OBJECTIVE: To assess the efficacy and tolerability of orlistat (Xenical®) in producing and maintaining weight loss over a 12-month period.
DESIGN: Patients were randomized to double-blind treatment with either orlistat 120 mg or placebo three times daily, in conjunction with a low-energy diet, for 12 months.
SETTING: Five centres in the UK.
SUBJECTS: 228 obese adult patients with body mass index between 30 and 43 kg/m2 and mean weight 97 kg (range 74–144 kg).
INTERVENTIONS: All patients were prescribed a low-energy diet, providing 30% of energy from fat, designed to produce an individually tailored energy deficit of approximately 600 kcal/day, for a run-in period of 4 weeks and then 12 months, plus orlistat 120 mg or placebo three times daily.
MAIN OUTCOME MEASURES: Change in body weight (the primary efficacy parameter), waist circumference and adverse events were reviewed regularly, together with serum lipids, insulin, glucose and plasma levels of fat-soluble vitamins and β carotene.
RESULTS: Based on an intent-to-treat analysis, after 1 y of treatment patients receiving orlistat had lost an average of 8.5% of their initial body weight compared with 5.4% for placebo-treated patients; 35% of the orlistat group lost at least 5% of body weight compared with 21% of the placebo group (P<0.05), and 28% and 17%, respectively (P=0.04) lost at least 10% of body weight. Orlistat-treated patients showed significant decreases (P<0.05) in serum levels of total cholesterol, low density lipoprotein cholesterol, and in the low density lipoprotein:high density lipoprotein ratio in comparison with placebo. Both groups had similar adverse-event profiles, except for gastrointestinal events, which were 26% more frequent in the orlistat group but were mostly mild and transient. To maintain normal plasma levels of fat-soluble vitamins, supplements of vitamins A, D and E were given to 1.8%, 8.0% and 3.6%, respectively, of orlistat-treated patients, compared with 0.9% of placebo-treated patients for each vitamin type. After 1 y, the decrease in vitamin E and β carotene was significantly greater in orlistat-treated patients compared with those receiving placebo (P<0.001). No significant change was found in the mean vitamin E:total cholesterol ratio in either group after 52 weeks.
Conclusions: Orlistat, in conjunction with a low-energy diet, produced greater and more frequent significant weight loss than placebo during 1 y of treatment. One-third of orlistat-treated patients achieved clinically relevant weight loss (≥5% initial body weight). There was also an improvement in relevant serum lipid parameters. Fat-soluble vitamin supplements may be required during chronic therapy. Orlistat was well tolerated and offers a promising new approach to the long-term management of obesity.
Obesity is an important cause of preventable premature death. It causes a large number of chronic symptoms and predisposes to serious diseases, including non-insulin dependent (type 2) diabetes mellitus, hypertension, cerebrovascular disease, ischaemic heart disease, gallstones, respiratory dysfunction and cancer.1,2 In the UK, the prevalence of obesity has increased from 6% of men and 8% of women in 1980 to 16% of men and 17.3% of women in 1996.3 In 1992, recognition of the threat of obesity prompted the UK government to set targets for decreasing its prevalence by one-quarter and one-third in men and women, respectively, by 2005.4
Genetic factors predispose to the development of obesity,5 and their interaction with environmental factors, especially low levels of physical activity, seems to be responsible for the increasing prevalence.6 Obese individuals have great difficulty in losing and then maintaining weight loss solely by means of restricted dietary intake.7 Accordingly, there is a need for pharmacological agents as adjuncts to lifestyle changes aimed at promoting and maintaining weight loss.8,9
Most anti-obesity drugs act on the central nervous system to suppress appetite and reduce food intake. Serious adverse effects of older drugs (e.g. amphetamines) and the association of the fenfluramines with cardiovascular side effects,10,11,12 which led to their withdrawal, have made physicians and general practitioners reluctant to prescribe anti-obesity drugs.
Orlistat (Xenical®) is a new agent designed for the long-term management of obesity. It inhibits the activity of pancreatic and gastric lipases, the key enzymes involved in triglyceride hydrolysis, an essential step for absorption of fat.13 Early studies indicated that orlistat produced a dose-dependent reduction in dietary fat absorption, which is near maximal (approximately 35%) at a dose of 120 mg three times daily.14 Its specific mode of action could be of particular importance since it targets one of the principal causes of weight gain, namely dietary fat.
Previous short-term (12- or 16-week) placebo-controlled studies showed that orlistat leads to additional weight loss compared with diet alone,15,16 and other studies have confirmed the long-term efficacy over 1–2 y.17,18,19 The present study aimed to evaluate the efficacy and acceptability of orlistat 120 mg three times daily, in combination with dietary advice, as therapy for weight loss over 52 weeks in a large group of obese patients.
Patients and methods
Obese patients aged ≥18 y, with a body mass index of between 30 and 43 kg/m2, were recruited at five centres in the UK by local advertisement or by referral from general practitioners. The study conformed with the principles of the Declaration of Helsinki. The Ethics Committees of each centre approved the study and all patients gave written informed consent.
The main exclusion criteria were: weight loss >4 kg in the 3 months before screening; history of any serious systemic disease, including diabetes; uncontrolled hypertension; previous gastrointestinal surgery for weight reduction; history of post-surgical adhesions; history or presence of cancer; psychiatric or neurological disorder requiring chronic medications or liable to prejudice patient compliance; evidence of alcohol or substance abuse; bulimia or evidence of laxative abuse; pregnancy or lactation (women of childbearing potential were only allowed to enter the study if using adequate contraceptive precautions); and post-menopausal women who had been amenorrhoeic for less than 1 y. Patients were excluded if they had taken drugs capable of influencing body weight, resins for lipid lowering, anti-coagulants, digoxin or lipid-soluble vitamin supplements within the previous month.
This was a double-blind, randomized, parallel-group, placebo-controlled trial. A 4-week, single-blind, placebo run-in period was followed by a 52-week, double-blind treatment period during which patients who achieved >75% compliance with therapy (calculated from the number of returned capsules) were randomized to receive either orlistat 120 mg or placebo orally three times daily with meals. Blinded code numbers, randomized in blocks of four, were printed on the labels of double-blind medication (matching orlistat and placebo) and supplied in identical blister packs to each study centre. Patients were randomized in blocks in order to have equal numbers of orlistat and placebo recipients.
The amount of weight lost during the run-in period was taken as an indicator of the potential for that individual to lose weight (affected by compliance, motivation and initial body mass index). To ensure balance in terms of probably success at weight loss, randomization to placebo or orlistat was stratified (stratum 1: ≤2.0 kg weight loss during run-in; stratum 2: >2.0 kg weight loss during run-in).
Patients were reviewed at the start and end of the run-in period, then every 2 weeks until week 12, and monthly thereafter. At the screening visit the dietary requirements for the study were fully explained.
Patients were instructed on a nutritionally balanced low-energy diet starting at the beginning of the 4-week, placebo run-in period. The lowest energy intake allowed to be prescribed at this stage was 1200 kcal/day. Each individual patient's diet was calculated from estimated total daily energy expenditure minus 600 kcal/day.20 Individual total daily energy expenditure was estimated by multiplying the basal metabolic rate (estimated from height, weight, age and sex) by 1.3 to account for the energy needs of metabolically adapted slimming obese patients engaged in mild daily activity.21 The diet prescription contained 30% of energy derived from fat. Alcohol consumption was limited to 150 g/week. The diet aimed to produce an initial weight loss of 0.25–0.5 kg/week, whatever the initial weight, body mass index or energy requirement.
To compensate for the anticipated decrease in energy requirements following expected weight loss, the prescribed daily energy intake was further reduced by approximately 300 kcal/day in all patients at the end of week 24, regardless of whether or not body weight had stabilized. Patients prescribed the minimum energy intake at screening (1200 kcal/day), had energy intake adjusted to 1000 kcal/day at the end of week 24 and maintained to the end of week 52.
Primary efficacy parameter
Change in body weight, the primary efficacy parameter, was assessed consistently (patients wore light indoor clothing and no shoes) at each clinic visit using calibrated weighing scales.
Secondary outcome measures
Secondary outcome measures included total cholesterol, low density lipoprotein, high density lipoprotein, and very low density lipoprotein cholesterol, triglycerides, lipoprotein(a), fasting serum glucose and fasting serum insulin. Haematology and clinical chemistry tests (including lipid-soluble vitamins and β carotene) were analysed centrally (Medi-Lab BioProfil, Copenhagen, Denmark). Sitting blood pressure and heart rate were measured at each clinic visit. Waist circumference was also measured, according to World Health Organization criteria, at the beginning of double-blind treatment, and at weeks 12, 24 and 52; values of ≥88 cm in women and ≥102 cm in men were considered to indicate increased cardiovascular risk.22,23
All adverse events were documented and their severity and apparent relationship to drug or placebo administration recorded by the investigator at each clinic visit.
Given orlistat's ability to increase fat excretion, altered defecation patterns were expected. Gastrointestinal side effects were uniformly classified as displayed in Table 4. In this report, faecal incontinence, flatus with discharge and oily spotting are grouped under the term ‘uncontrolled oily discharge’; oily evacuation, fatty/oily stool, liquid stools and soft stools are grouped under the term ‘loose stools’.
A fasting blood sample and a urine specimen were collected from each patient at the beginning of treatment and at weeks 4, 10, 24, 28 and 52 for assessment of haematology, fasting blood chemistry and urinalysis (protein, ketones, blood, etc.). Investigators were notified immediately if plasma levels of vitamins A, D or E, or β carotene fell below normal ranges (vitamin A, 1.58–3.97 μmol/l; vitamin D, 18–121 nmol/l; vitamin E, 18.1–50.6 μmol/l; β carotene, 0.09–1.06 μmol/l). Dietary vitamin supplementation was recommended if low levels were found to persist. Patients’ stools were examined for the presence of occult blood at the start of treatment and then at weeks 24, 36 and 52. A gallbladder and renal ultrasound were performed at the beginning and end of the treatment period, to anticipate possible consequences from orlistat's mode of action on fat absorption.
A 1 y trial of dexfenfluramine in obesity (one of the few published long-term, controlled studies of weight loss in obese patients) indicated that about 40% of patients discontinued prematurely from the study.24 We therefore allowed for 50% of patients to discontinue in this study and, accordingly, 56 evaluable patients per treatment group would be required to detect a 4 kg difference in weight change between the two groups, with at least 80% power at the 0.05 level of significance if the variance of weight loss was similar to that observed in the dexfenfluramine study. Based on these assumptions, a total sample size of 270 was estimated as necessary.
Complete analysis was conducted with investigators and statisticians remaining blinded to treatment. The study population was examined in two ways for the purposes of efficacy analyses: intention-to-treat population (patients who were assessed clinically and received at least one dose of the study medication) and completer population (patients who completed 52 weeks of treatment without protocol violation). The intent-to-treat analysis data set included observed data and data from the last observation carried forward to week 52.
The null hypothesis that there was no difference in mean weight change after 52 weeks between the placebo and orlistat groups was tested by Analysis of Variance. For each centre, the 95% confidence interval of treatment difference based on least squares mean was provided and the least squares mean differences from each centre used to explore any centre by treatment interaction. The least squares mean was compared as the primary endpoint for analysis.
A total of 267 patients entered the 4-week, placebo run-in period. Thirty-nine patients (15%) were withdrawn during the run-in period, of whom 18 were lost to follow up (Figure 1). One hundred and thirty nine of 218 patients completed the 1 y treatment period, 73 (66%) from the orlistat group and 66 (61%) from the placebo group. According to the protocol, 10 patients were excluded from the intent-to-treat analysis (six because of insufficient safety assessments and four because of insufficient evaluations for efficacy). Seventy-one patients dropped out during active treatment and could not therefore be included in the completers analysis. In the intent-to-treat population (n=218), of the 64 patients assigned to stratum 1 (initial weight loss ≤2 kg), 32 received orlistat (mean/median weight loss during run-in 0.4/0.7 kg) and 32 received placebo (mean/median weight loss during run-in 0.9/1.3 kg), while of the 154 patients allocated to stratum 2 (initial weight loss >2 kg), 78 received orlistat (mean/median weight loss during run-in 3.9/3.8 kg) and 76 received placebo (mean/median weight loss during run-in 3.7/3.4 kg) after run-in.
Patient characteristics (age, race, gender and BMI) for the orlistat and placebo treatment groups were similar (Table 1). Elevated low density lipoprotein cholesterol levels (≥3.36 mmol/l) were frequent in both groups (52% of orlistat, 53% of placebo group). Elevated SBP (≥140 mmHg) was present in 5.5% of patients in the orlistat group and 2% of patients in the placebo group (P=NS). Diastolic blood pressure of ≥90 mmHg was present in 18% of orlistat-treated patients and 22% of placebo-treated patients. No patients had diabetes since this was an exclusion criteria.
Effects on body weight and anthropometry
Treatment effects were consistent across all centres involved in the study and centre-by-treatment interactions were not significant. During the placebo lead-in period, both groups in the intent-to-treat population lost similar amounts of weight (approximately 3 kg). Differences in body weight loss between the two groups became apparent within the first 4 weeks of starting the double-blind phase (Figure 2).
After 52 weeks of treatment, the average loss of initial body weight in the intent-to-treat analysis was 8.5% for orlistat-treated patients compared with 5.4% for those receiving placebo (P=0.016). Similar findings in the analysis of the completer population, loss of initial body weight of 8.8% for orlistat-treated patients and 5.5% for those receiving placebo, did not achieve statistical significance. The least squares mean difference from placebo for change in body weight after 24 weeks of double-blind treatment was statistically significant (1.8 kg, 95% confidence intervals −2.96 to −0.56; P=0.004) for orlistat-treated patients in the intent-to-treat population. This difference was larger in the completer population (2.4 kg, 95% confidence intervals −3.82 to −0.88; P=0.002). After 52 weeks of treatment, the difference from placebo for change in initial body weight was also statistically significant for the orlistat group (2.0 kg, 95% confidence intervals −3.6 to −0.38; P<0.05) in the intent-to-treat population, but not for the completer population (2.5 kg, 95% confidence intervals −5.38 to 0.42; P=0.092); Table 2.
When the data for the intent-to-treat population were stratified by weight loss during the run-in period, patients with run-in weight loss >2.0 kg (stratum 2) lost more weight at 12 months with orlistat treatment than those who had lost ≤2.0 kg (stratum 1). In patients randomized to orlistat treatment, mean weight loss during the run-in period was 0.4 kg in stratum 1 and 3.9 kg in stratum 2. After 52 weeks, orlistat-treated patients in stratum 1 lost on average 0.95 kg more than placebo-treated patients (least squares mean difference) in the same stratum, while those in stratum 2 lost on average 2.6 kg more than the placebo group (LSM difference).
We also assessed the proportions of patients achieving more than 5% or 10% weight loss, because these thresholds have been regarded by the US Food and Drug Administration and the European Committee for Proprietary Medicinal Products as clinically important targets. In the intent-to-treat population, 28% of orlistat-treated patients lost more than 10% of initial body weight during the study (including the lead-in period) compared with 17% of placebo-treated patients (P=0.04). Thirty-five per cent of orlistat-treated patients lost at least 5% of body weight compared with 21% of the placebo group (P=0.02), and 16% of orlistat-treated patients lost at least 10% of body weight vs 6% of the placebo group (P=0.02) during double-blind treatment.
In females with waist circumference ≥88 cm at the start of double-blind treatment, the mean decrease after 52 weeks was 6.3 cm in orlistat-treated patients and 5.1 cm in patients who received placebo (P=NS). Of the men with waist circumferences ≥102 cm, there was a mean decrease of 4.1 cm at 52 weeks in those who received orlistat, compared with 3.9 cm in the placebo group (P=NS).
Effects on metabolic parameters and blood pressure
During the run-in period, diet and weight loss reduced total cholesterol (−0.44 mmol/l orlistat vs −0.43 mmol/l placebo) and low density lipoprotein cholesterol (−0.21 mmol/l orlistat vs −0.23 mmol/l placebo) equally in both patient groups (Table 3). The subsequent changes from the start of double-blind treatment to the end of week 52 in total cholesterol (percentage difference from placebo −5.65, 95% confidence intervals −8.99 to −2.32), low density lipoprotein cholesterol (percentage difference from placebo −8.98, 95% confidence intervals −13.23 to −4.75) and the low density lipoprotein:high density lipoprotein ratio (difference from placebo −0.27, 95% confidence intervals −0.45 to −0.10) were significantly greater in orlistat-treated patients compared with the placebo group (P=0.002 for least squares mean difference from placebo). High density lipoprotein cholesterol levels increased by similar amounts in both groups (Table 3). In the orlistat group, the least squares mean differences from placebo in levels of triglycerides, lipoprotein(a) and very low density lipoprotein cholesterol were not statistically significant after 52 weeks of double-blind treatment.
There was a trend towards a reduction in fasting insulin and, to a lesser extent, in fasting glucose levels associated with weight loss in both groups. In patients with elevated low-density lipoprotein cholesterol (≥3.36 mmol/l) at the start of double-blind treatment, the mean value decreased by 7.1% in orlistat-treated patients and 1.3% in placebo-treated patients after 52 weeks. Between weeks 24 and 52, diastolic blood pressure tended to fall in patients with elevated levels (≥90 mmHg) at baseline.
Except for gastrointestinal events, adverse events were similar in both treatment groups, mild to moderate in intensity, and mainly temporary (Table 4).
As expected, gastrointestinal events occurred more frequently in the orlistat treatment group than in the placebo group; 82.1% and 56.4%, respectively, had at least one gastrointestinal event. Fifty-nine per cent of orlistat-treated patients had at least one of the listed gastrointestinal events compared with 15.4% of placebo patients. Most occurred early in the study, and were generally transient (≤4 days). Most patients in both groups had only one or two episodes of gastrointestinal symptoms, although some orlistat-treated patients had more than three episodes of loose stools (eight patients), increased defecation (one patient), faecal urgency (two patients) and uncontrolled oily discharge (one patient) during the 52 weeks of treatment.
Nine orlistat- and seven placebo-treated patients withdrew prematurely from the study because of adverse events. Three orlistat-treated patients withdrew because of gastrointestinal adverse events (abdominal pain, liquid stools, increased defecation), while one placebo-treated patient withdrew because of a gastrointestinal adverse event (oesophagitis).
Vitamin A, D and E supplementation was given to 1.8%, 8.0% and 3.6%, respectively, of orlistat-treated patients compared with 0.9% of placebo-treated patients for each vitamin type. β carotene supplementation was given to 0.9% of orlistat-treated patients. With such supplementation, mean levels of vitamins A, D and E, and β carotene remained within normal clinical ranges throughout the study in both treatment groups. The difference from placebo for the least squares mean change in vitamin levels after 52 weeks of treatment was statistically significant (P<0.001) among orlistat-treated patients for vitamin E (least squares mean difference from placebo −2.08 μmol/l, 95% confidence intervals −3.07 to −1.08) and β carotene (least squares mean difference from placebo −0.11 μmol/l, 95% confidence intervals −0.14 to −0.11), but not for vitamins A or D (intent-to-treat population). The concentration of vitamin E in plasma is dependent on the concentration of the carrier molecule cholesterol and no statistically significant change emerged in the mean vitamin E:total cholesterol ratio in their treatment group after 52 weeks of treatment.
Gallstone formation was not increased by weight loss associated with orlistat use. During the study, 7% and 11% of orlistat- and placebo-treated patients, respectively, developed gallbladder abnormalities (mostly asymptomatic stones detected by ultrasound). Renal abnormalities (mainly stones and cysts) developed in 3% of orlistat-treated patients and 2% of placebo-treated patients.
Excessive dietary fat is the most energy dense nutrient (9 kcal/g) and a major factor that contributes to the development and maintenance of obesity.25 In the typical diet of Western industrialized nations, as much as 40% of energy is derived from fat. Thus, a compound that selectively limits the intestinal absorption of dietary fat is potentially useful in the long-term treatment of obesity.
The present double-blind, randomized, placebo-controlled study was designed to assess the effect of orlistat, a novel gastrointestinal inhibitor, on weight loss and weight maintenance in obese patients over a 12 month period. All patients were followed to study endpoint, including those who did not respond to treatment. In real life or routine situations patients who do not respond to a drug would never continue on therapy for 1 y and thus the purpose of this study was to prove efficacy and not to indicate the results which would be expected in clinical practice.
The study demonstrated that obese patients maintained on a hypocaloric diet lost significantly more weight when treated with diet and placebo for 4 weeks and then for 52 weeks with orlistat 120 mg three times daily than with placebo three times daily throughout; average loss from initial body weight was 8.5% and 5.4%, respectively. In addition, 35% of orlistat-treated patients (14% more than in the placebo group) lost at least 5% of body weight during the orlistat treatment phase. At week 52, the placebo group had regained some weight, while the orlistat-treated patients tended to maintain weight loss: between weeks 24 and 52 patients on placebo regained more weight (1.34%) compared with the orlistat group (0.6%).
Obese patients who achieve and maintain a weight loss of 5–10% or more improve glycaemic control, lower blood pressure and cholesterol levels, are less likely to develop co-morbid conditions and may live longer.26,27,28,29 In the completer population, 41% of orlistat- and 25% of placebo-treated patients lost more than 10% of initial body weight. This is comparable with the results of a 12-month trial conducted with dexfenfluramine, a centrally acting serotoninergic drug.24 After one year of treatment, orlistat-treated patients in the ‘high-risk’ groups had greater reductions in waist circumference than patients treated with placebo, although these differences were not statistically significant.
Data collected at one of the centres in this study confirmed that faecal loss of fat accounted for most of the additional weight loss achieved with orlistat. Mean changes from baseline in faecal fat excretion was approximately 16 g/day in the orlistat group and 0.14 g/day in the placebo group. At 52 weeks absolute faecal fat excretion was 18.5 g/day and 2.8 g/day for the orlistat and placebo groups, respectively. The excess of unabsorbed fat would contain about 170 kcal/day, which is sufficient to account for the additional 3 kg weight loss over 6 months (the time when most of the weight was lost). Furthermore, the information from patient diet diaries showed no important differences between the orlistat groups in either total energy or fat intake.
Patients with elevated diastolic blood pressure (≥90 mmHg) at randomization in both the orlistat and placebo groups had levels reduced to within the normal range over time. A similar trend for fasting insulin levels was also seen. These changes were related to change in weight in these patients.
Orlistat was generally well tolerated and most adverse events were mild and transient. Gastrointestinal events occurred more frequently in the orlistat-treated patients, as would be predicted from the drug's pharmacological effect, but led to treatment withdrawal in only three patients. From this evidence it appears that patients recognized that the effect was to be expected if fat intake increased and considered that this was of assistance to reinforce compliance with the appropriate fat-restricted diet.
There is little evidence that higher faecal fat content per se is disadvantageous, but certain modifications of cholesterol/phospholipids/bile salt ratio in the gallbladder might induce gallstone formation,30 while calcium soap formation could enhance oxaluria with a risk of renal stones. In practice, over the 1 y period, gallstones and renal stone formation were no more common in orlistat-treated patients than in those on placebo. However, larger and longer trials will be needed to exclude these possible adverse effects.
The long-term effects of orlistat on fat-soluble vitamin absorption require consideration. The effects observed were similar to those reported previously in healthy volunteers.31,32 Vitamin levels were monitored and more orlistat-treated patients received supplements than those on placebo. It may be pragmatic clinical practice routinely to give vitamin supplements to patients treated with orlistat, and monitoring blood levels for fat-soluble vitamins should be considered after 12–24 months. Patients entered into clinical trials are all selected as being healthy, so more patients with low or marginal vitamin levels may be met in clinical practice. The effect on plasma vitamin D levels will need longer monitoring, although the principal source of vitamin D results from the action of sunlight on the skin. Any impact on systemic carotenoid supply might be overcome by incorporating an appropriate drink, e.g. of tomato/carrot juice, or a salad snack into a regimen at a time of day when orlistat is not being taken (i.e. between meals). While orlistat-induced reductions in the levels of anti-oxidant vitamins and nutrients may theoretically aggravate cardiovascular risk, vitamin E:total cholesterol ratio predicts cardiovascular risk best and the benefits of lowering total and low density lipoprotein cholesterol suggest that orlistat treatment is more likely overall to improve cardiovascular risk. The impact on other fat-soluble compounds in foods and on fat-soluble drugs needs to be considered.
In conclusion, this study suggests that orlistat given in combination with dietary advice induces clinically significant weight loss in up to one-third of patients treated for 1 y. Orlistat's peripheral action (within the gut) and its general lack of serious adverse effects indicate a favourable benefit/risk ratio for the use of this drug in the long-term treatment of obesity.
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This study was financially supported by F Hoffmann-La Roche. The authors acknowledge and thank the medical staff, research nurses and dietitians for their work: Dr MK Sridhar, Mrs S Stump, Mrs M Martin, Dr R Stancio and Ms C Hankey.
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Cite this article
Finer, N., James, W., Kopelman, P. et al. One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor. Int J Obes 24, 306–313 (2000). https://doi.org/10.1038/sj.ijo.0801128
- gastrointestinal lipase inhibitor
- weight loss
- cardiovascular risk factors
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