Introduction

The management of obesity is a major challenge for both physicians and patients. Conventional treatment based on dietary restriction and behavioral modification generally results in only limited success, with the majority of obese patients unable to maintain short-term weight losses (1, 2, 3). Therefore, there is a recognized need for safe and effective adjunctive pharmacotherapy.

The role of dietary fat in the etiology of obesity is widely accepted (4, 5). Orlistat (Xenical; Hoffmann-La Roche, Basel, Switzerland) is a novel, nonsystemically acting weight management agent that partially inhibits gastrointestinal lipase activity, thereby reducing dietary fat absorption approximately 33% (6). The efficacy of orlistat as an aid to weight reduction has been clearly demonstrated in a series of 2-year multicenter, randomized, placebo-controlled trials (7, 8, 9, 10).

Chitosan is an N-deacetylated form of chitin that is extracted from the shells of crustaceans (11). Orally administered chitosan is positively charged and, in theory, binds to negatively charged dietary fat in the intestine. Thus, dietary fat would be excreted in the feces rather than being absorbed (12). This apparent inhibition of fat absorption by chitosan has resulted in its widespread promotion as a nonprescription weight loss agent. Chitosan is marketed under a variety of names, e.g., Fat Blocker and Fat Absorb, and is widely available over-the-counter from health food and dietary supplement stores as well as numerous Internet sites. However, very little evidence to support weight loss claims made for chitosan has been published in peer-reviewed journals. Additionally, studies that have been published suggest that chitosan has little or no effect on body weight or related risk factors in obese subjects (13, 14).

The aim of the present proof-of-concept study was to compare the effects of treatment with orlistat or chitosan on fecal fat excretion, a marker of pharmacodynamic effect.

Research Methods and Procedures

Patients and Methods

A total of 12 healthy volunteers (7 men and 5 women) ages 18 to 45 years were recruited for this single-center, randomized, open-label, two-period crossover study. Subjects were eligible if they were within 20% of their ideal weight according to Metropolitan Life Insurance tables. Women of child-bearing potential were included provided that they were using a reliable form of contraception.

Subjects were excluded if they were treated with prescription medications within 2 weeks or over-the-counter medications (including vitamin supplements) within 3 days of screening. Other exclusion criteria included active gastrointestinal disease; diarrhea within 1 week or constipation within 2 weeks of the start of the study; previous gastrointestinal surgery or a history of postsurgical adhesions; a history of bulimia or laxative abuse; or known allergy or sensitivity to orlistat, chitosan, or shellfish. Subjects were also excluded if they had special dietary requirements, e.g., vegetarian, kosher, or lactose-intolerant, or if they smoked >10 cigarettes a day or had a history of substance abuse, including excessive alcohol intake.

After screening, subjects entered a 7-day run-in period during which they followed the standardized diet before being randomized to two 7-day open-label treatment regimens in a sequential manner. Regimen A consisted of treatment with orlistat (120 mg; Xenical) three times daily (TID), whereas regimen B consisted of treatment with two capsules of chitosan (445 mg; Fat Binder; East Anglia Pharmaceutical, United Kingdom) TID. After 7 days, subjects crossed-over treatment regimen for an additional 7-day period (AB or BA), such that subjects receiving orlistat (120 mg) in the first week of treatment received chitosan (890 mg) in the second week, and vice versa, thereby acting as their own controls. Study medication was administered TID with main meals at breakfast (8:00 AM to 9:00AM), lunch (12:00 AM to 1:00 PM) and dinner (6:00 PM to 7:00 PM).

Standardized meals were supplied throughout the 21-day study. Caloric intake was 2500 kcal/d, of which 50% was carbohydrate, 20% protein, and 30% fat (83 g/d). Cholesterol intake did not exceed 300 mg/d. Meals were prepared in accordance with dieticians' instructions and the food intake of all subjects was monitored.

All feces were collected on days 4 to 7 of the run-in period (baseline) and throughout the two 7-day treatment periods. Feces were collected, weighed, and stored at -20 °C before being sent for fecal fat analysis at a central laboratory (MediLab BioProfil, Copenhagen, Denmark). The amount of fat excreted in the feces was quantified by the method of Van de Kamer et al. (15).

Subjects were monitored daily for adverse events and vital signs throughout the 21-day study and at a poststudy examination. Urine and fasting blood samples were taken for standard laboratory analyses.

All participants gave written informed consent. The study protocol was approved by the Cambridge Local Research Ethics Committee and conformed with the Declaration of Helsinki.

Assessments

Mean 24-hour fecal fat excretion at baseline and during each treatment regimen was considered the primary pharmacodynamic parameter. An ANOVA model was used for the two-period, two-sequence crossover design to assess possible sequence (carryover) effect or period effect.

Mean SD changes from baseline were calculated for both treatment regimens and 95% confidence intervals (CIs) were constructed. Mean changes from baseline between treatment regimens were compared using paired t tests. Because the sample size was small, nonparametric tests were also performed to confirm statistical comparisons. A sample size of 12 patients provides 80% power to detect between-group differences of 10 g/24-h fecal fat at a p = 0.05 level of significance. Within-group mean changes from baseline were also assessed.

Results

Among the 12 subjects in this study, mean ( SD) baseline fecal fat excretion was 1.36 0.45 g/d. During treatment with orlistat (120 mg TID), mean fecal fat excretion increased from baseline by 16.13 7.27 g/d (95% CI: 11.51; 20.75). This increase from baseline in fecal fat was statistically significant (p < 0.001). However, treatment with chitosan (890 mg TID) had no significant effect on fecal fat excretion (mean change: 0.27 1.02; 95% CI: -0.38; 0.92; p = 0.379). Fecal fat excretion was significantly greater during treatment with orlistat than with chitosan (p < 0.001; 95% CI: 11.73; 20.00;Figure 1 ). All p values determined by paired t tests were confirmed by Mann–Whitney U tests. No significant sequence (p = 0.503) or period effect (p = 0.457) was present (Table 1 ).

Figure 1.

Mean ( SD) 24-hour fecal fat excretion in a 7-day run-in period (baseline) and during treatment with orlistat (120 mg) or chitosan (890 mg) TID in 12 healthy non-obese volunteers.

Full figure and legend (57K)

Table 1 - Mean ( SD) 24-hour fecal fat excretion in 1 7-day run-in period (baseline) and during treatment with orlistat (120 mg) or chitosan (890 mg) TID in 12 healthy non-obese volunteers.

Full table

Both treatments were well-tolerated, with no subjects reporting severe adverse events or discontinuing the study for adverse events. The majority of adverse events were gastrointestinal in nature, reported by 66% of subjects while receiving orlistat (vs. 8% of subjects during chitosan treatment). These gastrointestinal effects are probably related to the pharmacological action of orlistat.

Discussion

Previous studies have clearly demonstrated the inhibitory effect of orlistat on dietary fat absorption (16). Moreover, the ability of adjunctive orlistat treatment to promote clinically significant weight loss in overweight or obese patients has been shown in several clinical trials (7, 8, 9, 10). In comparison, the efficacy of chitosan as an aid to weight loss in humans is largely unproven. Increased fat excretion during chitosan administration has been demonstrated in animal studies (17, 18, 19). However, the dosages of chitosan used in these studies were 15 to 22 times higher than the equivalent recommended dose in humans (2000 to 3000 mg/d). A number of short-term studies in which subjects received chitosan with a hypocaloric diet have suggested statistically greater weight loss with chitosan compared with placebo (20, 21). However, the validity of these findings has been questioned (13). Moreover, chitosan treatment did not produce weight loss in obese subjects in two recent randomized, placebo-controlled trials. In one study of 34 overweight volunteers, chitosan (1000 mg twice daily) had no effect on body weight after 4 weeks of treatment (13). Similarly, chitosan (1200 mg twice daily for 8 weeks) failed to reduce body weight in a study of 51 obese women (14). In addition, chitosan had no significant effect on total serum cholesterol in either study. These findings are in direct contrast with claims that chitosan is an effective aid to weight loss.

In the present study, orlistat significantly increased fecal fat excretion, whereas no significant effect was observed with chitosan. These data are in accordance with a previous nonrandomized, noncontrolled pilot investigation that compared fecal fat excretion with orlistat and chitosan in healthy volunteers (22).

The pharmacological treatment of obesity is recognized as an important aspect of long-term weight management. However, the use of pharmacotherapy to treat obesity has a contentious and controversial history, with unapproved, inappropriate, and sometimes unsafe agents having previously been used by persons wishing to lose weight (23). As such, it is essential that new agents, promoted as aids to weight loss, be rigorously evaluated for both clinical efficacy and safety.

The gastrointestinal lipase inhibitor, orlistat, has been shown to promote weight loss and long-term weight maintenance in overweight and obese patients in a series of well-designed, large-scale clinical trials (7, 8, 9, 10). Chitosan is also marketed as a noncentrally acting weight loss agent, despite very little clinical evidence to support claims of efficacy. In the present study, the inhibitory effect of orlistat on dietary fat absorption was clearly shown. However, in contrast, chitosan failed to produce short-term inhibition of dietary fat absorption. As such, it is unlikely that chitosan would effectively produce long-term weight loss.

References

1. Kramer, F. M., Jeffery, R. W., Forster, J. L., Snell, M. K. (1989) Long-term follow-up of behavioral treatment for obesity: patterns of weight regain among men and women. Int J Obes Relat Metab Disord 13: 123–136. | ChemPort |
2. Wadden, T. A. (1993) Treatment of obesity by moderate and severe calorie restriction: results of clinical research trials. Arch Intern Med 119: 688–693.
3. Sarlio-Lähteenkorva, S., Rissanen, A., Kaprio, J. (2000) A descriptive study of weight loss maintenance: 6- and 15-year follow-up of initially overweight adults. Int J Obes Relat Metab Disord 24: 116–125. | Article | PubMed | ChemPort |
4. Golay, A., Bobbioni, E. (1997) The role of dietary fat in obesity. Int J Obes Relat Metab Disord 21(suppl 3): S2–S11. | PubMed |
5. Bray, G. A., Popkin, B. M. (1998) Dietary fat intake does affect obesity!. Am J Clin Nutr 68: 1157–73. | PubMed | ISI | ChemPort |
6. Guerciolini, R. (1997) Mode of action of orlistat. Int J Obes Relat Metab Disord 21(suppl 3): S12–SS3. | PubMed | ChemPort |
7. Sjöström, L., Rissanen, A., Andersen, T., et al (1998) Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 352: 167–172. | Article | PubMed | ISI | ChemPort |
8. Davidson, M. H., Hauptman, J., DiGirolamo, M., et al (1999) Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat. JAMA 281: 235–242. | Article | PubMed | ISI | ChemPort |
9. Rössner, S., Sjöström, L., Noack, R., Meinders, A. E., Noseda, G. (2000) Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. Obes Res 8: 49–61. | PubMed | ChemPort |
10. Hauptman, J., Lucas, C., Boldrin, M., Collins, H., Segal, K. R. (2000) Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med 9: 160–167. | Article | PubMed | ChemPort |
11. Muzzarelli, R. A., Ilari, P., Petrarulo, M. (1994) Solubility and structure of N-carboxy-methylchitosan. Int J Biol Macromol 16: 177–180.
12. Kanaucho, O., Deuchi, K., Imasato, Y., Shizukuishi, M., Kobayashi, E. (1995) Mechanism of fat digestion by chitosan and for the synergistic effect of ascorbate. Biosci Biotech Biochem 59: 786–790. | ChemPort |
13. Pittler, M. H., Abbot, N. C., Harkness, E. F., Ernst, E. (1999) Randomized, double-blind trial of chitosan for body weight reduction. Eur J Clin Nutr 53: 379–381. | Article | PubMed | ChemPort |
14. Wuolijoki, E., Hirvelä, T., Ylitalo, P. (1999) Decrease in serum LDL cholesterol with microcrystalline chitosan. Methods Find Exp Clin Pharmacol 21: 357–361. | Article | PubMed | ChemPort |
15. Van de Kamer, B. J., ten Bokkel Huinink, H., Weyers, H. A. (1949) Rapid method for the determination of fat in feces. J Biol Chem 177: 347–55. | ChemPort |
16. Zhi, J., Melia, A. T., Guerciolini, R., et al (1994) Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmacol Ther 56: 82–85. | PubMed | ISI | ChemPort |
17. Sugano, M., Jujikawa, T., Hiratsuji, Y., Nakashima, K., Fukuda, N., Hasegawa, Y. (1980) A novel use of chitosan as a hypercholesterolaemic agent in rats. Am J Clin Nutr 33: 787–793. | PubMed |
18. Deuchi, K., Kanauchi, O., Imasato, Y., Kobayashi, E. (1994) Decreasing effect of chitosan on the apparent fat digestibility by rats fed on a high-fat diet. Biosci Biotech Biochem 58: 1613–1616.
19. Ormrod, D. J., Holmes, C. C., Miller, T. E. (1998) Dietary chitosan inhibits hypercholesterolaemia and atherogenesis in the apolipoprotein E-deficient mouse model of atherosclerosis. Atherosclerosis 138: 329–334. | Article | PubMed |
20. Veneroni, G., Veneroni, F., Contos, S., et al (1996) Effect of a new chitosan on hyperlipidemia and overweight in obese patients. Muzzarelli, RAAA eds. Chitin Enzymology 63–67. Aztec Edizioni Italy.
21. Ventura, P. (1996) Lipid lowering activity of chitosan, a new dietary integrator. Muzzarelli, RAAA eds. Chitin Enzymology 55–62. Aztec Edizioni Italy.
22. Lengsfeld, H., Fleury, A., Nölte, M., et al (1999) Effect of orlistat and chitosan on faecal fat excretion in young healthy volunteers. Obes Res 7(suppl 1): O132 (abst).
23. Bray, G. A. (1998) Pharmacological treatment of obesity. Bray, GA Bouchard, C James, WPT eds. Handbook of Obesity 953–976. Marcel Dekker New York, NY.

Acknowledgments

Funding for this study was provided by F. Hoffmann-La Roche.