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Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients
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Articles
Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients
Lars Sjöström, Aila Rissanen, Teis Andersen, Mark Boldrin, Alain Golay, Hans P F Koppeschaar, Michel Krempf, for the European Multicentre Orlistat Study Group*
Summary Background We undertook a randomised controlled trial to assess the efficacy and tolerability of orlistat, a gastrointestinal lipase inhibitor, in promoting weight loss and preventing weight regain in obese patients over a 2year period. Methods 743 patients (body-mass index 28–47 kg/m2), recruited at 15 European centres, entered a 4-week, single-blind, placebo lead-in period on a slightly hypocaloric diet (600 kcal/day deficit). 688 patients who completed the lead-in were assigned double-blind treatment with orlistat 120 mg (three times a day) or placebo for 1 year in conjunction with the hypocaloric diet. In a second 52-week double-blind period patients were reassigned orlistat or placebo with a weight maintenance (eucaloric) diet. Findings From the start of lead-in to the end of year 1, the orlistat group lost, on average, more bodyweight than the placebo group (10·2% [10·3 kg] vs 6·1% [6·1 kg]; LSM difference 3·9 kg [p<0·001] from randomisation to the end of year 1). During year 2, patients who continued with orlistat regained, on average, half as much weight as those patients switched to placebo (p<0·001). Patients switched from placebo to orlistat lost an additional 0·9 kg during year 2, compared with a mean regain of 2·5 kg in patients who continued on placebo (p<0·001). Total cholesterol, low-density lipoprotein (LDL) cholesterol, LDL/high-density lipoprotein ratio, and concentrations of glucose and insulin decreased more in the orlistat group than in the placebo group. Gastrointestinal adverse events were more common in the orlistat group. Other adverse symptoms occurred at a similar frequency during both treatments.
*Members listed at end of paper Sahlgrenska University Hospital, Göteborg, Sweden (Prof L Sjöström MD); Helsinki University Central Hospital, Helsinki, Finland (Prof A Rissanen MD); Hvidovre University Hospital, Copenhagen, Denmark (T Andersen MD); Hoffmann-La Roche, Nutley, New Jersey, USA (M Boldrin MS); University Hospital Geneva, Switzerland (A Golay MD) Academisch Ziekenhuis Utrecht, Utrecht, Netherlands (H P F Koppeschaar MD); and Hotel Dieu, Nantes, France (M Krempf MD) Correspondence to: Prof Lars Sjöström, SOS-Sekretariatet, Medical Department, Sahlgrenska University Hospital, 41345 Göteborg, Sweden
THE LANCET • Vol 352 • July 18, 1998
Interpretation Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period. The use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events.
Lancet 1998; 352: 167–73 See Commentary page ???
Introduction Obesity is becoming increasingly common and is recognised as a major public health problem worldwide.1–3 In the UK, the overweight and obese population increased by almost 15% between 1980 and 1992, by which time an estimated 54% of men and 45% of women were affected.2 Similar increases have been noted in many countries, such as the USA,4 Sweden,5 and the Netherlands.6 Guidelines published in 1996 for the management of obesity recommended modest weight loss and weight maintenance, rather than a target of ideal weight.7 Many obese patients who lose at least 5% of their initial bodyweight show improvement in cardiovascular risk factors and coexisting disorders.8 Pharmacological therapy has been proposed as an adjunct to diet and lifestyle changes to improve longterm weight loss.9 Clinicians may be uncertain, however, about appropriate use of drug therapy in the management of obesity.9 Given the central role of dietary fat in obesity,10,11 a logical way to achieve and maintain weight loss is to decrease the amount of fat available to be metabolised. Orlistat promotes weight loss by inhibiting gastrointestinal lipases, thus lowering absorption of dietary fat, on average by 30% with a dose of 120 mg three times a day.12 Our objectives were to examine the efficacy and tolerability of orlistat in promoting weight loss and preventing regain after the initial loss, and to assess effects on major cardiovascular risk factors.
Methods Patients This European 2-year multicentre trial had a double-blind, randomised, placebo-controlled, and parallel-group design. Obese (body-mass index 28–47 kg/m2) men and women, aged 18 years and over, were eligible for inclusion. Recruitment was from hospital waiting lists or by local advertising. Women of childbearing potential were included if they were using adequate contraception. The study conformed with the
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into the double-blind labelling. Without the prior knowledge of the investigators, the randomisation was done in blocks of four so that there were equal numbers of 194 not eligible patients with orlistat and placebo groups. Patients were stratified according to 743 enrolled in single-blind run-in weight loss during the lead-in period (聿2 kg or >2 kg) to achieve orlistat/placebo balance among these categories. 55 withdrew During the lead-in and 52-week treatment periods, patients were 688 completed run-in, randomised prescribed a hypocaloric diet containing roughly 30% of energy as fat. The energy content of the diet was calculated from the patients’ estimated basal metabolic rate multiplied by 1·3 to estimate the total 343 assigned 345 assigned daily energy expenditure.13 From energy placebo orlistat expenditure, 600 kcal/day (1 kcal=4·2 kJ) was subtracted to obtain a mildly 3 withdrew early 2 withdrew early hypocaloric diet. Between weeks ⫺4 (placebo lead-in) and 24, the minimum prescribed energy intake was 1200 340 in year-1 343 in year-1 kcal/day. To compensate for the ITT analysis ITT analysis anticipated reduction in energy expenditure accompanying the weight loss, the prescribed energy intake was 80 withdrew 59 withdrew further reduced by about 300 kcal/day at the end of week 24. For participants 260 completed 284 completed initially prescribed the minimum energy year 1 year 1 intake, energy intake was adjusted to 1000 kcal/day. At the end of year 1, eligible patients 7 not reassigned 11 not reassigned (>75% compliance) in each treatment group were reassigned either to continue on the same regimen (orlistat 120 mg or 253 reassigned 273 reassigned placebo three times a day) or to switch to the alternative regimen for a further 52 weeks, so that we could assess the impact 126 placebo 127 orlistat 138 placebo 135 orlistat of treatment on prevention of weight regain. At the start of year 2, patients 2 withdrew 2 withdrew 3 withdrew were prescribed a weight-maintenance early early early (eucaloric) diet designed to maintain stable bodyweight. Patients were advised 21 withdrew 23 withdrew 21 withdrew 19 withdrew not to return to a hypocaloric diet at any later later later later time during year 2. Weight reduction during year 1 and maintenance of lost weight during year 2 Placebo placebo Placebo orlistat Orlistat placebo Orlistat orlistat were the primary efficacy variables. 123 analysed 123 analysed 138 analysed 133 analysed Bodyweight was measured (with 102 completed 102 completed 117 completed 114 completed calibrated scales) before and during runin, at randomisation, every 2 weeks for Figure 1: Trial profile the first 3 months after randomisation, ITT=intention to treat. and monthly thereafter until the end of Declaration of Helsinki. The ethics committees of all centres year 1, and at eight scheduled visits in year 2. Fasting serum approved the study, and all participants gave verbal or written concentrations of glucose, insulin, total cholesterol, low-densityinformed consent. lipoprotein (LDL) cholesterol (measured by ultraPatients with serious diseases (defined in the research centrifugation), high-density-lipoprotein (HDL) cholesterol, protocol), including uncontrolled hypertension and and triglycerides were measured before run-in, at pharmacologically treated diabetes, were excluded. Other randomisation, and at the end of months 1, 3, 6, 12, 13, 14, 16, exclusion criteria were weight loss of more than 4 kg in the 3 months before screening, surgery for weight reduction, a history Characteristic Placebo (n=340) Orlistat (n=343) of post surgical adhesions, bulimia or laxative abuse, use of any Sex drug that might have influenced bodyweight or plasma lipids in Male 57 (16·8%) 59 (17·2%) the month before study entry, and drug or alcohol abuse. Female 283 (83·2%) 284 (82·8%) 937 screened
Age (years)*
Design After a single-blind lead-in period lasting 4 weeks, during which patients received placebo three times a day with meals, eligible patients (>75% compliance with therapy calculated from the number of capsules returned) were randomly assigned doubleblind treatment with either orlistat 120 mg or placebo, three times daily with meals for 52 weeks. Randomisation numbers for patients were generated by the sponsor and incorporated
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Anthropometry* Weight (kg) Height (cm) Body-mass index (kg/m2)† Waist circumference (cm)
44·3 (18·0–77·0)
45·2 (20·0–76·0)
99·8 (64·2–137·2) 166·1 (143·0–190·0) 36·1 (29·2–43·5) 105·9 (71–135)
99·1 (61·0–148·6) 165·7 (140·0–197·0) 36·0 (28·3–47·2) 105·4 (70–149)
*Mean (range). †Measured at start of lead-in period (day ⫺28).
Table 1: Characteristics of intention-to-treat population at first randomisation (day 1)
THE LANCET • Vol 352 • July 18, 1998
Change in bodyweight (%)
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0 –1 –2 –3 –4 –5 –6 –7 –8 –9 –10 –11 –12
change from the start of the lead-in period to the end of year 1 was used as a covariate. Similar models were used to calculate differences and changes in risk factors. Two-sided tests were used and p values <0·05 were taken to be significant.
Placebo Orlistat
Results
–10 0
10 20 30 40 50 60 70 80 90 100 110
Week SB
DB
DB
Slightly hypocaloric diet
Weight maintenance (eucaloric) diet Figure 2: Mean percentage change in bodyweight from start of single-blind lead-in until 2-year examination in orlistat and placebo groups Initial bodyweight was close to a mean of 100 kg in both groups (table 1)—percentage change therefore approximately matches kg lost. SB=single-blind lead-in period of 4 weeks; DB=double-blind, placebocontrolled treatment during years 1 and 2. Error bars=SE.
18, and 24. Blood pressure and heart rate were measured at each visit. Blood and urine samples taken when the patient had fasted overnight were collected regularly for standard haematological, clinical chemistry (including vitamins A, D [measured as 25hydroxy vitamin D], and E, prothrombin time, and -carotene), and urine analysis assessments. Vitamin results were concealed from the investigators, although notification of concentrations below the normal range was given. Additional dietary counselling, or vitamin supplementation when necessary, was provided if two consecutive measurements were below normal. Plasma samples collected after 6 months, 1 year, and 2 years were analysed for the presence of orlistat by high-performance liquid chromatography. Laboratory samples were immediately transported on ice by courier to a certified laboratory in Copenhagen, Denmark, for standard biochemical tests. All adverse events were recorded and the potential relation to treatment was judged by the investigator. Standard terms were developed to describe gastrointestinal events expected with increased excretion of fat due to orlistat treatment.
Statistical analysis Published results of a long-term obesity study (n=227) reported an SD of 7·5 kg (SE 0·49) associated with weight loss over 1 year. With this information, power calculations indicated that we would need 56 patients per treatment group to detect a 4 kg difference in weight change with a power of 80% at the 0·05 significance level. The planned sample size of 600 patients was based on the assumption of withdrawal rates of 50% during year 1 and 25% during year 2. Efficacy was assessed by intention to treat. The intention-totreat population for both years consisted of patients who had had at least one dose of the test medication and at least one follow-up bodyweight measurement. For individuals withdrawing during year 1 or 2, the last available examination was carried forward to the end of year 1 or 2, respectively, in the least squares mean (LSM) calculations. The null hypothesis of no difference between the treatment groups was tested with general linear models. To assess year-1 weight loss, we did ANCOVA with the following variables: treatment (placebo or orlistat), centre (1–15), and stratum (weight-loss group assigned during lead-in). Second-order interaction terms were also used and results were expressed as LSM difference from placebo (with SE). During year 2, weight
THE LANCET • Vol 352 • July 18, 1998
Enrolment and follow-up A total of 937 patients were screened, of whom 743 entered a 4-week, placebo lead-in. 688 patients who completed the lead-in were randomised to double-blind treatment with orlistat 120 mg or placebo three times a day (figure 1). Five early withdrawals (four no safety assessment, one no trial medication), reduced the year-1 intention-totreat population to 683 patients, 544 of whom completed treatment. Immediately after completion of year 1, 18 patients withdrew mainly owing to non-compliance. Consequently, 273 former orlistat-group patients and 253 former placebo-group patients were reassigned for year 2 (figure 1). At the end of year 2, the intention-to-treat population consisted of 519 (75% of randomised) patients of whom 435 (63% of randomised) completed treatment. Analysis of the participants who completed year 2 gave similar results to the intention-to-treat analysis (data not shown). Demographic and anthropometric characteristics did not differ significantly between treatment groups at the start of the lead-in period (not shown) or at randomisation (table 1). None of the cardiovascular risk factors differed between groups at the start of the lead-in period or at randomisation. Weight loss and weight regain After year 1, the mean decrease in bodyweight from values at the start of the placebo run-in period was 10·2% (or 10·3 kg) in the orlistat group, compared with 6·1% (or 6·1 kg) in the placebo group (figure 2). Thus, the decrease in weight was 68% greater with orlistat than with placebo (LSM weight-loss difference from randomisation 3·9 kg; p<0·001). At the end of year 1, 9·3% of the orlistat group versus 2·1% of the placebo group had lost more than 20% of initial bodyweight; 29·5% versus 15·6% had lost 10·1–20·0% of bodyweight; 29·7% versus 31·5% had lost 5·1–10·0% of bodyweight; and 23·6% versus 32·7% had lost 0·1–5·0% of bodyweight. 7·9% versus 18·2% had unchanged or increased bodyweight. Figure 2 illustrates the effect of orlistat during year 2, when patients were prescribed a eucaloric diet. In former placebo-group patients, orlistat reduced bodyweight (LSM difference in weight loss orlistat⫺placebo 3·6 kg [SE 0·6]; p<0·001). In former orlistat-group patients, the weight regain was smaller with orlistat than with placebo (LSM difference in weight loss orlistat⫺placebo 2·4 kg [0·6]; p<0·001). After 2 years of continuous orlistat treatment, 57·1% of the patients maintained a weight loss greater than 5%; the corresponding percentage for 2 years’ placebo treatment was 37·4%. Cardiovascular risk factors Cardiovascular risk factors, measured on 11 occasions during the 2-year study period, are reported only from the start of the lead-in (week 4), randomisation (day 1), week 52, and week 104 (table 2). For brevity, data at 169
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Start of lead-in
Plasma lipids Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) LDL/HDL ratio Triglycerides (mmol/L)
Day 1
Week 52
Placebo (n=340)
Orlistat (n=343)
Placebo (n=340)
Orlistat (n=343)
Placebo (n=340)
Orlistat (n=343)
Model A
Model A
Model B
Model B
Model C
Model C
p
5·69 (0·06) 3·72 (0·05) 1·24 (0·02) 3·17 (0·06) 1·72 (0·06)
5·78 (0·06) 3·82 (0·05) 1·25 (0·02) 3·23 (0·06) 1·66 (0·06)
5·36 (0·03)* 3·55 (0·03)* 1·16 (0·01)* 3·23 (0·03) 1·53 (0·05)*
5·39 (0·03)* 3·55 (0·03)* 1·15 (0·01)* 3·25 (0·03) 1·60 (0·05)
5·59 (0·04) 3·68 (0·03) 1·26 (0·01) 3·09 (0·03) 1·59 (0·04)
5·31 (0·04) 3·46 (0·03) 1·25 (0·01) 2·92 (0·03) 1·53 (0·04)
<0·0001 <0·0001 0·3076 0·0002 0·3951
Other biochemistry Fasting blood glucose (mmol/L) Fasting plasma insulin (pmol/L)
6·04 (0·06) 107 (3·2)
5·92 (0·06) 109 (3·1)
5·83 (0·03)* 97·1 (4·1)*
5·84 (0·03)* 98·7 (3·9)†
5·77 (0·04) 95·6 (4·5)
5·63 (0·04) 87·0 (4·3)
0·0098 0·1667
Blood pressure (mm Hg) Systolic Diastolic
132 (0·83) 84·8 (0·49)
133 (0·82) 84·8 (0·49)
128 (0·60)* 81·9 (0·40)*
129 (0·60)* 82·4 (0·40)*
129 (0·71) 82·1 (0·43)
127 (0·70) 80·3 (0·43)
0·0189 0·0022
For within-group changes between start of lead-in and day 1: *p<0·001; †p<0·1; others p>0·1. Model A=group (placebo=0 and orlistat=1) only; B=group and start of lead-in value of risk factor under consideration; C=group, day-1 value of risk factor under consideration, number of the centre (1–15) the patient belonged to, and group⫻centre. Missing data: placebo group—for lipids n聿5, glucose n聿5, insulin n聿39, blood pressure n聿1; orlistat group—for lipids n聿6, glucose n聿11, insulin n聿35.
Table 2: LSM (SE) of cardiovascular risk factors in intention-to-treat population from start of the lead-in period to week 104
week 104 are presented only for the groups receiving either placebo for 2 years or orlistat for 2 years. The weight reduction observed during the placebo lead-in was accompanied by significant (p<0·001) decreases within the future placebo and orlistat groups in total cholesterol, LDL cholesterol, HDL cholesterol, fasting blood glucose, and blood pressure. In the future placebo group, triglycerides and plasma insulin were also reduced (table 2). There were no significant differences between the placebo and orlistat groups at the start of the lead-in or at randomisation (table 2). In the placebo group total cholesterol and LDL cholesterol gradually returned towards values at the start of lead-in at 1 year and 2 years. By contrast, concentrations of these lipids fell further during the 2 years in the orlistat group, and these changes were significantly different from those in the placebo group both at 1 year and at 2 years (table 2). The changes in HDL cholesterol in the two treatment groups were similar, with a small drop at day 1 compared with mean values at the start of run-in and after 1 year and 2 years. As a consequence the LDL/HDL ratio was unchanged within both groups at day 1. Later, the reductions were larger in the orlistat group (table 2). Changes in triglycerides were similar in both groups throughout the study. The orlistat group showed significantly larger decreases than the placebo group in fasting glucose and insulin at 2 years and systolic and diastolic blood pressure at 1 year. To examine whether orlistat has effects on risk factors beyond its weight-reducing properties, percentage riskfactor change (week 52 or week 104 minus day 1) was modelled with a general linear model as a function of treatment (orlistat or placebo) with, as covariates, percentage weight change and value of risk factor under consideration at day 1. Under these circumstances baseline risk-factor value and weight reduction were significant at 52 and 104 weeks for all risk-factor changes given in table 2. Treatment was also a significant predictor for change in total cholesterol at week 52 (p=0·0001) and at week 104 (p=0·0002), and for change in LDL cholesterol at week 52 (p=0·0003) and at week 104 (p=0·0463). At week 104, treatment was also a significant predictor (p=0·0236) for change in the LDL/HDL ratio (not shown in tables).
Adverse events The overall frequency of adverse events was slightly higher in the orlistat group than in the placebo group 170
during year 1 (94 vs 82%) and similar in the four treatment groups during year 2 (table 3). With the exception of some gastrointestinal events, the adverse events were judged by the investigators to be unrelated or remotely related to treatment. Most of the gastrointestinal events (table 3) happened early in orlistat treatment and were of short duration (<4 days). Patients treated with orlistat experienced far fewer gastrointestinal events during year 2 than in year 1. Serious adverse events were reported by 24 patients in the placebo group and 25 in the orlistat group during year 1, with only one adverse event in each group being judged by the investigators to be related to treatment. Similarly, two serious adverse events that were judged possibly related to treatment happened during year 2. One case of gastrointestinal neoplasm occurred in a patient treated with placebo for 2 years. No other malignant disorders were observed in the course of this study. The total number of premature withdrawals was higher in the placebo group than in the orlistat group during year 1 (83 vs 61) and virtually the same in both groups during year 2 (45 vs 46). Adverse gastrointestinal events, however, were a more common reason for premature withdrawals in the orlistat group than in the placebo group (table 4). There were no clinically or statistically significant changes in the mean values of any laboratory measurements during the study, and the frequency of laboratory abnormalities was evenly distributed between the treatment groups (data not shown). After an initial small decrease, mean concentrations of vitamins A, D, and E, and -carotene stabilised and remained within normal clinical ranges throughout the study in both groups (data not shown). During year 1, 41 patients in the orlistat group and 18 in the placebo group had two or more consecutive low vitamin concentrations recorded (table 3), but only 16 and four patients, respectively, received vitamin supplementation. During year 2, vitamin supplementation was received by four patients in the orlistat/orlistat group, by one placebo/placebo patient, by three patients in the placebo/orlistat group, and by one patient in the orlistat/placebo group. Pharmacokinetic analysis of blood samples showed measurable, but minute, concentrations (0·208–2·078 g/L) of unchanged orlistat in the plasma of only a few patients at 24 weeks (13/281 [4·6%] orlistat-treated patients), 52 weeks (17/236 [7·2%]), and 104 weeks THE LANCET • Vol 352 • July 18, 1998
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Percentage change, week 52 minus day 1
Week 104 p
Percentage change, week 104 minus day 1
Placebo (n=340)
Orlistat (n=343)
Pla/pla (n=123)
Orl/orl (n=133)
Model C
Model C
p
Model C
Model C
4·91 (0·66) 5·18 (0·87) 11·0 (0·93) ⫺3·25 (0·97) 4·99 (2·11)
⫺0·36 (0·66) ⫺1·15 (0·86) 9·8 (0·92) ⫺8·56 (0·97) 4·02 (2·09)
<0·0001 <0·0001 0·3789 0·0001 0·7450
5·69 (0·07) 3·74 (0·05) 1·28 (0·02) 3·06 (0·06) 1·80 (0·13)
5·27 (0·06) 3·46 (0·05) 1·30 (0·02) 2·81 (0·05) 1·48 (0·12)
<0·0001 0·0002 0·3900 0·0014 0·0770
6·51 (1·25) 6·05 (1·92) 12·8 (1·69) ⫺4·57 (1·72) 16·6 (6·01)
⫺1·14 (1·18) ⫺0·62 (1·82) 15·3 (1·60) ⫺12·7 (1·63) 2·95 (5·68)
0·0000 0·0123 0·2927 0·0007 0·1000
Other biochemistry ⫺1·02 (0·54) 7·61 (4·57)
⫺3·15 (0·54) ⫺1·54 (4·38)
0·0053 0·1493
6·08 (0·08) 104 (5·62)
5·82 (0·08) 83·4 (5·3)
0·0260 0·0073
2·33 (1·07) 19·1 (5·28)
⫺0·92 (1·02) ⫺5·05 (4·97)
0·0290 0·0010
Blood pressure (mm Hg) 1·18 (0·55) ⫺0·57 (0·55) 0·64 (0·54) ⫺1·74 (0·54)
0·0256 0·0019
130 (1·19) 83·6 (0·82)
0·5188 0·4098
2·30(0·93) 1·95 (1·04)
1·08 (0·87) 0·78 (0·98)
0·3406 0·4103
129 (1·12) 82·7 (0·77)
Pla/pla (n=123)
Orl/orl (n=133)
Model C
Model C
p
Table 2: Continued
(2/75 [2·7%]). These findings indicate low systemic absorption of orlistat after 2 years of treatment, with no evidence of accumulation.
Discussion This randomised study showed that orlistat provided sustained improvements in weight loss and weight maintenance for up to 2 years. In addition, there were beneficial changes in several risk factors. During year 2 orlistat prevented or inhibited regain of weight compared with placebo. Cessation of orlistat therapy resulted in a marked rebound effect. Patients on orlistat for the whole 2 years, however, also relapsed slightly during year 2, apparently because of the change from a hypocaloric to eucaloric diet. This change was a consequence of the protocol and in practice it resulted in increased energy intake in patients whose weight stabilised for the last 3 months of year 1. Whether the weight could have been maintained during year 2 with an unchanged diet, which in reality was eucaloric, is not known. A 2-year study with continuous hypocaloric diet recommendations is in progress (the XENDOS study). Large energy deficits, for instance with very lowenergy diets, might have resulted in the same weight reduction during year 1 as the orlistat treatment. It is well known, however, that the greater the weight Year 1
reduction, the greater the relapse,14 a fact that is also illustrated by the two placebo groups during year 2 in our study. In agreement with short-term trials,15–18 the weight reduction in the orlistat group was accompanied by beneficial changes in several cardiovascular risk factors. Plasma total cholesterol and LDL-cholesterol concentrations fell in the orlistat group further than would have been expected from weight loss alone. This independent cholesterol-lowering effect is likely to reflect the ability of orlistat to induce weight loss by specifically reducing energy uptake from fat.12 As in previous short-term (聿1 year) studies,8 the placebo group in our study showed improvements in most risk factors after 4 weeks of run-in on a hypocaloric diet. Nevertheless, despite a maintained weight reduction of about 5% in the placebo group, risk-factor values were back at baseline at the 2-year examination. This finding accords with 2-year observations in the Swedish Obese Subjects study, showing that during steady-weight conditions, previous weight reductions of about 10% are required for long-lasting risk-factor improvements to be detected.19 Premature withdrawals were less frequent than expected,20 with 76% of the placebo group and 82% of the orlistat group completing year 1. The full 2 years were completed by 63% of all randomised patients.
Year 2
Placebo (n=340)
Orlistat (n=343)
Placebo/placebo (n=123)
Orlistat/placebo (n=138)
Placebo/orlistat (n=125)
Orlistat/orlistat (n=133)
Overall adverse events
279 (82%)
322 (94%)
90 (73%)
109 (79%)
109 (87%)
102 (77%)
Gastrointestinal system Fatty/oily stool Increased defecation Oily spotting Soft stool Liquid stools Abdominal pain Faecal urgency Flatulence Flatus with discharge Faecal incontinence Oily evacuation
17 (5%) 25 (7%) 4 (1%) 30 (9%) 34 (10%) 30 (9%) 11 (3%) 9 (3%) 0 0 2 (1%)
106 (31%) 69 (20%) 60 (18%) 52 (15%) 45 (13%) 25 (7%) 33 (10%) 24 (7%) 24 (7%) 24 (7%) 21 (6%)
1 (1%) 2 (2%) 1 (1%) 3 (2%) 6 (5%) 8 (7%) 2 (2%) 3 (2%) 0 0 0
3 (2%) 2 (1%) 1 (1%) 9 (7%) 3 (2%) 7 (5%) 1 (1%) 3 (2%) 1 (1%) 0 0
38 (30%) 12 (10%) 13 (10%) 14 (11%) 17 (14%) 10 (8%) 10 (8%) 5 (4%) 14 (11%) 6 (5%) 5 (4%)
11 (8%) 2 (2%) 8 (6%) 8 (6%) 11 (8%) 9 (7%) 4 (3%) 4 (3%) 1 (1%) 3 (2%) 6 (5%)
Central nervous system Headache
15 (4%)
19 (6%)
4 (3%)
1 (1%)
2 (2%)
2 (2%)
0·3% 0·6% 0·6% 0·9%
1·2% 0·3% 5·1% 4·6%
0·8% 0·8% 0·8% 0%
0% 0% 2·3% 0%
5·8% 0·8% 5·0% 3·3%
2·4% 0% 3·1% 1·6%
Two consecutive low values -carotene Vitamin A Vitamin D Vitamin E
Events that occurred in less than 5·0% of patients are not included.
Table 3: Adverse events remotely, possibly, or probably related to treatment
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Acknowledgments
Gastrointestinal adverse events
Other adverse events
Other reasons*
2 (0·6%) 12 (3·5%)
7 (2·0%) 11 (3·2%)
74 (21·6%) 38 (11·0%)
2 (1·6%) 5 (3·9%) 0 2 (1·5%)
1 (0·8%) 1 (0·8%) 4 (2·9%) 1 (0·7%)
21 (16·7%) 19 (15·0%) 17 (12·3%) 18 (13·3%)
2
*Other reasons for premature withdrawal in order of frequency were: did not cooperate, lost to follow-up, refused treatment, administrative, treatment failure, protocol violation, entry violation, died during study.
4
Year 1 Placebo (n=343) Orlistat (n=345) Year 2 Placebo/placebo (n=126) Placebo/orlistat (n=127) Orlistat/placebo (n=138) Orlistat/orlistat (n=135)
This study was supported by a research grant from F Hoffman-La Roche (Basel, Switzerland).
References 1
3
Table 4: Reasons for premature withdrawals
Although the participants in this study did not constitute all obese people within a randomly selected population, they were probably representative of individuals who seek help for their obesity. Long-term pharmacological treatment with anorectic agents has been associated with addiction and tolerance and with the risk of primary pulmonary hypertension, valvular heart disease, and systemic hypertension.21 These potential effects are related to the systemic mode of action of such drugs via the central nervous system. Orlistat belongs to a class of antiobesity agents that act directly and specifically at the site of fat breakdown in the lumen of the stomach and small intestine. The systemic absorption is negligible and the potential for systemic adverse events thus seems to be small. As expected, however, from the pharmacological mode of action of orlistat,12,15–18 there is an increased likelihood of gastrointestinal events. These were more common in the orlistat group during year 1 of the study, but the frequency of these events was lower during year 2 among participants who continued on orlistat treatment. Very few orlistat-group patients withdrew from the study because of gastrointestinal events. Orlistat’s pharmacological activity raises the possibility of decreased absorption of fat-soluble vitamins.22,23 Although absolute concentrations of vitamins D and E and -carotene decreased during orlistat treatment, the concentrations remained within the normal range and only a few individuals with low values needed supplementation. These results support orlistat’s potential for long-term management of obese patients in conjunction with an appropriate diet.
5
6 7
8 9
10 11 12
13
14
15 16
17
18
Contributors
19
All authors took part in the planning of the study. Lars Sjöström was the principal investigator of the trial and wrote the manuscript with Aila Rissanen. Mark Boldrin was responsible for all statistical evaluations. All authors were involved in revision of the manuscript.
20
European Multicentre Investigators
21 22
Austria: K Irsigler. Denmark: T Andersen, H W Hendel, K Hermansen, J Hilsted. Finland: A Rissanen, M Uusitupa. France: M Krempf, J-P Louvet. Germany: H Ditschuneit, G Prager. Netherlands: H P F Koppeschaar, P M J Zelissen. Sweden: S Rössner, L Sjöström, L Larsson, T William-Olsson. Switzerland: A Golay, T Moccetti, T Lehmann.
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Foreyt J, Goodrick K. The ultimate triumph of obesity. Lancet 1995; 346: 34–35. Nutrition and Physical Activity Task Force. Department of Health. London: HMSO, 1995. Prescott-Clark P, Primatesta P. Health survey for England 1995. Department of Health, London: HMSO, 1997. Kuczmarski RJ, Flegal KM, Campbell SM, Jonson CL. Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys 1960 to 1961. JAMA 1994; 272: 205–11. Kuskowa-Wolk A, Bergström R. Trends in body mass index and prevalence of obesity in Swedish women 1980–89. J Epidemiol Community Health 1993; 47: 195–99. Seidell JC. Time trends in obesity: an epidemiological perspective. Horm Metab Res 1997; 29: 155–58. SIGN. Obesity in Scotland: integrating prevention with weight management. A National Clinical Guideline recommended for use in Scotland by the Scottish Intercollegiate Guidelines Network. Pilot edition, November, 1996. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes 1992; 6: 397–415. National Task Force on the Prevention and Treatment of Obesity. Long term pharmacotherapy in the management of obesity. JAMA 1996; 276: 1907–15. Lissner L, Heitmann BL. Dietary fat and obesity: evidence from epidemiology. Eur J Clin Nutr 1995; 49: 79–90. Golay A, Bobbioni E. The role of dietary fat in obesity. Int J Obes 1997; 21 (suppl): S2–11. Zhi J, Melia AT, Guerciolini R, et al. Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmacol Ther 1994; 56: 82–85. James WPT, Schofield EC. Human energy requirements: a manual for planners and nutritionalists. Published by arrangement with the Food and Agriculture Organization of the United Nations. Oxford: Oxford University Press, 1990. Krotkiewski M, Sjöström L, Björntorp P, Carlgren G, Garellick G, Smith U. Adipose tissue cellularity in relation to prognosis for weight reduction. Int J Obes 1977; 1: 395–416. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes 1993; 17: 241–44. Drent ML, Larsson I, William-Olsson T, et al. Orlistat (Ro 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study. Int J Obes 1995; 19: 221–26. Hauptman JB, Jeunet FS, Hartmann D. Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro18-0647 (tetrahydrolipstatin). Am J Clin Nutr 1992; 55: 309S–13S. Tonstad S, Pometta D, Erkelens DW, et al. The effect of the gastrointestinal lipase inhibitor, orlistat, on serum lipids and lipoproteins in patients with primary hyperlipidaemia. Eur J Clin Pharmacol 1994; 46: 405–10. Sjöström CD, Lissner L, Sjöström L. Relationships between changes in body composition and changes in cardiovascular risk factors: the SOS intervention study. Obes Res 1997; 5: 519–30. Guy-Grand B, Apfelbaum M, Crepaldi G, et al. International trial of long-term dexfenfluramine in obesity. Lancet 1989; i: 1142–45. Editorial. Diet pills Redux. N Engl J Med 1997; 337: 629–30. Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol 1996; 36: 647–53. Zhi J, Melia AT, Koss-Twardy SG, et al. The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of carotene in healthy volunteers. J Clin Pharmacol 1996; 36: 152–59.
THE LANCET • Vol 352 • July 18, 1998
Articles
Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients
Lars Sjöström, Aila Rissanen, Teis Andersen, Mark Boldrin, Alain Golay, Hans P F Koppeschaar, Michel Krempf, for the European Multicentre Orlistat Study Group*
Summary Background We undertook a randomised controlled trial to assess the efficacy and tolerability of orlistat, a gastrointestinal lipase inhibitor, in promoting weight loss and preventing weight regain in obese patients over a 2year period. Methods 743 patients (body-mass index 28–47 kg/m2), recruited at 15 European centres, entered a 4-week, single-blind, placebo lead-in period on a slightly hypocaloric diet (600 kcal/day deficit). 688 patients who completed the lead-in were assigned double-blind treatment with orlistat 120 mg (three times a day) or placebo for 1 year in conjunction with the hypocaloric diet. In a second 52-week double-blind period patients were reassigned orlistat or placebo with a weight maintenance (eucaloric) diet. Findings From the start of lead-in to the end of year 1, the orlistat group lost, on average, more bodyweight than the placebo group (10·2% [10·3 kg] vs 6·1% [6·1 kg]; LSM difference 3·9 kg [p<0·001] from randomisation to the end of year 1). During year 2, patients who continued with orlistat regained, on average, half as much weight as those patients switched to placebo (p<0·001). Patients switched from placebo to orlistat lost an additional 0·9 kg during year 2, compared with a mean regain of 2·5 kg in patients who continued on placebo (p<0·001). Total cholesterol, low-density lipoprotein (LDL) cholesterol, LDL/high-density lipoprotein ratio, and concentrations of glucose and insulin decreased more in the orlistat group than in the placebo group. Gastrointestinal adverse events were more common in the orlistat group. Other adverse symptoms occurred at a similar frequency during both treatments.
*Members listed at end of paper Sahlgrenska University Hospital, Göteborg, Sweden (Prof L Sjöström MD); Helsinki University Central Hospital, Helsinki, Finland (Prof A Rissanen MD); Hvidovre University Hospital, Copenhagen, Denmark (T Andersen MD); Hoffmann-La Roche, Nutley, New Jersey, USA (M Boldrin MS); University Hospital Geneva, Switzerland (A Golay MD) Academisch Ziekenhuis Utrecht, Utrecht, Netherlands (H P F Koppeschaar MD); and Hotel Dieu, Nantes, France (M Krempf MD) Correspondence to: Prof Lars Sjöström, SOS-Sekretariatet, Medical Department, Sahlgrenska University Hospital, 41345 Göteborg, Sweden
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Interpretation Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period. The use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events.
Lancet 1998; 352: 167–73 See Commentary page ???
Introduction Obesity is becoming increasingly common and is recognised as a major public health problem worldwide.1–3 In the UK, the overweight and obese population increased by almost 15% between 1980 and 1992, by which time an estimated 54% of men and 45% of women were affected.2 Similar increases have been noted in many countries, such as the USA,4 Sweden,5 and the Netherlands.6 Guidelines published in 1996 for the management of obesity recommended modest weight loss and weight maintenance, rather than a target of ideal weight.7 Many obese patients who lose at least 5% of their initial bodyweight show improvement in cardiovascular risk factors and coexisting disorders.8 Pharmacological therapy has been proposed as an adjunct to diet and lifestyle changes to improve longterm weight loss.9 Clinicians may be uncertain, however, about appropriate use of drug therapy in the management of obesity.9 Given the central role of dietary fat in obesity,10,11 a logical way to achieve and maintain weight loss is to decrease the amount of fat available to be metabolised. Orlistat promotes weight loss by inhibiting gastrointestinal lipases, thus lowering absorption of dietary fat, on average by 30% with a dose of 120 mg three times a day.12 Our objectives were to examine the efficacy and tolerability of orlistat in promoting weight loss and preventing regain after the initial loss, and to assess effects on major cardiovascular risk factors.
Methods Patients This European 2-year multicentre trial had a double-blind, randomised, placebo-controlled, and parallel-group design. Obese (body-mass index 28–47 kg/m2) men and women, aged 18 years and over, were eligible for inclusion. Recruitment was from hospital waiting lists or by local advertising. Women of childbearing potential were included if they were using adequate contraception. The study conformed with the
167
ARTICLES
into the double-blind labelling. Without the prior knowledge of the investigators, the randomisation was done in blocks of four so that there were equal numbers of 194 not eligible patients with orlistat and placebo groups. Patients were stratified according to 743 enrolled in single-blind run-in weight loss during the lead-in period (聿2 kg or >2 kg) to achieve orlistat/placebo balance among these categories. 55 withdrew During the lead-in and 52-week treatment periods, patients were 688 completed run-in, randomised prescribed a hypocaloric diet containing roughly 30% of energy as fat. The energy content of the diet was calculated from the patients’ estimated basal metabolic rate multiplied by 1·3 to estimate the total 343 assigned 345 assigned daily energy expenditure.13 From energy placebo orlistat expenditure, 600 kcal/day (1 kcal=4·2 kJ) was subtracted to obtain a mildly 3 withdrew early 2 withdrew early hypocaloric diet. Between weeks ⫺4 (placebo lead-in) and 24, the minimum prescribed energy intake was 1200 340 in year-1 343 in year-1 kcal/day. To compensate for the ITT analysis ITT analysis anticipated reduction in energy expenditure accompanying the weight loss, the prescribed energy intake was 80 withdrew 59 withdrew further reduced by about 300 kcal/day at the end of week 24. For participants 260 completed 284 completed initially prescribed the minimum energy year 1 year 1 intake, energy intake was adjusted to 1000 kcal/day. At the end of year 1, eligible patients 7 not reassigned 11 not reassigned (>75% compliance) in each treatment group were reassigned either to continue on the same regimen (orlistat 120 mg or 253 reassigned 273 reassigned placebo three times a day) or to switch to the alternative regimen for a further 52 weeks, so that we could assess the impact 126 placebo 127 orlistat 138 placebo 135 orlistat of treatment on prevention of weight regain. At the start of year 2, patients 2 withdrew 2 withdrew 3 withdrew were prescribed a weight-maintenance early early early (eucaloric) diet designed to maintain stable bodyweight. Patients were advised 21 withdrew 23 withdrew 21 withdrew 19 withdrew not to return to a hypocaloric diet at any later later later later time during year 2. Weight reduction during year 1 and maintenance of lost weight during year 2 Placebo placebo Placebo orlistat Orlistat placebo Orlistat orlistat were the primary efficacy variables. 123 analysed 123 analysed 138 analysed 133 analysed Bodyweight was measured (with 102 completed 102 completed 117 completed 114 completed calibrated scales) before and during runin, at randomisation, every 2 weeks for Figure 1: Trial profile the first 3 months after randomisation, ITT=intention to treat. and monthly thereafter until the end of Declaration of Helsinki. The ethics committees of all centres year 1, and at eight scheduled visits in year 2. Fasting serum approved the study, and all participants gave verbal or written concentrations of glucose, insulin, total cholesterol, low-densityinformed consent. lipoprotein (LDL) cholesterol (measured by ultraPatients with serious diseases (defined in the research centrifugation), high-density-lipoprotein (HDL) cholesterol, protocol), including uncontrolled hypertension and and triglycerides were measured before run-in, at pharmacologically treated diabetes, were excluded. Other randomisation, and at the end of months 1, 3, 6, 12, 13, 14, 16, exclusion criteria were weight loss of more than 4 kg in the 3 months before screening, surgery for weight reduction, a history Characteristic Placebo (n=340) Orlistat (n=343) of post surgical adhesions, bulimia or laxative abuse, use of any Sex drug that might have influenced bodyweight or plasma lipids in Male 57 (16·8%) 59 (17·2%) the month before study entry, and drug or alcohol abuse. Female 283 (83·2%) 284 (82·8%) 937 screened
Age (years)*
Design After a single-blind lead-in period lasting 4 weeks, during which patients received placebo three times a day with meals, eligible patients (>75% compliance with therapy calculated from the number of capsules returned) were randomly assigned doubleblind treatment with either orlistat 120 mg or placebo, three times daily with meals for 52 weeks. Randomisation numbers for patients were generated by the sponsor and incorporated
168
Anthropometry* Weight (kg) Height (cm) Body-mass index (kg/m2)† Waist circumference (cm)
44·3 (18·0–77·0)
45·2 (20·0–76·0)
99·8 (64·2–137·2) 166·1 (143·0–190·0) 36·1 (29·2–43·5) 105·9 (71–135)
99·1 (61·0–148·6) 165·7 (140·0–197·0) 36·0 (28·3–47·2) 105·4 (70–149)
*Mean (range). †Measured at start of lead-in period (day ⫺28).
Table 1: Characteristics of intention-to-treat population at first randomisation (day 1)
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Change in bodyweight (%)
ARTICLES
0 –1 –2 –3 –4 –5 –6 –7 –8 –9 –10 –11 –12
change from the start of the lead-in period to the end of year 1 was used as a covariate. Similar models were used to calculate differences and changes in risk factors. Two-sided tests were used and p values <0·05 were taken to be significant.
Placebo Orlistat
Results
–10 0
10 20 30 40 50 60 70 80 90 100 110
Week SB
DB
DB
Slightly hypocaloric diet
Weight maintenance (eucaloric) diet Figure 2: Mean percentage change in bodyweight from start of single-blind lead-in until 2-year examination in orlistat and placebo groups Initial bodyweight was close to a mean of 100 kg in both groups (table 1)—percentage change therefore approximately matches kg lost. SB=single-blind lead-in period of 4 weeks; DB=double-blind, placebocontrolled treatment during years 1 and 2. Error bars=SE.
18, and 24. Blood pressure and heart rate were measured at each visit. Blood and urine samples taken when the patient had fasted overnight were collected regularly for standard haematological, clinical chemistry (including vitamins A, D [measured as 25hydroxy vitamin D], and E, prothrombin time, and -carotene), and urine analysis assessments. Vitamin results were concealed from the investigators, although notification of concentrations below the normal range was given. Additional dietary counselling, or vitamin supplementation when necessary, was provided if two consecutive measurements were below normal. Plasma samples collected after 6 months, 1 year, and 2 years were analysed for the presence of orlistat by high-performance liquid chromatography. Laboratory samples were immediately transported on ice by courier to a certified laboratory in Copenhagen, Denmark, for standard biochemical tests. All adverse events were recorded and the potential relation to treatment was judged by the investigator. Standard terms were developed to describe gastrointestinal events expected with increased excretion of fat due to orlistat treatment.
Statistical analysis Published results of a long-term obesity study (n=227) reported an SD of 7·5 kg (SE 0·49) associated with weight loss over 1 year. With this information, power calculations indicated that we would need 56 patients per treatment group to detect a 4 kg difference in weight change with a power of 80% at the 0·05 significance level. The planned sample size of 600 patients was based on the assumption of withdrawal rates of 50% during year 1 and 25% during year 2. Efficacy was assessed by intention to treat. The intention-totreat population for both years consisted of patients who had had at least one dose of the test medication and at least one follow-up bodyweight measurement. For individuals withdrawing during year 1 or 2, the last available examination was carried forward to the end of year 1 or 2, respectively, in the least squares mean (LSM) calculations. The null hypothesis of no difference between the treatment groups was tested with general linear models. To assess year-1 weight loss, we did ANCOVA with the following variables: treatment (placebo or orlistat), centre (1–15), and stratum (weight-loss group assigned during lead-in). Second-order interaction terms were also used and results were expressed as LSM difference from placebo (with SE). During year 2, weight
THE LANCET • Vol 352 • July 18, 1998
Enrolment and follow-up A total of 937 patients were screened, of whom 743 entered a 4-week, placebo lead-in. 688 patients who completed the lead-in were randomised to double-blind treatment with orlistat 120 mg or placebo three times a day (figure 1). Five early withdrawals (four no safety assessment, one no trial medication), reduced the year-1 intention-totreat population to 683 patients, 544 of whom completed treatment. Immediately after completion of year 1, 18 patients withdrew mainly owing to non-compliance. Consequently, 273 former orlistat-group patients and 253 former placebo-group patients were reassigned for year 2 (figure 1). At the end of year 2, the intention-to-treat population consisted of 519 (75% of randomised) patients of whom 435 (63% of randomised) completed treatment. Analysis of the participants who completed year 2 gave similar results to the intention-to-treat analysis (data not shown). Demographic and anthropometric characteristics did not differ significantly between treatment groups at the start of the lead-in period (not shown) or at randomisation (table 1). None of the cardiovascular risk factors differed between groups at the start of the lead-in period or at randomisation. Weight loss and weight regain After year 1, the mean decrease in bodyweight from values at the start of the placebo run-in period was 10·2% (or 10·3 kg) in the orlistat group, compared with 6·1% (or 6·1 kg) in the placebo group (figure 2). Thus, the decrease in weight was 68% greater with orlistat than with placebo (LSM weight-loss difference from randomisation 3·9 kg; p<0·001). At the end of year 1, 9·3% of the orlistat group versus 2·1% of the placebo group had lost more than 20% of initial bodyweight; 29·5% versus 15·6% had lost 10·1–20·0% of bodyweight; 29·7% versus 31·5% had lost 5·1–10·0% of bodyweight; and 23·6% versus 32·7% had lost 0·1–5·0% of bodyweight. 7·9% versus 18·2% had unchanged or increased bodyweight. Figure 2 illustrates the effect of orlistat during year 2, when patients were prescribed a eucaloric diet. In former placebo-group patients, orlistat reduced bodyweight (LSM difference in weight loss orlistat⫺placebo 3·6 kg [SE 0·6]; p<0·001). In former orlistat-group patients, the weight regain was smaller with orlistat than with placebo (LSM difference in weight loss orlistat⫺placebo 2·4 kg [0·6]; p<0·001). After 2 years of continuous orlistat treatment, 57·1% of the patients maintained a weight loss greater than 5%; the corresponding percentage for 2 years’ placebo treatment was 37·4%. Cardiovascular risk factors Cardiovascular risk factors, measured on 11 occasions during the 2-year study period, are reported only from the start of the lead-in (week 4), randomisation (day 1), week 52, and week 104 (table 2). For brevity, data at 169
ARTICLES
Start of lead-in
Plasma lipids Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) LDL/HDL ratio Triglycerides (mmol/L)
Day 1
Week 52
Placebo (n=340)
Orlistat (n=343)
Placebo (n=340)
Orlistat (n=343)
Placebo (n=340)
Orlistat (n=343)
Model A
Model A
Model B
Model B
Model C
Model C
p
5·69 (0·06) 3·72 (0·05) 1·24 (0·02) 3·17 (0·06) 1·72 (0·06)
5·78 (0·06) 3·82 (0·05) 1·25 (0·02) 3·23 (0·06) 1·66 (0·06)
5·36 (0·03)* 3·55 (0·03)* 1·16 (0·01)* 3·23 (0·03) 1·53 (0·05)*
5·39 (0·03)* 3·55 (0·03)* 1·15 (0·01)* 3·25 (0·03) 1·60 (0·05)
5·59 (0·04) 3·68 (0·03) 1·26 (0·01) 3·09 (0·03) 1·59 (0·04)
5·31 (0·04) 3·46 (0·03) 1·25 (0·01) 2·92 (0·03) 1·53 (0·04)
<0·0001 <0·0001 0·3076 0·0002 0·3951
Other biochemistry Fasting blood glucose (mmol/L) Fasting plasma insulin (pmol/L)
6·04 (0·06) 107 (3·2)
5·92 (0·06) 109 (3·1)
5·83 (0·03)* 97·1 (4·1)*
5·84 (0·03)* 98·7 (3·9)†
5·77 (0·04) 95·6 (4·5)
5·63 (0·04) 87·0 (4·3)
0·0098 0·1667
Blood pressure (mm Hg) Systolic Diastolic
132 (0·83) 84·8 (0·49)
133 (0·82) 84·8 (0·49)
128 (0·60)* 81·9 (0·40)*
129 (0·60)* 82·4 (0·40)*
129 (0·71) 82·1 (0·43)
127 (0·70) 80·3 (0·43)
0·0189 0·0022
For within-group changes between start of lead-in and day 1: *p<0·001; †p<0·1; others p>0·1. Model A=group (placebo=0 and orlistat=1) only; B=group and start of lead-in value of risk factor under consideration; C=group, day-1 value of risk factor under consideration, number of the centre (1–15) the patient belonged to, and group⫻centre. Missing data: placebo group—for lipids n聿5, glucose n聿5, insulin n聿39, blood pressure n聿1; orlistat group—for lipids n聿6, glucose n聿11, insulin n聿35.
Table 2: LSM (SE) of cardiovascular risk factors in intention-to-treat population from start of the lead-in period to week 104
week 104 are presented only for the groups receiving either placebo for 2 years or orlistat for 2 years. The weight reduction observed during the placebo lead-in was accompanied by significant (p<0·001) decreases within the future placebo and orlistat groups in total cholesterol, LDL cholesterol, HDL cholesterol, fasting blood glucose, and blood pressure. In the future placebo group, triglycerides and plasma insulin were also reduced (table 2). There were no significant differences between the placebo and orlistat groups at the start of the lead-in or at randomisation (table 2). In the placebo group total cholesterol and LDL cholesterol gradually returned towards values at the start of lead-in at 1 year and 2 years. By contrast, concentrations of these lipids fell further during the 2 years in the orlistat group, and these changes were significantly different from those in the placebo group both at 1 year and at 2 years (table 2). The changes in HDL cholesterol in the two treatment groups were similar, with a small drop at day 1 compared with mean values at the start of run-in and after 1 year and 2 years. As a consequence the LDL/HDL ratio was unchanged within both groups at day 1. Later, the reductions were larger in the orlistat group (table 2). Changes in triglycerides were similar in both groups throughout the study. The orlistat group showed significantly larger decreases than the placebo group in fasting glucose and insulin at 2 years and systolic and diastolic blood pressure at 1 year. To examine whether orlistat has effects on risk factors beyond its weight-reducing properties, percentage riskfactor change (week 52 or week 104 minus day 1) was modelled with a general linear model as a function of treatment (orlistat or placebo) with, as covariates, percentage weight change and value of risk factor under consideration at day 1. Under these circumstances baseline risk-factor value and weight reduction were significant at 52 and 104 weeks for all risk-factor changes given in table 2. Treatment was also a significant predictor for change in total cholesterol at week 52 (p=0·0001) and at week 104 (p=0·0002), and for change in LDL cholesterol at week 52 (p=0·0003) and at week 104 (p=0·0463). At week 104, treatment was also a significant predictor (p=0·0236) for change in the LDL/HDL ratio (not shown in tables).
Adverse events The overall frequency of adverse events was slightly higher in the orlistat group than in the placebo group 170
during year 1 (94 vs 82%) and similar in the four treatment groups during year 2 (table 3). With the exception of some gastrointestinal events, the adverse events were judged by the investigators to be unrelated or remotely related to treatment. Most of the gastrointestinal events (table 3) happened early in orlistat treatment and were of short duration (<4 days). Patients treated with orlistat experienced far fewer gastrointestinal events during year 2 than in year 1. Serious adverse events were reported by 24 patients in the placebo group and 25 in the orlistat group during year 1, with only one adverse event in each group being judged by the investigators to be related to treatment. Similarly, two serious adverse events that were judged possibly related to treatment happened during year 2. One case of gastrointestinal neoplasm occurred in a patient treated with placebo for 2 years. No other malignant disorders were observed in the course of this study. The total number of premature withdrawals was higher in the placebo group than in the orlistat group during year 1 (83 vs 61) and virtually the same in both groups during year 2 (45 vs 46). Adverse gastrointestinal events, however, were a more common reason for premature withdrawals in the orlistat group than in the placebo group (table 4). There were no clinically or statistically significant changes in the mean values of any laboratory measurements during the study, and the frequency of laboratory abnormalities was evenly distributed between the treatment groups (data not shown). After an initial small decrease, mean concentrations of vitamins A, D, and E, and -carotene stabilised and remained within normal clinical ranges throughout the study in both groups (data not shown). During year 1, 41 patients in the orlistat group and 18 in the placebo group had two or more consecutive low vitamin concentrations recorded (table 3), but only 16 and four patients, respectively, received vitamin supplementation. During year 2, vitamin supplementation was received by four patients in the orlistat/orlistat group, by one placebo/placebo patient, by three patients in the placebo/orlistat group, and by one patient in the orlistat/placebo group. Pharmacokinetic analysis of blood samples showed measurable, but minute, concentrations (0·208–2·078 g/L) of unchanged orlistat in the plasma of only a few patients at 24 weeks (13/281 [4·6%] orlistat-treated patients), 52 weeks (17/236 [7·2%]), and 104 weeks THE LANCET • Vol 352 • July 18, 1998
ARTICLES
Percentage change, week 52 minus day 1
Week 104 p
Percentage change, week 104 minus day 1
Placebo (n=340)
Orlistat (n=343)
Pla/pla (n=123)
Orl/orl (n=133)
Model C
Model C
p
Model C
Model C
4·91 (0·66) 5·18 (0·87) 11·0 (0·93) ⫺3·25 (0·97) 4·99 (2·11)
⫺0·36 (0·66) ⫺1·15 (0·86) 9·8 (0·92) ⫺8·56 (0·97) 4·02 (2·09)
<0·0001 <0·0001 0·3789 0·0001 0·7450
5·69 (0·07) 3·74 (0·05) 1·28 (0·02) 3·06 (0·06) 1·80 (0·13)
5·27 (0·06) 3·46 (0·05) 1·30 (0·02) 2·81 (0·05) 1·48 (0·12)
<0·0001 0·0002 0·3900 0·0014 0·0770
6·51 (1·25) 6·05 (1·92) 12·8 (1·69) ⫺4·57 (1·72) 16·6 (6·01)
⫺1·14 (1·18) ⫺0·62 (1·82) 15·3 (1·60) ⫺12·7 (1·63) 2·95 (5·68)
0·0000 0·0123 0·2927 0·0007 0·1000
Other biochemistry ⫺1·02 (0·54) 7·61 (4·57)
⫺3·15 (0·54) ⫺1·54 (4·38)
0·0053 0·1493
6·08 (0·08) 104 (5·62)
5·82 (0·08) 83·4 (5·3)
0·0260 0·0073
2·33 (1·07) 19·1 (5·28)
⫺0·92 (1·02) ⫺5·05 (4·97)
0·0290 0·0010
Blood pressure (mm Hg) 1·18 (0·55) ⫺0·57 (0·55) 0·64 (0·54) ⫺1·74 (0·54)
0·0256 0·0019
130 (1·19) 83·6 (0·82)
0·5188 0·4098
2·30(0·93) 1·95 (1·04)
1·08 (0·87) 0·78 (0·98)
0·3406 0·4103
129 (1·12) 82·7 (0·77)
Pla/pla (n=123)
Orl/orl (n=133)
Model C
Model C
p
Table 2: Continued
(2/75 [2·7%]). These findings indicate low systemic absorption of orlistat after 2 years of treatment, with no evidence of accumulation.
Discussion This randomised study showed that orlistat provided sustained improvements in weight loss and weight maintenance for up to 2 years. In addition, there were beneficial changes in several risk factors. During year 2 orlistat prevented or inhibited regain of weight compared with placebo. Cessation of orlistat therapy resulted in a marked rebound effect. Patients on orlistat for the whole 2 years, however, also relapsed slightly during year 2, apparently because of the change from a hypocaloric to eucaloric diet. This change was a consequence of the protocol and in practice it resulted in increased energy intake in patients whose weight stabilised for the last 3 months of year 1. Whether the weight could have been maintained during year 2 with an unchanged diet, which in reality was eucaloric, is not known. A 2-year study with continuous hypocaloric diet recommendations is in progress (the XENDOS study). Large energy deficits, for instance with very lowenergy diets, might have resulted in the same weight reduction during year 1 as the orlistat treatment. It is well known, however, that the greater the weight Year 1
reduction, the greater the relapse,14 a fact that is also illustrated by the two placebo groups during year 2 in our study. In agreement with short-term trials,15–18 the weight reduction in the orlistat group was accompanied by beneficial changes in several cardiovascular risk factors. Plasma total cholesterol and LDL-cholesterol concentrations fell in the orlistat group further than would have been expected from weight loss alone. This independent cholesterol-lowering effect is likely to reflect the ability of orlistat to induce weight loss by specifically reducing energy uptake from fat.12 As in previous short-term (聿1 year) studies,8 the placebo group in our study showed improvements in most risk factors after 4 weeks of run-in on a hypocaloric diet. Nevertheless, despite a maintained weight reduction of about 5% in the placebo group, risk-factor values were back at baseline at the 2-year examination. This finding accords with 2-year observations in the Swedish Obese Subjects study, showing that during steady-weight conditions, previous weight reductions of about 10% are required for long-lasting risk-factor improvements to be detected.19 Premature withdrawals were less frequent than expected,20 with 76% of the placebo group and 82% of the orlistat group completing year 1. The full 2 years were completed by 63% of all randomised patients.
Year 2
Placebo (n=340)
Orlistat (n=343)
Placebo/placebo (n=123)
Orlistat/placebo (n=138)
Placebo/orlistat (n=125)
Orlistat/orlistat (n=133)
Overall adverse events
279 (82%)
322 (94%)
90 (73%)
109 (79%)
109 (87%)
102 (77%)
Gastrointestinal system Fatty/oily stool Increased defecation Oily spotting Soft stool Liquid stools Abdominal pain Faecal urgency Flatulence Flatus with discharge Faecal incontinence Oily evacuation
17 (5%) 25 (7%) 4 (1%) 30 (9%) 34 (10%) 30 (9%) 11 (3%) 9 (3%) 0 0 2 (1%)
106 (31%) 69 (20%) 60 (18%) 52 (15%) 45 (13%) 25 (7%) 33 (10%) 24 (7%) 24 (7%) 24 (7%) 21 (6%)
1 (1%) 2 (2%) 1 (1%) 3 (2%) 6 (5%) 8 (7%) 2 (2%) 3 (2%) 0 0 0
3 (2%) 2 (1%) 1 (1%) 9 (7%) 3 (2%) 7 (5%) 1 (1%) 3 (2%) 1 (1%) 0 0
38 (30%) 12 (10%) 13 (10%) 14 (11%) 17 (14%) 10 (8%) 10 (8%) 5 (4%) 14 (11%) 6 (5%) 5 (4%)
11 (8%) 2 (2%) 8 (6%) 8 (6%) 11 (8%) 9 (7%) 4 (3%) 4 (3%) 1 (1%) 3 (2%) 6 (5%)
Central nervous system Headache
15 (4%)
19 (6%)
4 (3%)
1 (1%)
2 (2%)
2 (2%)
0·3% 0·6% 0·6% 0·9%
1·2% 0·3% 5·1% 4·6%
0·8% 0·8% 0·8% 0%
0% 0% 2·3% 0%
5·8% 0·8% 5·0% 3·3%
2·4% 0% 3·1% 1·6%
Two consecutive low values -carotene Vitamin A Vitamin D Vitamin E
Events that occurred in less than 5·0% of patients are not included.
Table 3: Adverse events remotely, possibly, or probably related to treatment
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Acknowledgments
Gastrointestinal adverse events
Other adverse events
Other reasons*
2 (0·6%) 12 (3·5%)
7 (2·0%) 11 (3·2%)
74 (21·6%) 38 (11·0%)
2 (1·6%) 5 (3·9%) 0 2 (1·5%)
1 (0·8%) 1 (0·8%) 4 (2·9%) 1 (0·7%)
21 (16·7%) 19 (15·0%) 17 (12·3%) 18 (13·3%)
2
*Other reasons for premature withdrawal in order of frequency were: did not cooperate, lost to follow-up, refused treatment, administrative, treatment failure, protocol violation, entry violation, died during study.
4
Year 1 Placebo (n=343) Orlistat (n=345) Year 2 Placebo/placebo (n=126) Placebo/orlistat (n=127) Orlistat/placebo (n=138) Orlistat/orlistat (n=135)
This study was supported by a research grant from F Hoffman-La Roche (Basel, Switzerland).
References 1
3
Table 4: Reasons for premature withdrawals
Although the participants in this study did not constitute all obese people within a randomly selected population, they were probably representative of individuals who seek help for their obesity. Long-term pharmacological treatment with anorectic agents has been associated with addiction and tolerance and with the risk of primary pulmonary hypertension, valvular heart disease, and systemic hypertension.21 These potential effects are related to the systemic mode of action of such drugs via the central nervous system. Orlistat belongs to a class of antiobesity agents that act directly and specifically at the site of fat breakdown in the lumen of the stomach and small intestine. The systemic absorption is negligible and the potential for systemic adverse events thus seems to be small. As expected, however, from the pharmacological mode of action of orlistat,12,15–18 there is an increased likelihood of gastrointestinal events. These were more common in the orlistat group during year 1 of the study, but the frequency of these events was lower during year 2 among participants who continued on orlistat treatment. Very few orlistat-group patients withdrew from the study because of gastrointestinal events. Orlistat’s pharmacological activity raises the possibility of decreased absorption of fat-soluble vitamins.22,23 Although absolute concentrations of vitamins D and E and -carotene decreased during orlistat treatment, the concentrations remained within the normal range and only a few individuals with low values needed supplementation. These results support orlistat’s potential for long-term management of obese patients in conjunction with an appropriate diet.
5
6 7
8 9
10 11 12
13
14
15 16
17
18
Contributors
19
All authors took part in the planning of the study. Lars Sjöström was the principal investigator of the trial and wrote the manuscript with Aila Rissanen. Mark Boldrin was responsible for all statistical evaluations. All authors were involved in revision of the manuscript.
20
European Multicentre Investigators
21 22
Austria: K Irsigler. Denmark: T Andersen, H W Hendel, K Hermansen, J Hilsted. Finland: A Rissanen, M Uusitupa. France: M Krempf, J-P Louvet. Germany: H Ditschuneit, G Prager. Netherlands: H P F Koppeschaar, P M J Zelissen. Sweden: S Rössner, L Sjöström, L Larsson, T William-Olsson. Switzerland: A Golay, T Moccetti, T Lehmann.
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