Clinical and Experimental Medicine

, Volume 10, Issue 3, pp 179–184

Comparison of the effects of sibutramine versus sibutramine plus metformin in obese women

Authors

    • Department of Internal Medicine, Division of Endocrinology and Metabolism, School of MedicineAkdeniz University
  • Esin Eray
    • Department of Internal Medicine, Division of Endocrinology and Metabolism, School of MedicineAkdeniz University
  • Sabahat Ozdem
    • Department of Clinical Chemistry, Central Laboratory, School of MedicineAkdeniz University
  • Halide Akbas
    • Department of Clinical Chemistry, Central Laboratory, School of MedicineAkdeniz University
  • Erkan Coban
    • Department of Internal Medicine, School of MedicineAkdeniz University
Original Article

DOI: 10.1007/s10238-009-0080-y

Cite this article as:
Sari, R., Eray, E., Ozdem, S. et al. Clin Exp Med (2010) 10: 179. doi:10.1007/s10238-009-0080-y

Abstract

Sibutramine and metformin are drugs commonly used to obtain weight loss. We aimed to compare the effects of sibutramine alone with that of sibutramine plus metformin combination on weight loss, insulin sensitivity, leptin and C reactive protein in obese women. Seventy obese women were included. After a diet period of month (baseline), each individual was randomly assigned to receive 15 mg sibutramine (sibutramine group; n = 36) or 15 mg sibutramine plus 1,700 mg metformin per day (sibutramine plus metformin group; n = 34) during the next 12 months. Body weight, insulin resistance by the homeostasis model assessment model (HOMA-IR), leptin and C reactive protein were measured at baseline, after 3 months and after 12 months. Mean weight losses in sibutramine and sibutramine plus metformin groups were 5.3 ± 4.0% (P < 0.001) and 6.8 ± 3.9% (P < 0.001) after 3 months, and 10.5 ± 4.4% (P < 0.001) and 15.7 ± 4.6% (P = 0.007) after 12 months, respectively. HOMA-IR value also decreased in both sibutramine (P = 0.045 and P = 0.002) and sibutramine plus metformin groups (P = 0.04 and P = 0.015) after 3 and 12 months, respectively. Similarly, serum leptin levels decreased in both sibutramine (P = 0.04, P = 0.01) and sibutramine plus metformin groups (P = 0.023, P = 0.025) after 3 and 12 months, respectively. There was also significant reductions in serum C reactive protein levels in both sibutramine (P = 0.045, P = 0.02) and sibutramine plus metformin groups (P = 0.007, P = 0.001) after 3 and 12 months, respectively. These decrements of body weight, HOMA-IR, serum leptin and C reactive protein levels were not statistical significance between these two groups both after 3 and 12 months (P > 0.05). Combination of sibutramine with metformin did not result in any further effects on weight loss, insulin resistance, leptin and C reactive protein levels when compared to sibutramine alone.

Keywords

ObesityInsulin resistanceLeptinInflammationMetforminSibutramine

Introduction

Obesity is associated with diabetes, insulin resistance, cardiovascular disease, hypertension and dyslipidemia. Obese women are five times more probable to die from cardiovascular disease than women in the general population, and cardiovascular risk increases by 3.1% for each kilogram of weight gain [1, 2]. Insulin resistance, elevated serum leptin and high sensitive C reactive protein (hsCRP) levels are common features of obesity in humans and experimental animals [37]. Weight loss is associated with reduced morbidity and mortality in obese individuals [8]. Despite a modest weight reduction of 3–5%, this was associated with disproportionate improvement in most of the cardiovascular risk factors [4, 9, 10].

Sibutramine is a norepinephrine–serotonin re-uptake inhibitor, and it is currently used for induction and maintenance of weight loss. In recent literature, sibutramine has enabled a 7% reduction in initial weight after 1 year of therapy [1113]. Generally, sibutramine treatment is associated with significant improvement in the insulin sensitivity, serum leptin and hsCRP [1419]. On the other hand, it has also been demonstrated that metformin, an antihyperglycemic agent, decreases hyperinsulinemia and the insulin resistance leading to decreased adiposity in obese and noninsulin-dependent diabetes mellitus [20, 21]. In recent studies, metformin treatment is also associated with significant improvement in the insulin sensitivity, serum leptin and hsCRP levels [2224].

Some investigators have suggested that greater weight loss might be achieved by combining these anti-obesity drugs [25, 26] since they have different mechanisms of actions. To our knowledge, a possible further effect of combination of metformin with sibutramine compared to that of sibutramine alone on weight loss, insulin resistance, serum leptin and hsCRP levels in obese subjects with normal glucose tolerance subject has not been investigated yet. Therefore, in this prospective, we assessed and compared the effects of 12 months of sibutramine plus metformin treatment with that of sibutramine alone on weight loss, insulin sensitivity, and serum leptin and hsCRP levels in obese women by a randomized trial.

Patients and methods

We conducted a prospective and randomized study. The study population consisted of 70 obese women having a body mass index (BMI) ≥30 kg/m² and normal glucose tolerance. Informed consent was obtained from the subjects. Eligible subjects underwent a comprehensive assessment including the documentation of medical history, physical examination, anthropometric indices, 75 gr oral glucose tolerance test and the measurement of laboratory variables. Body weight (kilogram) and height (meter) were measured with the patient in light clothes and without shoes. Body weight, insulin resistance, serum leptin and hsCRP levels were measured at baseline, after 3 months and after 12 months during treatment.

Fasting plasma insulin levels were measured with Roche Modular Analytics E170 immunoassay system (Roche Diagnostics GmbH, Mannheim, Germany) using electrochemiluminescence immunoassay method (ECLIA). Fasting plasma glucose levels were determined by enzymatic colorimetric assay method (GLU, Roche Diagnostics GmbH, Mannheim, Germany). Insulin resistance was estimated using the homeostasis model assessment (HOMA-IR) derived from the following equation [HOMA-IR = (Fasting plasma glucose level × fasting plasma insulin level)/22.5]. Fasting serum leptin levels were measured by two-site immunoradiometric assay method (Active Human Leptin IRMA, DSL-23100, USA). High sensitive C reactive protein levels were measured by nepholometric method on BNII nepholometer (Dade Behring, Germany).

Exclusion criteria include impaired glucose tolerance (by 75 gr oral glucose tolerance test), diabetes mellitus (by 75 gr oral glucose tolerance test), hyperlipidemia (triglyceride or total cholesterol levels higher than 200 mg/dL), hypertension (blood pressure higher than 140/90 mm Hg), pregnancy, lactation, childbearing potential with inadequate contraceptive measures, psychiatric or neurological disorders, alcohol or other substance abuse, a history of recurrent nephrolithiasis or symptomatic cholelithiasis, previous gastrointestinal tract surgery for weight reduction, a history or the presence of malignancy, a significant history of cardiovascular complications and renal impairment with a plasma creatinine level of greater than 1.3 mg/dL.

All subjects took the same content and caloric diet therapy during the study. Diet therapy was based partially on National Heart, Lung, and Blood Institute suggestion [27]. Energy requirements of patients were calculated, and they were instructed to consume a diet of 1,200–1,600 kcal/day [(25 kcal/kg) ideal body weight], representing a deficit of approximately 600–850 kcal/day. A balanced diet with approximately 50% of calories from carbohydrate, 20% from protein and ≤30% from fat was recommended.

At the end of the first month of diet therapy (baseline), each individual was assigned randomly to receive either 15 mg sibutramine, once daily (Reductil, Abbott LTD) (sibutramine group; n = 36; mean age 46.0 ± 10.7 years, mean BMI 37.4 ± 4.8 kg/m²) or 15 mg sibutramine (Reductil, Abbott LTD, ones daily) plus 850 mg metformin (Glucophage, Merck LTD, twice daily) (sibutramine plus metformin group; n = 34; mean age 47.8 ± 6.9 years, mean BMI 42.1 ± 5.7 kg/m²) for 12 months. Diet and drug compliance of the subjects were evaluated by a dietitian and physician during the study. Nine patients in sibutramine group and nine patients in sibutramine plus metformin group were dropped due to diet incompliance between 3 and 12 months.

Statistical analysis

Statistical analysis was done by SPSS statistical software (SPSS 10.0 for Windows, standard version). The results were presented as mean ± SD. Continuous variables were tested for normality using the Kolmogorov–Smirnov test. Nonparametric tests were used in our study, because variables distribution was abnormal. Kruskal–Wallis test was performed to compare the groups. Nonparametric Friedman test was performed to examine differences in the dependent variables between baseline, 3 and 12 months. Correlation analysis was done by Spearman test. A P value <0.05 was considered statistically significant.

Results

Baseline values for body weight, BMI, glucose, insulin, HOMA-IR, leptin and hsCRP were similar in two groups (P > 0.05) (Table 1). BMI values correlated positively with HOMA-IR (r = 0.3, P = 0.045), leptin (r = 0.4, P = 0.01) and hsCRP levels (r = 0.42, P = 0.006).
Table 1

Comparison of the baseline parameters in groups

 

Sibutramine N = 36

Sibutramine plus metformin N = 34

P value

Age (years)

46.0 ± 10.7

47.8 ± 6.9

0.21

Body weight (kg)

90.4 ± 13.0

97.9 ± 13.2

0.08

BMI (kg/m2)

37.4 ± 4.8

42.1 ± 5.7

0.09

Glucose (mmol/L)

4.8 ± 0.7

5.1 ± 0.42

0.16

Insulin (mIU/L)

12.7 ± 5.7

15.1 ± 7.7

0.69

HOMA-IR

3.0 ± 1.9

3.8 ± 1.9

0.13

Leptin (ng/mL)

70.7 ± 25.2

60.8 ± 20.5

0.3

hsCRP (mg/L)

0.67 ± 0.36

0.84 ± 0.52

0.41

Mean weight loss in sibutramine group was 5.3 ± 4.0% after 3 months (P < 0.001) and 10.5 ± 4.4% after 12 months (P < 0.001). Mean weight loss in sibutramine plus metformin group was 6.8 ± 3.9% after 3 months (P < 0.001), and 15.7 ± 4.6% after the 12 months (P = 0.007) (Table 2; Fig. 1). The reduction in body weight during the study period was not significantly different between these two groups (P > 0.05).
Table 2

Study parameters at baseline, after 3 and 12 months

 

Baseline

3 months

12 months

Body weight (kg)

 Sibutramine

90.4 ± 13.0

85.7 ± 13.5

79.9 ± 13.3

 Sibutramine plus metformin

97.9 ± 13.2

91.3 ± 13.9

83.9 ± 13.1

BMI (kg/m2)

 Sibutramine

37.4 ± 4.8

35.4 ± 5.0

32.4 ± 5.1

 Sibutramine plus metformin

42.1 ± 5.7

39.3 ± 6.1

35.3 ± 6.1

HOMA-IR

 Sibutramine

3.0 ± 1.9

2.7 ± 2.0

2.5 ± 2.1

 Sibutramine plus metformin

3.8 ± 1.9

3.4 ± 2.0

2.9 ± 2.3

Leptin (ng/mL)

 Sibutramine

70.7 ± 25.2

60.6 ± 30.3

49.6 ± 30.0

 Sibutramine plus metformin

60.8 ± 20.5

46.2 ± 22.0

40.2 ± 22.0

hsCRP (mg/L)

 Sibutramine

0.67 ± 0.36

0.58 ± 0.34

0.50 ± 0.31

 Sibutramine plus metformin

0.84 ± 0.52

0.67 ± 0.39

0.56 ± 0.29

https://static-content.springer.com/image/art%3A10.1007%2Fs10238-009-0080-y/MediaObjects/10238_2009_80_Fig1_HTML.gif
Fig. 1

Change in body weight (kg) during the study period

There were significant reductions in HOMA-IR value in both sibutramine (P = 0.045, P = 0.002) and sibutramine plus metformin groups (P = 0.04, P = 0.015) after 3 and 12 months, respectively (Table 2; Fig. 2); but these reductions did not reach a statistical significance between the groups (P > 0.05).
https://static-content.springer.com/image/art%3A10.1007%2Fs10238-009-0080-y/MediaObjects/10238_2009_80_Fig2_HTML.gif
Fig. 2

Change in HOMA-IR during the study period

Similarly, serum leptin levels decreased in both sibutramine (P = 0.04, P = 0.01) and sibutramine plus metformin groups (P = 0.023, P = 0.025) after 3 and 12 months, respectively (Table 2; Fig. 3). These decrements of serum leptin levels were not statistical significance between the groups (P > 0.05).
https://static-content.springer.com/image/art%3A10.1007%2Fs10238-009-0080-y/MediaObjects/10238_2009_80_Fig3_HTML.gif
Fig. 3

Change in leptin (ng/mL) during the study period

There was significant reductions in serum C reactive protein levels both sibutramine (P = 0.045, P = 0.02) and sibutramine plus metformin groups (P = 0.007, P = 0.001) after 3 and 12 months, respectively (Table 2; Fig. 4). These decrements of serum C reactive protein levels were similar in two groups (P > 0.05).
https://static-content.springer.com/image/art%3A10.1007%2Fs10238-009-0080-y/MediaObjects/10238_2009_80_Fig4_HTML.gif
Fig. 4

Change in hsCRP (mg/L) during the study period

The reduction in body weight correlated positively with the reductions in HOMA-IR scores (r = 0.25, P = 0.046) and serum leptin (r = 0.6, P < 0.001), and serum hsCRP (r = 0.43, P = 0.005) levels.

Both sibutramine and metformin therapies were well-tolerated, and no subject discontinued the therapy because of adverse events. Five patients in combination group and three patients in sibutramine group experienced mild and transient gastrointestinal discomfort.

Discussion

Obesity is considered by the World Health Organization to be a chronic disease and a massive public health problem [28]. Many studies have confirmed the close associations between obesity and Type 2 diabetes, hypertension, dyslipidemia, insulin resistance, hyperleptinemia and low-grade inflammation [16]. The clustering of these risk factors acts synergistically to increase cardiovascular morbidity and mortality. A weight reduction of 5–10% has been shown to improve the cardiovascular risk profile [9, 10].

Apart from dietary restriction and lifestyle modification, pharmacological agents are often used in weight reduction programs. Various pharmacological agents have been used in the efforts to improve success with long-term weight maintenance. One of them is sibutramine which is a norepinephrine–serotonin re-uptake inhibitor that is currently used for induction and maintenance of weight loss [1114]. In controlled trials, sibutramine has enabled a 7% reduction in initial weight after 1 year of therapy [1113]. Accordingly, in most of the recent studies, we found 5.3 and 10.5% reductions in body weight after 3 and 12 months of sibutramine therapy, respectively.

The effect of metformin on weight loss in obese diabetic and nondiabetic subjects was controversial [10, 14, 2932]. Kay et al. [31] evaluated the antiobesity effect of metformin in 24 hyperinsulinemic nondiabetic obese adolescents. Compared to the placebo group, the metformin group had greater weight loss (6.5%). In contrast, it has also been reported that metformin treatment for 6 months did not cause a significant alteration in BMI [32]. Furthermore, in another study, it was found those 3 months of metformin treatment caused a slight but nonsignificant weight loss [29].

Weight loss has been shown to improve the cardiovascular risk profile in obese population [9, 10]. In a recent meta-analysis, modest weight reduction has also been shown to improve glucose intolerance [33]. Similarly, sibutramine treatment is associated with significant improvement in the insulin sensitivity indexes [1419]. In the present study, we also detected a significant improvement in the HOMA-IR index after 3 and 12 months of sibutramine treatment.

Several studies have demonstrated that insulin-sensitizing agents such as metformin decrease hyperinsulinemia, and increase insulin-stimulated glucose disposal and a progressive improve hepatic insulin sensitivity [10, 14, 29, 32]. In a study in fifteen adolescents with polycystic ovary syndrome and impaired glucose tolerance, 3 months of metformin treatment improved the glucose intolerance and even normalized it in eight (57%) subjects [29]. In contrast, in another study, insulin sensitivity as assessed by the ratio of fasting insulin to glucose concentrations and HOMA-IR indices increased slightly in the metformin-treated participants [32]. Moreover, first and second phase insulin levels during the hyperglycemic clamp were found to be not significantly different before and after metformin treatment [29].

Gokcel et al. [14] evaluated the effect of metformin and sibutramine per se on weight loss and insulin resistance. After 6 months of treatment, both sibutramine and metformin caused significant reductions in BMI (13.57% in sibutramine and 9.9% in metformin groups). Insulin resistance as assessed by HOMA-IR was reported to decrease 38.63 and 39.28% after 6 months of sibutramine and metformin therapies, respectively. We have detected approximately 10 and 16.6% decrements on HOMA-IR index after 3 and 12 months of sibutramine treatment.

Obesity is strongly associated with hyperleptinemia and low-grade inflammation [36, 34]. We also detected significant correlations between BMI and serum leptin levels and hsCRP levels in obese population. There are a few studies comparing the effects of different obesity medications on serum leptin and hsCRP levels. Both sibutramine and metformin therapies have been shown to reduce serum hsCRP in previous studies [18, 23, 24]. In our study, serum leptin and hsCRP levels also decreased after both 3 and 12 months of sibutramine therapy. Furthermore, the decrements in serum leptin and hsCRP levels correlated weight loss in our study.

Studies suggest that the “desired” weight loss of obese patients is 2 to 3 times greater (a 22–34% reduction in body weight) than the feasible and health promoting levels that is recommended by physicians [25]. However, overwhelming majority of studies has shown that mono drug therapy may not be enough to reach patient targets. Some investigators have suggested that greater weight loss might be achieved by combining the anti-obesity drugs [26, 35] as they have different mechanisms of actions. Recently, Wadden et al. [36] reported that the addition of orlistat to sibutramine did not induce further weight loss when compared to treatment by sibutramine alone. In another study, the combination of sibutramine and orlistat was more effective than orlistat therapy alone. However, significant difference was not noted between combination of sibutramine with orlistat and sibutramine alone [37]. Recently, we reported that the combination of metformin with orlistat did not induce further weight loss or reduction in HOMA-IR when compared to treatment of orlistat alone [38]. Similarly, combination of sibutramine and metformin therapy during the 12 months did not significantly induce greater weight loss, reduction in insulin resistance, serum leptin and serum hsCRP levels when compared to sibutramine alone in present study. It cannot be excluded that metformin will never work as body weight reducing agent when given concomitantly with sibutramine-metformin helps reduce body weight mainly through its anorectic action, and appetite is already suppressed when sibutramine is being taken.

Metformin and sibutramine therapies were well-tolerated during our study. The combination of these two medications did not appear to result in any unexpected side effects. Five patients in combination group and three patients in sibutramine group experienced mild gastrointestinal discomfort that was transient.

In conclusion, the findings of the present study suggested that sibutramine plus metformin and sibutramine alone treatment regimens induce significant improvements in body weight, insulin resistance, and serum leptin and hs-CRP levels in obese women. However, combination of sibutramine with metformin did not cause a significant further beneficial effect on these parameters when compared with sibutramine alone. Our results should be interpreted with caution because of relatively small sample size. Therefore, new studies that have more sample sizes are necessary for this purpose.

Conflict of interest statement

We declare that we have no conflict of interest related to the publication of this manuscript.

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© Springer-Verlag 2009