OBJECTIVES: This placebo-controlled open study was designed to test the hypothesis that most of the gastrointestinal (GI) side events induced by treatment of obese patients with orlistat (a gastrointestinal lipase inhibitor) could be prevented or ameliorated by concomitant use of natural fibers (psyllium mucilloid).
DESIGN: Two groups of obese women (BMI>27 kg/m2) were treated with orlistat 120 mg three times a day. One group (A, n=30) was randomized to receive orlistat and, approximately 6.0 g of orange-flavored psyllium mucilloid dissolved in water and the other group (B, n=30) received orlistat and orange-flavored placebo. At the end of 30 days and 2 weeks of washout, group A switched to placebo and group B received psyllium while continuing orlistat three times a day.
SUBJECTS: Sixty professional women, more than 21-y-old with a body mass index (BMI) between 27.3 and 48.0 kg/m2, who were not receiving any other medication.
MEASUREMENTS: Assessments included weekly visits to attending physician, filling a form in which GI events were recorded, monthly measurements of body weight, blood pressure and serum lipids. The frequency and severity of GI events were evaluated by a score system, based on information provided by the patients.
RESULTS: Both groups A and B significantly lost (P<0.01) weight after 60 days of orlistat (A=96.8 to 94.9 kg and B=98.7 to 96.5 kg). Similarly, BMI values declined significantly in both groups. While in the psyllium plus orlistat group (group A) the mean ±s.e.m. of the scores reflecting GI events was 13.0±1.8, the placebo plus orlistat group (B) had a value of 35.9±2.7 (P<0.01). When the reverse situation was instituted the placebo and orlistat group presented a mean score of 36.1±3.6 and the psyllium plus orlistat a mean score of 8.9±1.5 (P<0.01).
CONCLUSIONS: Psyllium hydrophilic mucilloid concomitantly prescribed to obese patients receiving 120 mg of orlistat three times a day is an effective and safe adjunct therapy that is helpful in controlling the GI side effects of this pancreatic lipase inhibitor.
Orlistat, a hydrogenated derivative of lipstatin is a potent inhibitor of gastric and pancreatic lipase.1,2,3,4,5,6 By inhibiting the intestinal lipase the therapeutic use of orlistat leads to a decreased fat absorption and subsequent excretion of the unabsorbed triglycerides, cholesterol and fat in the fecal excreta. In volunteers and obese subjects the maximal fecal fat loss, depending on the dose of orlistat and the amount of fat in the diet, was about one-third (30%) of the ingested fat, reaching a plateau with doses around 360 mg/day.
The side effects with orlistat are to be expected from its mechanism of action on pancreatic lipase. These include intestinal flatulence, borborygmi and abdominal cramps.5 The most troubling were fecal incontinence, oily spotting and flatus with discharge. In a large European Multicentre Orlistat study group2 adverse gastrointestinal (GI) events were a common reason for premature withdrawals in the orlistat treated group. In another randomized controlled trial of obese subjects treated for 2 y with orlistat (Multicentre American Study) at least one GI event was experienced by 79% of the subjects in the orlistat group.4 Gastrointestinal adverse events seem to increase with large doses of orlistat3 and have a tendency to be less frequent in the second year of the trial.2
Psyllium is a water-soluble, gel-forming fiber derived from the husks of blonde psyllium seeds (Plantago ovata, English plantain, commonly referred as ‘ispaghula’). Psyllium belongs to a group of soluble fibers that show cholesterol-lowering effects when added to patients' diets.7,8,9,10,11 Moreover, dietary fiber, such as psyllium, may increase the fractional turnover of bile acids, probably by increasing their fecal elimination. Also psyllium has been used to absorb intestinal fat both in obese and diabetic patients.10 Thus it was assumed that the constant use of psyllium hydrophilic mucilloid might be effective in diminishing the adverse effects of unabsorbed fat caused by orlistat.
In this study we have decided to use the beneficial gastrointestinal effects of a psyllium hydrophilic mucilloid in patients treated with orlistat, in order to minimize the GI events that are relatively common in this therapy.
Eligible obese patients all women, with ages from 27 to 42-y-old (mean±s.d. 40.9±8.9-y-old) with body mass index (BMI)>27 kg/m2, were recruited by advertisement in the university hospital weekly newsletter. All of them were employed by the hospital as officials, nurses and laboratory personnel. Women of childbearing potential were included if they were using adequate contraception. The study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of the University Hospital. All participants gave written informed consent. The main reason for using the university hospital personnel was to have a uniform group of obese patients that were not actually being treated for obesity, would have a predictable low drop-out rate, would be able to report accurately signs and symptoms related to GI events during orlistat therapy and could be easily contacted, on a daily basis, during the period of the project.
A total of 110 obese patients were initially eligible for the study. Of these, 60 obese women were finally recruited by personal interview. They were lacking major complications of obesity, were not under treatment for other conditions, were willing to cooperate and had no gastrointestinal signs or symptoms. Other exclusion criteria were weight loss of more than 4 kg in the 3 months before screening, bulimia and laxative abuse, use of any drug that might have influenced bodyweight, alcohol abuse, history of prior cholecystectomy or intestinal surgery, and inability to follow instructions or to accurately report symptoms. After a single lead-in period of 4 weeks during which the patients received nutritional advice and were instructed to exercise according to their possibilities and capacities, the patients were randomly assigned to two groups of 30 subjects (Table 1).
Group A (n=30), mean±s.e.m. age, 40.8±7.9-y-old, with a mean±s.e.m. weight of 98.82±17.8, a BMI of 38.09±5.26 kg/m2, were assigned to receive orlistat 120 mg three times daily, with the meals, for a period of 4 weeks. The patients were instructed to ingest the orlistat capsules with approximately 6.0 g of orange-flavored psyllium hydrophillic mucilloid, with no added sugar, dissolved in a glass of water.
Group B (n=30), mean±s.e.m. age 41.7±8.9 y, with a mean±s.e.m. weight of 98.78±16.81 kg, BMI of 38.17±4.81 kg/m2, were similarly assigned to receive orlistat 120 mg three times daily with meals for 4 weeks. These patients also received, approximately, 6.0 g of a soluble orange-flavored powder (placebo) to be dissolved in water and ingested with the orlistat capsules three times a day. Both the psyllium powder and the placebo orange powder were packed in small identical sachets to be open at home. Both the patient and the attending physician were blind to the content of the packed powder.
After 15 days of a washout period, the patients from group A were assigned to receive orlistat plus placebo and those from group B received the orlistat capsules plus psyllium (Figure 1).
All patients were seen by one of the authors (HC) on a weekly basis. At each visit the patients were asked to return a printed form in which each GI event occurring during the week was recorded, on a daily basis (Table 2). The attending physician, therefore, was able to assign the number of points to reach the GI events score for that week. At the end of 30 days, the total number of points for each patient was recorded and tabulated for further statistical analysis.
After this first part of the study was completed it was noticed that most patients complained that it was not agreeable to ingest the orlistat capsules with the psyllium orange-flavored drink, at each meal, mainly in public places such as restaurants, cafeterias and social gatherings. Therefore, we started a new study design in which orlistat capsules (120 mg) were prescribed to be taken three times a day, with meals, as previously done but the psyllium or placebo were given as a single drink with approximately 12 g of orange-flavored powder in water, at bedtime. Only 30 patients from the original group of 60 subjects volunteered for this second part of the project, being randomly assigned, as previously described, 15 to each group of placebo and psyllium during the following 30 days.
During the 60 days of treatment periods, patients were prescribed a standard mildly hypocaloric diet containing roughly 30% of energy as fat. The estimated energy intake was 1200 kcal/day. The same diet was prescribed in the second part of the study.
The score system
The scoring system was previously designed by interviewing obese patients in orlistat treatment. The major adverse and troubling events were oily spotting (flatus with discharge) and fecal incontinence. Therefore it was decided to assign to these events, respectively, a scoring of 4 and 5 (in a scale of 0–5). Similarly, other side effects such as increased defecation, soft stools, flatulence, abdominal pain and fecal urgency received scores between 1 and 3. When the adverse events were more frequent (in a weekly basis) the scores would concomitantly increase, as shown in Table 2. Previous to the start of this study, the scoring system was tested in a group of obese patients on orlistat treatment and we concluded that it reflected the actual intensity of the adverse effects.
The data was analyzed with a GraphPad Prism software (version 2.0, Graphpad Software Inc., San Diego, CA, USA). Analysis of variance was used to examine body weight, BMI and serum-lipids values. Paired t-tests were used to examine differences between means. The χ2 method was employed for differences between frequency of GI events in specific groups of patients.
The weekly visit to the attending physician and the need to hand out the printed form where the GI events were recorded was considered to be an excellent way to prevent withdrawals and to achieve compliance. All 60 patients completed the two periods of 30 days each. For the second part of the project we randomly assigned the 30 patients that volunteered to continue the study for another 30 days to two groups of 15 patients, as previously mentioned.
Demographic and anthropometric characteristics did not differ significantly between treatment groups both at the start of the lead-in period or at the beginning of the trial.
Both groups A and B similarly had a significant weight loss (P<0.01) that was also documented by a significant (P<0.01) variation in the BMI (Table 1). Considering the two periods of 30 days each, approximately 36.7% of the patients lost more than 2 kg each and 46.7% lost between 0.1 and 1.9 kg. The remaining 16.6% did not change their initial weight or gained weight during the trial.
In Table 3, the mean±s.e.m. of the score of GI events obtained for each patient is shown for both groups A and B. There was a significant (P<0.01) difference between the low prevalence of GI events, as indicated by the low score of GI events, when the patients were using psyllium hydrophillic mucilloid as compared with placebo. The same results were obtained when groups A and B were submitted after the washout period, respectively to placebo and psyllium. Overall, 71% of patients while on orlistat plus placebo had GI events as compared with 29% of patients while using orlistat and psyllium mucilloid.
There was no statistical difference between means±s.e.m. when orlistat and psyllium groups was compared with group placebo (group A vs group B). Similarly, when we compared the mean±s.e.m. of the scores of GI events between (1) psyllium three times a day plus orlistat and (2) psyllium 12.0 g at bedtime there was no statistical difference between them (10.8±1.7 vs 6.11±1.21), respectively.
In Table 4 we have listed the total number of GI events occurring with 60 patients either while on orlistat plus psyllium or orlistat plus placebo. Overall GI events were 2–6-fold more common during orlistat plus placebo as compared to orlistat plus psyllium. After analysis of the data by the χ2 statistical method, this difference was highly significant (P<0.01).
Orlistat belongs to a class of anti-obesity agents that act directly and specifically at the site of fat breakdown in the lumen of the intestinal tract. The systemic absorption of orlistat is negligible and the potential for systemic adverse events has been indicated as practically non-existent. Due to the pharmacological mode of action of orlistat5 there is an increased likelihood of gastrointestinal events. As pointed out by Sjoström et al.2 the GI events were more common in the orlistat-treated patients during the first year of their collaborative multicenter trial, the frequency being lower during year 2 among participants who continued on orlistat treatment. This has been interpreted as related to the fact that most patients would learn that orlistat treatment has to be associated with a moderate fat intake. During orlistat treatment the GI events are relatively important because it may be cause for early withdrawal from the trial or cause social embarrassment to the individual patient.
In order to circumvent the GI events that occur during orlistat treatment we have used the concomitant prescription of psyllium hydrophilic mucilloid. Previous reports suggest that this natural fiber may be effective in lowering serum cholesterol,8,9 increasing the fecal excretion of bile acids11 and absorbing free fat in the intestinal lumen.10 In this study we were able to demonstrate that the adjunct use of psyllium with orlistat effectively diminished the number and seventy of GI events during orlistat therapy, as compared with placebo. This was confirmed when the psyllium-treated group was switched to placebo and vice-versa. Therefore, we concluded that psyllium mucilloid had a protective action in the production of GI events, most probably by absorbing free fat (oil) and decreasing intestinal flatulence. Interestingly, most patients indicated that the number of bowel movements did not increase in number while on orlistat plus psyllium. The most important GI event that was prevented by the use of orlistat plus psyllium was the embarrassing oily spot, defined as yellow discharge with flatus during daily activities. Although psyllium was not totally effective in preventing this situation, oily spotting was 6-fold less frequent in the psyllium-treated group as compared to placebo.
Finally we concluded that the use of psyllium as a single dose of 12.0 g in water, at bedtime, is as effective as using psyllium three times a day, at meals time. Most patients considered that intake of psyllium at bedtime was far more convenient and comfortable as compared to the alternate use of psyllium three times a day.
In conclusion, psyllium hydrophilic mucilloid is an effective, practical and easy method to circumvent the GI events during orlistat treatment of obese patients, provided that a moderate fat intake is advised.
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We acknowledge the help of Creusa R Dal Bó in the statistical analysis of the data. This study was supported by Roche Pharmaceutical Co. and Procter & Gamble (Brazil). The expert secretarial work of Maria Suzette Pott is gratefully acknowledged. Part of this work was reported at the 9th European Congress on Obesity, Milan, Italy (1999).
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