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Keywords:

  • sibutramine;
  • weight loss;
  • blood pressure;
  • meta-analysis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. References

Objective: Sibutramine causes weight loss by suppressing the appetite and by promoting energy expenditure, but it can also increase blood pressure through a norepinephrine effect. The aim of this study was to provide a comprehensive meta-analysis of randomized, controlled trials on the effects of sibutramine on blood pressure and weight loss.

Research Methods and Procedures: Twenty-one placebo-controlled, double-blind, randomized trials of sibutramine were identified using MEDLINE, EMBASE, and a manual search. The effect sizes of sibutramine on weight and systolic (SBP) and diastolic (DBP) blood pressure changes were estimated. Subgroup analyses were undertaken to explore the relationship between effect sizes and the study characteristics.

Results: The effect size of sibutramine on weight change was −1.00 (−1.17 to −0.84), whereas the effect sizes on SBP and DBP changes were 0.16 (0.08 to 0.24) and 0.26 (0.18 to 0.33), respectively. By subgroup analysis, the effect sizes on weight loss were significantly larger when the dosage was ≥15 mg. The effect sizes on increased SBP were significantly larger when the initial body weight was ≥92 kg and the age was <44 years; similarly, the effect sizes on increased DBP were significantly larger when the initial weight was ≥92 kg.

Discussion: Sibutramine showed a large effect on weight loss. Because blood pressure was found to be increased slightly, but significantly, sibutramine should be used cautiously in patients with borderline or high blood pressure. Additional studies on its effect on blood pressure are needed.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. References

Obesity is a chronic disease, and its incidence is increasing worldwide. In the year 2000, 12 million people worldwide and 64.5% of American adults were overweight, defined as a BMI ≥25kg/m2 (1). As the life styles of Korean people continue to change, obesity is no longer a problem limited to the Western hemisphere. The Korean Nationwide Health Examination Survey of 1998 indicated that 26.3% of adults were overweight (2).

Physicians have been reluctant to adopt the pharmacological approach for the treatment of obesity because of serious side effects and potential abuse. However, obesity is not merely a cosmetic issue, but an issue of major public health concern, because of its high association with morbidity and mortality (3, 4). Thus, the long-term management of obesity through a multidisciplinary approach is necessary. In particular, the importance of pharmacological treatment has been reassessed positively in recent years.

Sibutramine was approved in 1997 by the FDA in the U.S. It is a serotonin-norepinephrine reuptake inhibitor that induces weight loss by enhancing satiety and by promoting energy expenditure (5, 6). Sibutramine has also been shown to lower blood sugar and lipid levels (7, 8, 9). However, it has been reported that because of its norepinephrine effect, sibutramine could increase blood pressure (8, 10, 11, 12, 13, 14), which would inevitably restrict its use in patients with hypertension (15). Some recent studies have suggested that sibutramine does not significantly increase blood pressure as compared with a placebo (16, 17, 18).

No meta-analysis has been performed on the effect of sibutramine on blood pressure, although a number of systematic reviews have demonstrated sibutramine's weight-loss effect (19, 20). However, because obese patients frequently have high blood pressure, we believed that a systematic review of the effect of sibutramine on blood pressure was necessary. The purpose of this study was to provide a comprehensive meta-analysis of randomized, controlled trials on the effect of sibutramine on blood pressure and weight loss.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. References

Search Strategy and Inclusion Criteria

Using the key word “sibutramine,” we initially conducted a comprehensive literature search of MEDLINE and EMBASE (1966 to September 2002). We also conducted a manual search of reference lists from original research papers and review articles.

Studies that met the following criteria were included in the review: 1) human studies; 2) double-blinded, randomized, placebo-controlled trials of sibutramine; 3) studies written in English with full-text versions available; 4) studies with participants who were obese or overweight; 5) studies with participants who had no eating or psychiatric disorders; and 6) studies that indicated a dosage of sibutramine of >5 mg. We did not limit the duration of intervention and the existence in participants of comorbidities such as diabetes, hypertension, or hyperlipidemia. Among studies that met the inclusion criteria, we excluded the following: 1) cross-over studies; 2) studies that did not provide any information for estimating an effect size of weight change; and 3) studies that used drugs for weight maintenance. In trials with multiple treatment groups, each treatment group was compared with the control group independently.

These articles were reviewed independently by two of the authors (S.H.K. and C.M.N.) to determine whether the articles met the inclusion criteria of the present study. The primary outcome measures were changes in weight (measured in kilograms), systolic blood pressure (SBP),1 and diastolic blood pressure (DBP) (measured in mm Hg).

Statistical Analysis

The effect size of sibutramine was defined as the standardized difference of changes (follow-up minus baseline) in weight and blood pressure between the treatment and the control groups. In studies not directly reporting the variance for changes in weight and blood pressure, variances were calculated from confidence intervals (CIs), statistical values, or p values. In cases reporting only p < 0.05 (p < 0.01), we replaced p values with p = 0.05 (p = 0.01) to produce our findings conservatively. In cases without any information for estimating the SDs of changes, we imputed them to the mean values of other studies. To estimate the overall effect sizes, we used the inverse variance method, which assigned the reciprocal of the variance to each study as a weight. A fixed effect model was used to estimate the overall effect size if the effect sizes were homogeneous across studies; otherwise, a random effect model was used.

Subgroup analyses were performed to investigate the further effects of weight at baseline, BMI, age, percentage of women, duration and dosage of intervention, and sample size of the study on the changes in weight and blood pressure. Finally, multiple regression analysis was carried out using weighted least square. To examine potential publication bias, we estimated Rosenthal's fail-safe N and also plotted sample size against effect sizes. Data analysis was performed using Metawin (version 2.0; Sinauer Associates, Inc., Sunderland, MA) and SAS software (version 8.1; SAS Institute, Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. References

Using the key word “sibutramine,” we found a total of 361 and 175 publications in EMBASE and MEDLINE, respectively. We first included 30 papers that met inclusion criteria 1 to 6 described above. Of the 30 papers, 9 were excluded for the following reasons: three were cross-over designs; five did not allow the effect size of the weight change to be estimated; and one study was focused on weight maintenance. Six articles with multiple treatment groups (10, 18, 22, 23, 24, 25) were divided into 16 independent trials according to the treatment dose. In the end, a total number of 31 individual trials were included in the analysis. The characteristics of the trials included in this meta-analysis are shown in Table 1.

Table 1.  Intervention and baseline characteristics of trials included in the meta-analyses
  InterventionBaseline
Trial no.Author, Year (Reference)Duration (weeks)Dosage (mg)Sample sizeWeight (kg)BMI (kg/m2)SBP (mm Hg)DBP (mm Hg)
  • *

    Lowercase letters (a, b, c, d, e) represent different dosages used in the same trials. We analyzed these dosages as independent trials.

1Weintraub et al., 1991 a* (25)8537    
2Weintraub et al., 1991 b (25)82039    
3Hanotin et al., 1998 a (22)12511583.732.3  
4Hanotin et al., 1998 b (22)121011884.532.0  
5Hanotin et al., 1998 c (22)121512186.232.7  
6Seagle et al., 1998 a (23)8103087.532.9  
7Seagle et al., 1998 b (23)8302988.133.1  
8Apfelbaum et al., 1999 (14)521015996.735.5  
9Bray et al., 1999 a (10)24519496.334.8  
10Bray et al., 1999 b (10)241018695.534.5  
11Bray et al., 1999 c (10)241518595.334.6  
12Bray et al., 1999 d (10)242018396.634.7  
13Bray et al., 1999 e (10)243018896.434.9  
14Hansen et al., 1999 (13)81532100.433.9 73.1
15Cuellar et al., 2000 (28)24156587.935.9  
16Fanghanel et al., 2000 (29)24108486.935.8117.377.5
17Finer et al., 2000 (30)12159083.630.8  
18Fujioka et al., 2000 (8)242012198.834.0128.079.0
19Hazenberg et al., 2000 (16)121011395.433.7152.897.6
20McMahon et al., 2000 (11)522021186.734.3133.784.0
21Dujovne et al., 2001 (7)2420303100.935.3119.977.8
22Gokcel et al., 2001 (9)24205495.538.4129.586.9
23Smith et al., 2001 a (24)521031187.032.7  
24Smith et al., 2001 b (24)521531087.032.5  
25Wirth et al., 2001 (31)441560698.534.8  
26Faria et al., 2002 (17)241086 39.5149.992.6
27McMahon et al., 2002 (12)522012097.433.9129.482.6
28Serrano-Rios et al., 2002 (32)241513493.1   
29Sramek et al., 2002 (33)12206195.133.9131.882.3
30Zannad et al., 2002 a (18)241012391.134.0121.175.2
31Zannad et al., 2002 b (18)242012091.533.7121.475.5

The overall effect size on weight change was −1.00 [95% CI: −1.17 to −0.84]. For SBP change, the effect sizes of the studies ranged from −0.38 to 0.45, and the overall effect size was 0.16 (0.08 to 0.24). The effect sizes of the studies on DBP change varied from −0.11 to 0.73, and the overall effect size was 0.26 (0.18 to 0.33). Sibutramine showed a large effect on weight loss but increased blood pressure significantly (Table 2). Figures 1 and 2 display the effect size of each study and the overall effect size on weight, SBP, and DBP changes.

Table 2.  Effect size and variance of each study for changes in weight and systolic and diastolic blood pressure
   WeightSBPDBP
Trial no.TrialsDosage (mg)ESVarESVarESVar
  1. ES, effect size; Var, variance.

1Weintraub, a5−0.680.12    
2Weintraub, b20−1.480.13    
3Hanotin, a5−0.260.04    
4Hanotin, b10−0.960.04    
5Hanotin, c15−0.900.04    
6Seagle, a10−1.720.18    
7Seagle, b30−2.140.22    
8Apfelbaum10−0.850.03  0.360.03
9Bray, a5−0.590.020.270.020.110.02
10Bray, b10−1.090.020.340.020.360.02
11Bray, c15−1.410.030.330.020.240.02
12Bray, d20−1.710.030.450.020.470.02
13Bray, e30−1.910.030.390.020.340.02
14Hansen15−1.700.17  0.730.14
15Cuellar15−1.500.08    
16Fanghanel10−0.980.050.210.050.270.05
17Finer15−1.180.05−0.040.04−0.040.04
18Fujioka20−0.360.030.160.030.280.03
19Hazenberg10−0.550.040.030.040.330.04
20McMahon20−0.280.020.110.020.280.02
21Dujovne20−1.010.020.190.010.350.01
22Gokcel20−1.520.10    
23Smith10−0.510.010.140.010.180.01
24Smith15−0.900.010.080.010.110.01
25Wirth15−0.670.01    
26Faria10−1.300.06−0.380.050.430.05
27McMahon20−0.390.040.270.040.540.04
28SerranoRios15−0.670.03−0.150.03  
29Sramek20−1.300.080.100.07  
30Zannad, a10−0.930.04−0.110.03−0.110.03
31Zannad, b20−1.250.040.170.030.130.03
Overall effect size (95% CI)  −1.00 (−1.17 to −0.84)0.16 (0.08 to 0.24)0.26 (0.18 to 0.33)
Rosenthal's fail-safe N  1788.299.6340.5
image

Figure 1. The effect size of each study and overall effect size on weight change. The numbers are the same as shown in Table 2.

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image

Figure 2. The effect size of each study and overall effect sizes on changes in SBP and DBP. The numbers are the same as shown in Table 2.

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Table 3 summarizes the overall effect sizes on weight and blood pressure in subgroups of trials according to weight at baseline, age, percentage of women, duration, dosage, and sample size. A greater increase in SBP was observed in younger people (<44 years old) and in larger trials (≥120 participants). People who were heavier (≥92 kg) experienced a significantly greater increase in DBP. By multiple regression (Table 4), the overall effect size on weight loss was significantly larger when the dosage exceeded 15 mg (p = 0.01). The overall effect sizes on increased SBP were significantly larger when the initial body weight was ≥92 kg (p = 0.01) and the age was <44 years (p = 0.03); similarly, the effect sizes on increased DBP were significantly larger when the initial weight was ≥92 kg (p = 0.03). Rosenthal's fail-safe N values are also shown in Table 2.

Table 3.  Differences of effect size on weight loss and changes in blood pressure in subgroups of trials defined by the study characteristics
 WeightSBPDBP
CharacteristicsnES95% CIp*nES95% CIpnES95% CIp
  • *

    p values were obtained from independent two-sample t test.

Weight (kg)            
 <9213−1.00−1.25 to −0.740.9670.09−0.05 to 0.230.0970.14−0.002 to 0.270.00
 ≥9215−0.97−1.23 to −0.71 110.230.12 to 0.34 110.330.22 to 0.45 
BMI (kg/m2)            
 <3414−0.89−1.14 to −0.650.5680.11−0.02 to 0.250.4980.210.07 to 0.340.09
 ≥3414−1.10−1.37 to −0.83 100.220.12 to 0.33 110.290.18 to 0.39 
Age (years)            
 <4419−1.09−1.31 to −0.870.16100.220.12 to 0.330.03120.230.13 to 0.320.64
 ≥4412−0.85−1.13 to −0.57 90.06−0.07 to 0.20 70.320.16 to 0.47 
Percentage of women            
 <8014−0.87−1.12 to −0.620.1790.150.02 to 0.280.8590.350.22 to 0.480.07
 ≥8017−1.11−1.34 to −0.87 100.170.06 to 0.28 100.190.09 to 0.30 
Duration (weeks)            
 <2411−1.07−1.41 to −0.730.3530.02−0.51 to 0.560.3530.24−0.33 to 0.810.78
 ≥2420−0.97−1.18 to −0.77 160.180.10 to 0.26 160.260.18 to 0.34 
Dosage (mg)            
 <1512−0.81−1.02 to −0.600.1070.13−0.02 to 0.270.3280.220.09 to 0.360.45
 ≥1519−1.12−1.36 to −0.88 120.190.09 to 0.29 110.280.17 to 0.38 
Sample size            
 <12014−1.16−1.45 to −0.870.075−0.02−0.29 to 0.250.0550.280.01 to 0.250.42
 ≥12017−0.90−1.12 to −0.67 140.190.11 to 0.28 140.250.17 to 0.33 
Table 4.  Regression coefficients of selected study characteristics
  WeightSBPDBP
Independent variablesReference categoryCoefficientpCoefficientpCoefficientp
Age (years)<440.250.22−0.300.03−0.090.39
Percentage of women<80−0.210.26−0.160.22−0.170.09
Weight (kg)<92  0.170.010.150.03
Duration (weeks)<24−0.240.38    
Dosage (mg)<15−0.470.01    
Sample size (n)<1200.530.060.030.730.010.92

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. References

In this study, we analyzed the effect of sibutramine on weight loss and blood pressure by meta-analysis. Haddock et al. (19) reviewed 108 clinical trials of pharmacotherapy for obesity and concluded that the mean weight loss from 4 trials on sibutramine was 3.5 kg. O'Meara et al. (20) reviewed 16 placebo-controlled trials and found that sibutramine caused significantly greater weight loss than a placebo (mean difference for weight change at 8 weeks: −3.4kg; mean difference range for weight change at 6 months: −4.0 to −9.1kg; and at 1 year: −4.1 to −4.8kg).

Some studies have reported that sibutramine has an adverse effect on blood pressure (8, 10, 11, 12, 13, 14), but others have found that it does not increase blood pressure significantly (16, 17, 18). Thus, we wanted to examine, using meta-analysis, the overall effect size of sibutramine on blood pressure. In the present study, the effect size on weight change was estimated using a random effect model, and the effect sizes on blood pressure changes were determined using fixed effect models. The weight-loss effect was confirmed by our study, and SBP and DBP were found to increase significantly: the effect size on SBP change was 0.16 (95% CI: 0.08 to 0.24), and that on DBP change was 0.26 (0.18 to 0.33). We found that the net increased blood pressure attributable to sibutramine was 1.6 mm Hg for SBP and 1.8 mm Hg for DBP under the assumption that SDs of changes in SBP and DBP during the intervention were 10 mm Hg and 7 mm Hg (estimated from included studies), respectively.

All studies that met the inclusion criteria should have been included in the meta-analysis. Based on this rule, by replacing p values with more conservative values, we included studies lacking complete information for estimating the effect sizes. It is important to note that blood pressure was found to be significantly increased, despite our use of conservative values. It is also noteworthy that the increased blood pressure induced by sibutramine was more pronounced in studies with heavier and/or younger patients.

We included only randomized, controlled trials because these studies produce high-quality evidence and have a lesser likelihood of biases (21). We excluded cross-over studies because of the possibility of carry-over effects and their inadequacy in terms of estimating effect size. In six articles with multiple treatment groups (10, 18, 22, 23, 24, 25), the effect sizes of the treatment groups when compared with the control groups were regarded as independent observations. To check the robustness of our main findings from these observations, we included only one trial per paper with the most frequently used dosage and found that the results were compatible with our main findings: the effect sizes on changes in weight, SBP, and DBP were −0.92, 0.10, and 0.28, respectively.

There are some limitations in this meta-analysis. First, our results could be over- or underestimated according to the inclusion criteria. Among excluded papers, one (26) allowed an estimate of the effect size on blood pressure. In this paper, blood pressure increased significantly. Thus, there was a possibility that the true overall effect sizes on changes in blood pressure would have been greater if we had searched papers by focusing on changes in blood pressure as a primary endpoint of sibutramine. Second, because all of the studies included in this review were done in Western countries, the results obtained have limited relevance in Asian countries, such as Korea. Third, a possible publication bias might have been introduced because we included only published studies. However, an examination of funnel plots showed no evidence of a publication bias. Furthermore, Rosenthal's fail-safe N values (27), defined by the number of unpublished negative studies that would nullify the significant results if published, were ∼100 for SBP and ∼341 for DBP, which are large enough to allow us to discount the existence of a publication bias.

In summary, we conclude that sibutramine has a large effect on weight loss and causes a small, but significant, increase in both SBP and DBP. It might be considered that the small increase in blood pressure is not important in the clinical setting in normotensive patients or patients with well-controlled hypertension. However, sibutramine should be used cautiously in patients with borderline or high blood pressure, because a slight increase in blood pressure is crucially important. More randomized, controlled trials that focus on the effect of sibutramine on blood pressure are needed, particularly in heavier and younger patients.

Footnotes
  • 1

    Nonstandard abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; CI, confidence interval.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. References
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