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Journal of Obesity
Volume 2010, Article ID 602537, 5 pages
http://dx.doi.org/10.1155/2010/602537
Clinical Study

Efficacy and Tolerability of the Association of Sibutramine and Orlistat for Six Months in Overweight and Obese Patients

1Group of Obesity & Metabolic Syndrome, Endocrinology Service, Hospital das Clínicas, Faculty of Medicine, University of Sao Paulo, 05410-000 São Paulo, Brazil
2Department of Nutrition and Dietitian, Clínica Alfredo Halpern, 05410-000 São Paulo, Brazil

Received 24 June 2009; Revised 17 November 2009; Accepted 3 December 2009

Academic Editor: Renato Pasquali

Copyright © 2010 Alfredo Halpern et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective. To assess the efficacy and tolerability of the association sibutramine (10–20 mg/day) and orlistat (120 mg 2-3 times a day) in the treatment of obesity in a six-month open trial. Methods. 446 overweight and obese patients who sought treatment for obesity in a private clinic were assessed every 2 weeks during a period of 3 and 6 months. Results. After 3 months, the mean weight loss was 10.5 kg ( 9.8% of the initial weight, ), and after 6 months, the mean weight loss was 13.9 kg ( 12.8% of the initial weight, ). The tolerability of such association was quite acceptable and coherent with the action mechanism of each component. Conclusions. The association of orlistat and sibutramine is quite efficient and it seems to promote a higher rate of weight loss than that reported in clinical studies performed with each drug separately.

1. Introduction

Obesity is a chronic disease with increasing prevalence [1]. Obesity leads to metabolic abnormalities that contribute to the development of diabetes and cardiovascular diseases. Most of these diseases require long-term treatments and are associated with increased risk of morbidity and mortality [2, 3].

Diet, behavioral changes and physical activities often fail to promote weight loss and maintenance [4, 5]. Pharmacological treatment can increase the motivation of the patient and adherence to the treatment. Therefore, it is considered a crucial approach.

Among the anti-obesity drugs, sibutramine and its metabolites affect the central nervous system, inhibiting serotonin and noradrenaline reuptake, increasing the sensation of satiety and thermogenesis [68].

Orlistat, on the other hand, is a chemically synthesized hydrogenated derivative of lipstatin that partially inhibits the activity of gastric and pancreatic lipase and carboxyl ester lipase in the gastrointestinal system, reducing the hydrolysis of triglycerides, and thus preventing the absorption of about 30% of the ingested fat [9, 10].

Since the mechanisms of action of these drugs are completely different, it is possible and reasonable, at least theoretically, to associate sibutramine to orlistat with the purpose of obtaining the benefits of both mechanisms, potentiating the weight loss.

In clinical practice we frequently use such a combination and, in this retrospective open trial, we analyzed the efficacy and tolerability of the association of sibutramine 10 to 20 mg/day and orlistat 120 mg two and three times a day in patients who sought treatment for obesity.

2. Methods

In the present study, 446 patients (208 men and 238 women) sought treatment for obesity at our private clinic from 08/1998 to 11/2006 and received a combination of sibutramine 10 to 20 mg/day and orlistat 120 mg 2-3 times a day associated with a hypocaloric diet and recommendation of regular physical activities since the beginning of the treatment. The patients who took the medication for at least 2 weeks since the beginning of the treatment were included in this study. The patients under 18 years of age (10 patients) who were included in the study had BMI > 32.5 kg/m2, which is considered a very severe class of obesity for this age group. These patients also had high blood pressure, dyslipidemia and orthopedic complications. Those individuals who had diabetes and uncontrolled high blood pressure were not included in the study. In addition, we also did not include the patients when sibutramine was contraindicated due to severe hepatic and renal failure, arrhythmia, myocardial infarction, and stroke, or those who were using monoamine oxidase enzyme inhibitors and tricyclic antidepressants. We also did not include in the study the patients with gastrointestinal problems for whom the use of orlistat was contraindicated.

All patients had a stable weight and were not taking any antiobesity drugs in the previous three months. The subjects received prescription of a hypocaloric diet containing up to 30% of fat and designed by a dietitian, based on an individual interview. During the first visit, the patients received guidance regarding techniques of behavioral change and they were urged to practice physical activities. Patients were assessed every 2 weeks for a period of 3 (263 patients) and 6 (97 patients) months. Weight, heart rate, blood pressure and adverse effects were recorded and the potential relation between adverse effects and treatment was assessed and analyzed by the investigator (AH), who used standardized terms especially designed to describe the expected gastrointestinal events due to the increased release of fat caused by the treatment with orlistat, as well as the side effects potentially caused by sibutramine. The adverse effects were analyzed after 4 weeks of treatment in order to include more individuals.

2.1. Statistical Analysis

The Student paired test was used to compare the data (baseline, 3 and 6 months), using the software SPSS 16.0.

3. Results

3.1. Followup and Weight Loss

The initial characteristics of the individuals are shown in Table 1.

tab1
Table 1: Initial characteristics of the individuals included in the study.

One hundred eighty-three out of 446 initial patients quit treatment during the first 3 months and 166 dropped out treatment between the visits in the 3rd and 6th months. The basic known reasons for quitting treatment were lack of weight-loss efficacy (10.9%) and lack of adherence to medication (7.7%). For the remaining patients, the reason for quitting the treatment was not known or could not be established because they just interrupted the scheduled visits. We used the method of last observation carried forward (LOCF). The results regarding weight loss for all patients are shown in Table 2 and in Figure 1.

tab2
Table 2: Weight loss of 446 patients in 3 and 6 months. (LOCF).
602537.fig.001
Figure 1: Weight loss of 446 patients in 3 and 6 months (LOCF).

Results shown in Figure 2 take into consideration only the individuals that completed the study at 3 and 6 months.

602537.fig.002
Figure 2: Evolution of weight loss in 3 and 6 months for patients who completed the study.

The weight loss in 3 and 6 months for female patients who completed the study was –9.9% and –13.4%, respectively. For male patients who completed the study, the weight loss in 3 and 6 months was –8.7% and –12.3%, respectively.

There was a statistically significant difference between initial weight and after 3 months (106.6 ± 22.9 kg versus 98.3 ± 21.4 kg, P <.001) as well as between initial BMI and after 3 months (36.7 ± 6.7 kg/m2 versus 34.0 ± 6.3 kg/m2, P <.001).

Statistically significant differences were also observed between initial weight and after 6 months (106.6 ± 22.9 kg versus 97.4 ± 21.2 kg, P <.001) as well as between initial BMI and after 6 months (36.7 ± 6.7 kg/m2 versus 33.6 ± 6.2 kg/m2, P <.001).

Furthermore, statistically significant differences were observed between weight after 3 months and weight after 6 months (98.3 ± 21.4 kg versus 97.4 ± 21.2 kg, P <.001) as well as BMI after 3 and 6 months (34.0 ± 6.3 kg/m2 versus 33.6 ± 6.2 kg/m2, P <.001).

In the categorical analysis, the percentage of individuals who lost more than 5% and more than 10% in 3 months was 83.6% (220 patients—123 F/97 M) and 41% (108 patients—58 F/50 M), respectively, and in 6 months was 88.7% (86 patients—47 F/39 M) and 66% (64 patients—35 F/29 M) (Figure 3). In the same analysis, the percentage of female patients who lost more than 5% and more than 10% in 3 months was 89.9% and 36.5%, respectively, and in 6 months was 92.2% and 68.6%. The percentage of male patients who lost more than 5% and more than 10% in 3 months was 77 % and 39.7%, respectively, and in 6 months was 84.8% and 63%.

602537.fig.003
Figure 3: Categorical analysis of weight loss (>5% and >10%) in 3 and 6 months.

One-fifth of the patients were postmenopausal women (n = 19, 19.6%) at the end of the follow-up. The weight loss was not statistically different when compared to the women in the premenopausal state.

3.2. Adverse Effects

In order to include a significant number of adverse effects, we studied the same effects after 4 weeks of treatment (446 patients).

One hundred nineteen (26.7%) out of 446 patients reported at least one adverse effect. Table 3 shows the adverse effects reported by more than 5% of the individuals.

tab3
Table 3: Adverse effects seen in more than 5% of the cases in the first month of treatment.

Eleven patients quit treatment due to adverse effects (headache, restlessness, and tachycardia).

Since this is an open trial and the laboratory tests were not performed in the same center, we did not consider the results of the lipid profile at the beginning and at the end of the treatment. On the other hand, we did not find clear changes in blood pressure and pulse rate.

4. Discussion

Obesity is a complex and multifactorial disease that similarly to high blood pressure and diabetes frequently requires pharmacological treatment.

Since the body weight regulation involves several modulating pathways and redundant systems in terms of physiological action and these mechanisms “protect” the individual who is undergoing diet and physical activity against “starvation”, it is probable that the ideal treatment for obesity might involve the association of two or more medications in the future [11].

The great majority of the studies on anti-obesity medications include only one drug. There are very few publications in the literature showing the effects of the pharmacological treatment for obesity with association of medications. In an attempt to compare these studies with our results, we designed Tables 4 and 5 to show the results of weight loss with sibutramine and with orlistat in 3 and 6 months.

tab4
Table 4: Studies carried out with sibutramine in non-diabetic patients.
tab5
Table 5: Studies carried out with orlistat in nondiabetic patients.

Most adverse effects reported in the present study are similar to those published in the other previous studies. Regarding orlistat, we found increased evacuation, oily feces and fecal urgency. Regarding sibutramine, the adverse effects reported were dry mouth and intestinal constipation. Other adverse effects found in other studies with sibutramine, such as headache and insomnia, were not reported by more than 5% of the patients at the end of the first 4 weeks of treatment. Such effects are consistent with the pharmacology of orlistat and sibutramine.

Only few studies previously assessed the association of sibutramine and orlistat. A 3-month study carried out with 86 patients compared four types of treatment: sibutramine, orlistat, association of sibutramine and orlistat, and only diet. We found that patients treated with medication had better results, but there was not a significant difference regarding weight loss between the groups treated only with sibutramine and the sibutramine and orlistat group [12]. Another study that also assessed the waist circumference with the same groups of treatment as the previous study found reduced BMI and waist circumference. These rates were higher in the treatment group that combined sibutramine and orlistat. However, after correlating the increased rates of BMI and waist circumference, the authors found that the best result was obtained in the group treated only with orlistat followed by the group that used the combined treatment. The worst result was obtained by the group treated only with sibutramine [13]. Nevertheless a study carried out with 34 obese women showed that after one year of treatment with sibutramine the addition of orlistat revealed little benefit in patients who had lost previously 11.6% of initial weight. However, the authors emphasize that the results must be interpreted with caution because of the small sample size [14].

In the present study, weight loss was evident, being comparable with (or higher than) that obtained with sibutramine or orlistat separately in 3- and 6-month studies [1520].

In the above mentioned studies, weight loss with sibutramine ranged from 6.1% to 8.8%, and with orlistat it ranged from 4.8% to 9.8%.

Sibutramine and orlistat are new drugs with different mechanisms of action; therefore, their association is very reasonable.

5. Conclusions

In conclusion, our data suggest that the association between orlistat and sibutramine is quite efficient and it seems to promote a higher rate of weight loss than that reported in clinical studies performed with each drug separately. The tolerability of such association is quite acceptable; therefore, it is a valid option for the treatment of obesity. Further long-term studies to evaluate the association of orlistat and sibutramine in the treatment of obesity are needed.

Conflicts of Interest

Dr. Halpern is member of the Advisory Board of Roche and speaker for Abbott, Medley and GlenMark. Dr. Mancini is speaker for Roche, Abbott, Medley and GlenMark.

References

  1. J. C. Seidell, “Obesity in Europe: scaling an epidemic,” International Journal of Obesity, vol. 19, supplement 3, pp. S1–S4, 1995. View at Google Scholar · View at Scopus
  2. F. X. Pi-Sunyer, “Medical hazards of obesity,” Annals of Internal Medicine, vol. 119, no. 7, part 2, pp. 655–660, 1993. View at Google Scholar · View at Scopus
  3. G. A. Bray, “Health hazards of obesity,” Endocrinology and Metabolism Clinics of North America, vol. 25, no. 4, pp. 907–919, 1996. View at Publisher · View at Google Scholar · View at Scopus
  4. P. R. Thomas, Ed., Weighing the Options: Criteria for Evaluating Weight-Management Programs, National Academy Press, Washington, DC, USA, 1996.
  5. S. Z. Yanovski, “Long-term pharmacotherapy in the management of obesity,” Journal of the American Medical Association, vol. 276, no. 23, pp. 1907–1915, 1996. View at Google Scholar · View at Scopus
  6. I. P. Connoley, D. J. Heal, and M. J. Stock, “A study in rats of the effects of sibutramine on food intake and thermogenesis,” British Journal of Pharmacology, vol. 114, supplement, p. 388, 1995. View at Google Scholar
  7. J. C. G. Halford, D. J. Heal, and J. E. Blundell, “Effects in the rat of sibutramine on food intake and the behavioural satiety sequence,” British Journal of Pharmacology, vol. 114, supplement, p. 387, 1995. View at Google Scholar
  8. I. P. Connoley, Y.-L. Liu, I. Frost, I. P. Reckless, D. J. Heal, and M. J. Stock, “Thermogenic effects of sibutramine and its metabolites,” British Journal of Pharmacology, vol. 126, no. 6, pp. 1487–1495, 1999. View at Google Scholar · View at Scopus
  9. R. Guerciolini, “Mode of action of orlistat,” International Journal of Obesity, vol. 21, supplement 3, pp. S12–S23, 1997. View at Google Scholar · View at Scopus
  10. J. Zhi, A. T. Melia, C. Funk et al., “Metabolic profiles of minimally absorbed orlistat in obese/overweight volunteers,” Journal of Clinical Pharmacology, vol. 36, no. 11, pp. 1006–1011, 1996. View at Google Scholar · View at Scopus
  11. M. C. Mancini and A. Halpern, “Investigational therapies in the treatment of obesity,” Expert Opinion on Investigational Drugs, vol. 15, no. 8, pp. 897–915, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. A. Kaya, N. Aydin, P. Topsever et al., “Efficacy of sibutramine, orlistat and combination therapy on short-term weight management in obese patients,” Biomedicine and Pharmacotherapy, vol. 58, no. 10, pp. 582–587, 2004. View at Publisher · View at Google Scholar · View at PubMed
  13. N. Aydin, P. Topsever, A. Kaya, M. Karasakal, C. Duman, and A. Daǧar, “Orlistat, sibutramine, or combination therapy: which performs better on waist circumference in relation with body mass index in obese patients?” Tohoku Journal of Experimental Medicine, vol. 202, no. 3, pp. 173–180, 2004. View at Publisher · View at Google Scholar
  14. T. A. Wadden, R. I. Berkowitz, L.G. Womble, D. B. Sarwer, M. E. Arnold, and C. M. Steinberg, “Effects of sibutramine plus orlistat in obese women following 1 year of treatment by sibutramine alone: a placebo-controlled trial,” Obesity Research, vol. 8, no. 6, pp. 431–437, 2000. View at Google Scholar
  15. C. Hanotin, F. Thomas, S. P. Jones, E. Leutenegger, and P. Drouin, “A comparison of sibutramine and dexfenfluramine in the treatment of obesity,” Obesity Research, vol. 6, no. 4, pp. 285–291, 1998. View at Google Scholar
  16. C. Hanotin, F. Thomas, S. P. Jones, E. Leutenegger, and P. Drouin, “Efficacy and tolerability of sibutramine in obese patients: a dose-ranging study,” International Journal of Obesity, vol. 22, no. 1, pp. 32–38, 1998. View at Google Scholar
  17. G. A. Bray, G. L. Blackburn, J. M. Ferguson et al., “Sibutramine produces dose-related weight loss,” Obesity Research, vol. 7, no. 2, pp. 189–198, 1999. View at Google Scholar
  18. M. L. Drent, I. Larsson, T. William-Olsson et al., “Orlistat (RO 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study,” International Journal of Obesity, vol. 19, no. 4, pp. 221–226, 1995. View at Google Scholar
  19. L. F. Van Gaal, J. I. Broom, G. Enzi, and H. Toplak, “Efficacy and tolerability of orlistat in the treatment of obesity: a 6-month dose-ranging study,” European Journal of Clinical Pharmacology, vol. 54, no. 2, pp. 125–132, 1998. View at Publisher · View at Google Scholar
  20. E. Muls, J. Kolanowski, A. Scheen, and L. Van Gaal, “The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study,” International Journal of Obesity, vol. 25, no. 11, pp. 1713–1721, 2001. View at Publisher · View at Google Scholar · View at PubMed