7 mmHg 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.

Six studies with diabetic patients treated with sibutramine have been published (19). In one study, patients were treated for 12 wk or 24 wk with sibutramine. In the 12-wk trial, patients with diabetes treated with sibutramine at 15 mg/d lost 2.4 kg (2.8%), compared with 0.1 kg (0.12%) in the placebo group (20). 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 by 0.3 mg/dL in the drug-treated patients and increased by 1.4 mg/dL in the placebo-treated group. In the 24-wk trial, the dose of sibutramine was increased from 5 to 20 mg/d over 6 wk (21). 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.

Sibutramine has been studied as part of a behavioral weight-loss program. With minimal behavioral intervention, the weight loss was approx 5 kg (5%) over 12 mo. When behavior modification was added, the weight loss increased to 10 kg, and when a structured meal plan was added to the medication and behavioral modification, the weight loss increased further to 15 kg (22).

Sibutramine has also been used in children and adolescents (23-25). The trial by Berkowitz et al. (23) included 85 adolescents 13 to 17 yr of age with a BMI of 32 to 44 kg/m2 who were treated for 6 mo. Weight loss in the drug-treated group was 7.8 kg, for an 8.5% reduction in BMI, compared with 3.2 kg for a 4.0% reduction in BMI. When the placebo group was switched to sibutramine after 6 mo, there was an additional significant weight loss in this group. In a multicenter trial, 498 adolescents aged 12 to 16 were randomized to receive either placebo or sibutramine for 12 mo. BMI was reduced by a mean of -7.9 kg/m2 (-8.2%) in those treated with sibutramine, compared with -0.3 kg/ m2 (-0.8%) in those treated with placebo. Lipids and insulin sensitivity were improved, but there was no significant difference in blood pressure changes between the groups (25).

Sibutramine is available in 5-, 10-, and 15-mg doses; 10 mg/d as a single dose is the recommended starting level, with titration up or down depending on response. Doses higher than 15 mg/d are not recommended. Of the patients who lost 2 kg (4 lb) in the first 4 wk of treatment, 60% achieved a weight loss of more than 5%, compared with less than 10% of those who did not lose 2 kg (4 lb) in 4 wk. 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.

Orlistat

Orlistat is a lipase inhibitor. In pharmacological studies, orlistat was shown to be a potent selective inhibitor of pancreatic lipase that reduces the intestinal digestion of fat. The drug has a dose-dependent effect on fecal fat loss, increasing it to approx 30% on 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 (8).

A number of 1- to 2-yr long-term clinical trials with orlistat have been published, and the results of a meta-analysis of these data are shown in Table 3 (5). The results of a 2-yr trial are shown in Fig. 3 (26). The trial consisted of two parts. In the first year, patients received a hypocaloric diet calculated to be 500 kcal/d less than the patient's requirements. During the second year, the diet was calculated to maintain 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% loss in the patients treated with orlistat for the full 2 yr.

In a second 2-yr study, 892 patients were randomized (27). One group (97 patients) remained on placebo throughout the 2 yr, and a second group (109 patients) remained

Table 3

Meta-Analysis of Net Weight Loss With Orlistat (Placebo Minus Drug)

Table 3

Meta-Analysis of Net Weight Loss With Orlistat (Placebo Minus Drug)

Davidson (1999)

-2.95

(95%

CI

-4.45

to

-1.45)

Hauptman (2000)

-3.80

(95%

CI

-5.37

to

-2.23)

Rossner (2000)

-3.00

(95%

CI

-4.17

to

-1.83)

Sjostrom (1998)

-4.20

(95%

CI

-5.26

to

-3.14)

Torgerson (2004)

-4.17

(95%

CI

-4.60

to

-3.74)

Adapted from ref. 5.

Adapted from ref. 5.

on orlistat (120 mg three times per day) for 2 yr. At the end of 1 yr, two-thirds of the group treated with orlistat for 1 yr were changed to orlistat (60 mg three times per day) (102 patients), and the others were switched to placebo (95 patients) (27). After 1 yr, 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 second year, those switched to placebo after 1 yr reached the same weight as those treated with placebo for 2 yr (-4.5% in those with placebo for 2 yr and -4.2% in those switched to placebo during year 2).

In a third 2-yr study, 783 patients remained in the placebo or orlistat-treated groups at 60 mg or 120 mg three times per day for the entire 2 yr (28). After 1 yr 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 60 mg orlistat three times daily, or the 9.8 kg lost by the group treated with 120 mg orlistat three times daily. During the second year, when the diet was liberalized to a "weight maintenance" diet, all three groups regained some weight. At the end of 2 yr, the patients in the placebo group were 4.3 kg below baseline, the patients treated with 60 mg orlistat three times per day were 6.8 kg below baseline, and the patients who took 120 mg orlistat three times per day were 7.6 kg below baseline.

The final 2-yr trial that has been published evaluated 796 subjects in a general-practice setting (29). After 1 yr of treatment with 120 mg orlistat three times per day, the orlistat-treated patients (n =117) had lost 8.8 kg, compared with 4.3 kg in the placebo group ( n =91). During the second year, when the diet was liberalized to "maintain body weight," both groups regained some weight. At the end of 2 yr, 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 results of a 4-yr double-blind, randomized, placebo-controlled trial with orlistat have also been reported (30). 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 yr of the trial, there was a small regain in weight, such that by the end of 4 yr, 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 at enrollment into the trial.

Fig. 3. Orlistat and body weight. (From ref. 26.)

Weight maintenance with orlistat was evaluated in a 1-yr study (8). Patients were enrolled if they had lost more than 8% of their body weight over 6 mo while eating a 1000 kcal/d (4,180 kJ/d) diet. The 729 patients were randomized to receive placebo or orlistat at 30, 60, or 120 mg three times per day for 12 mo. 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 120 mg orlistat three times per day. The other two doses of orlistat were not different from placebo in preventing the regain of weight.

Patients with diabetes treated with 120 mg orlistat three times daily for 1 yr lost more weight than the placebo-treated group (31-33). 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-yr studies described previously in which glucose tolerance tests were available (34). 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.

In a further analysis, patients who had participated in previously reported studies were divided into the highest and lowest quintiles for triglyceride and HDL cholesterol levels (35). 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 "non-syndrome X" controls. In this classification, there were almost no men in the non-syndrome X group, compared with an equal sex breakdown in the syn drome X group. In addition, the syndrome X group had slightly higher systolic and diastolic blood pressure levels and a nearly twofold 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 in the non-syndrome X group. All the clinical studies with orlistat have shown significant decreases in serum cholesterol and LDL cholesterol levels that usually are higher than can be accounted for by weight loss alone (8). One study showed that orlistat reduces the absorption of cholesterol from the GI tract, thus providing a mechanism for the clinical observations (36).

A multicenter trial tested the effect of orlistat in 539 obese adolescents (37). Subjects were randomized to placebo or 120 mg orlistat three 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. This difference was caused by differences in body fat. The side effects were gastrointestinal in origin as expected from the mode of action of orlistat.

Safety of Orlistat. Orlistat is not absorbed from the GI tract to any significant degree, and its side effects are thus related to the blockade of triglyceride digestion in the intestine (38). Fecal fat loss and related GI symptoms are common initially, but they subside as patients learn to use the drug (8). 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 clinically appropriate 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.

Combining Orlistat and Sibutramine. Because orlistat works peripherally to reduce triglyceride digestion in the GI tract and sibutramine works on noradrenergic and serotonergic reuptake mechanisms in the brain, 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 yr of treatment with sibutramine (Fig. 3) (39). During the additional 4 mo of treatment, there was no further weight loss. This result was a disappointment, but additional studies are needed.

Phentermine and Diethylpropion: Sympathomimetic Drugs Approved for Short-Term Use

Most of the data on phentermine, diethylpropion, benzphetamine, and phendimetrazine come from short-term trials (8). One of the longest of these clinical trials lasted 36 wk and compared placebo treatment with continuous phentermine or intermittent phentermine (40). Both continuous and intermittent phentermine therapy produced more weight loss than placebo. In the drug-free periods, the patients treated intermittently slowed their weight loss, only to lose more rapidly when the drug was reinstituted. Phentermine and diethylpropion are classified by the US 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 wk. 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 occur.

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