ARTICLES
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 2-
year 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 long-
term 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

937 screened the prior knowledge of the investigators,
the randomisation was done in blocks of
194 not eligible four so that there were equal numbers of
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
55 withdrew balance among these categories.
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
343 assigned 345 assigned rate multiplied by 1·3 to estimate the total
placebo orlistat daily energy expenditure.13 From energy
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
340 in year-1 343 in year-1 prescribed energy intake was 1200
ITT analysis ITT analysis kcal/day. To compensate for the
anticipated reduction in energy
expenditure accompanying the weight
80 withdrew 59 withdrew loss, the prescribed energy intake was
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
253 reassigned 273 reassigned on the same regimen (orlistat 120 mg or
placebo three times a day) or to switch to
the alternative regimen for a further 52
126 placebo 127 orlistat 138 placebo 135 orlistat weeks, so that we could assess the impact
of treatment on prevention of weight
regain. At the start of year 2, patients
3 withdrew 2 withdrew 2 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
Placebo placebo Placebo orlistat Orlistat placebo Orlistat orlistat maintenance of lost weight during year 2
123 analysed 123 analysed 138 analysed 133 analysed were the primary efficacy variables.
102 completed 102 completed 117 completed 114 completed Bodyweight was measured (with
calibrated scales) before and during run-
Figure 1: Trial profile in, at randomisation, every 2 weeks for
ITT=intention to treat. the first 3 months after randomisation,
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-density-
informed consent. lipoprotein (LDL) cholesterol (measured by ultra-
Patients 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%)
Age (years)* 44·3 (18·0–77·0) 45·2 (20·0–76·0)
Design Anthropometry*
After a single-blind lead-in period lasting 4 weeks, during which Weight (kg) 99·8 (64·2–137·2) 99·1 (61·0–148·6)
patients received placebo three times a day with meals, eligible Height (cm) 166·1 (143·0–190·0) 165·7 (140·0–197·0)
patients (>75% compliance with therapy calculated from the Body-mass index (kg/m2)† 36·1 (29·2–43·5) 36·0 (28·3–47·2)
Waist circumference (cm) 105·9 (71–135) 105·4 (70–149)
number of capsules returned) were randomly assigned double-
blind treatment with either orlistat 120 mg or placebo, three *Mean (range). †Measured at start of lead-in period (day ⫺28).
times daily with meals for 52 weeks. Randomisation numbers Table 1: Characteristics of intention-to-treat population at first
for patients were generated by the sponsor and incorporated randomisation (day 1)

168 THE LANCET • Vol 352 • July 18, 1998


Change in bodyweight (%)
0 change from the start of the lead-in period to the end of year 1
–1 Placebo
–2 Orlistat
–3
–4
–5
–6
–7
–8
–9
–10
–11
–12
–10 0 10 20 30 40 50 60 70 80 90 100 110
Week
SB DB DB
Slightly
Weight
hypocaloric diet
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, placebo-
controlled 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 25-
hydroxy 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-to-
treat 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
ARTICLES
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.
Results
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-to-
treat population to 683 patients, 544 of whom
completed treatment.
Immediately after completion of year 1, 18 patients
withdrew mainly owing to non-compliance. Con-
sequently, 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
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Start of lead-in Day 1 Week 52

Placebo (n=340) Orlistat (n=343) Placebo (n=340) Orlistat (n=343) Placebo (n=340) Orlistat (n=343) p
Model A Model A Model B Model B Model C Model C
Plasma lipids
Total cholesterol (mmol/L) 5·69 (0·06) 5·78 (0·06) 5·36 (0·03)* 5·39 (0·03)* 5·59 (0·04) 5·31 (0·04) <0·0001
LDL cholesterol (mmol/L) 3·72 (0·05) 3·82 (0·05) 3·55 (0·03)* 3·55 (0·03)* 3·68 (0·03) 3·46 (0·03) <0·0001
HDL cholesterol (mmol/L) 1·24 (0·02) 1·25 (0·02) 1·16 (0·01)* 1·15 (0·01)* 1·26 (0·01) 1·25 (0·01) 0·3076
LDL/HDL ratio 3·17 (0·06) 3·23 (0·06) 3·23 (0·03) 3·25 (0·03) 3·09 (0·03) 2·92 (0·03) 0·0002
Triglycerides (mmol/L) 1·72 (0·06) 1·66 (0·06) 1·53 (0·05)* 1·60 (0·05) 1·59 (0·04) 1·53 (0·04) 0·3951
Other biochemistry
Fasting blood glucose (mmol/L) 6·04 (0·06) 5·92 (0·06) 5·83 (0·03)* 5·84 (0·03)* 5·77 (0·04) 5·63 (0·04) 0·0098
Fasting plasma insulin (pmol/L) 107 (3·2) 109 (3·1) 97·1 (4·1)* 98·7 (3·9)† 95·6 (4·5) 87·0 (4·3) 0·1667
Blood pressure (mm Hg)
Systolic 132 (0·83) 133 (0·82) 128 (0·60)* 129 (0·60)* 129 (0·71) 127 (0·70) 0·0189
Diastolic 84·8 (0·49) 84·8 (0·49) 81·9 (0·40)* 82·4 (0·40)* 82·1 (0·43) 80·3 (0·43) 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 during year 1 (94 vs 82%) and similar in the four
either placebo for 2 years or orlistat for 2 years. treatment groups during year 2 (table 3). With the
The weight reduction observed during the placebo exception of some gastrointestinal events, the adverse
lead-in was accompanied by significant (p<0·001) events were judged by the investigators to be unrelated
decreases within the future placebo and orlistat groups in or remotely related to treatment. Most of the
total cholesterol, LDL cholesterol, HDL cholesterol, gastrointestinal events (table 3) happened early in orlistat
fasting blood glucose, and blood pressure. In the future treatment and were of short duration (<4 days). Patients
placebo group, triglycerides and plasma insulin were also treated with orlistat experienced far fewer
reduced (table 2). There were no significant differences gastrointestinal events during year 2 than in year 1.
between the placebo and orlistat groups at the start of Serious adverse events were reported by 24 patients in
the lead-in or at randomisation (table 2). In the placebo the placebo group and 25 in the orlistat group during
group total cholesterol and LDL cholesterol gradually year 1, with only one adverse event in each group being
returned towards values at the start of lead-in at 1 year judged by the investigators to be related to treatment.
and 2 years. By contrast, concentrations of these lipids Similarly, two serious adverse events that were judged
fell further during the 2 years in the orlistat group, and possibly related to treatment happened during year 2.
these changes were significantly different from those in One case of gastrointestinal neoplasm occurred in a
the placebo group both at 1 year and at 2 years (table 2). patient treated with placebo for 2 years. No other
The changes in HDL cholesterol in the two treatment malignant disorders were observed in the course of this
groups were similar, with a small drop at day 1 study.
compared with mean values at the start of run-in and The total number of premature withdrawals was
after 1 year and 2 years. As a consequence the higher in the placebo group than in the orlistat group
LDL/HDL ratio was unchanged within both groups at during year 1 (83 vs 61) and virtually the same in both
day 1. Later, the reductions were larger in the orlistat groups during year 2 (45 vs 46). Adverse gastrointestinal
group (table 2). events, however, were a more common reason for
Changes in triglycerides were similar in both groups premature withdrawals in the orlistat group than in the
throughout the study. The orlistat group showed placebo group (table 4).
significantly larger decreases than the placebo group in There were no clinically or statistically significant
fasting glucose and insulin at 2 years and systolic and changes in the mean values of any laboratory
diastolic blood pressure at 1 year. measurements during the study, and the frequency of
To examine whether orlistat has effects on risk factors laboratory abnormalities was evenly distributed between
beyond its weight-reducing properties, percentage risk- the treatment groups (data not shown). After an initial
factor change (week 52 or week 104 minus day 1) was small decrease, mean concentrations of vitamins A, D,
modelled with a general linear model as a function of and E, and ␤-carotene stabilised and remained within
treatment (orlistat or placebo) with, as covariates, normal clinical ranges throughout the study in both
percentage weight change and value of risk factor under groups (data not shown). During year 1, 41 patients in
consideration at day 1. Under these circumstances the orlistat group and 18 in the placebo group had two
baseline risk-factor value and weight reduction were or more consecutive low vitamin concentrations
significant at 52 and 104 weeks for all risk-factor changes recorded (table 3), but only 16 and four patients,
given in table 2. Treatment was also a significant respectively, received vitamin supplementation. During
predictor for change in total cholesterol at week 52 year 2, vitamin supplementation was received by four
(p=0·0001) and at week 104 (p=0·0002), and for change patients in the orlistat/orlistat group, by one
in LDL cholesterol at week 52 (p=0·0003) and at week placebo/placebo patient, by three patients in the
104 (p=0·0463). At week 104, treatment was also a placebo/orlistat group, and by one patient in the
significant predictor (p=0·0236) for change in the orlistat/placebo group.
LDL/HDL ratio (not shown in tables). Pharmacokinetic analysis of blood samples showed
measurable, but minute, concentrations (0·208–2·078
Adverse events ␮g/L) of unchanged orlistat in the plasma of only a few
The overall frequency of adverse events was slightly patients at 24 weeks (13/281 [4·6%] orlistat-treated
higher in the orlistat group than in the placebo group patients), 52 weeks (17/236 [7·2%]), and 104 weeks

170 THE LANCET • Vol 352 • July 18, 1998

 ARTICLES

Percentage change, week 52 minus day 1 Week 104 Percentage change, week 104 minus day 1
Placebo (n=340) Orlistat (n=343) p Pla/pla (n=123) Orl/orl (n=133) p Pla/pla (n=123) Orl/orl (n=133) p
Model C Model C Model C Model C Model C Model C

4·91 (0·66) ⫺0·36 (0·66) <0·0001 5·69 (0·07) 5·27 (0·06) <0·0001 6·51 (1·25) ⫺1·14 (1·18) 0·0000
5·18 (0·87) ⫺1·15 (0·86) <0·0001 3·74 (0·05) 3·46 (0·05) 0·0002 6·05 (1·92) ⫺0·62 (1·82) 0·0123
11·0 (0·93) 9·8 (0·92) 0·3789 1·28 (0·02) 1·30 (0·02) 0·3900 12·8 (1·69) 15·3 (1·60) 0·2927
⫺3·25 (0·97) ⫺8·56 (0·97) 0·0001 3·06 (0·06) 2·81 (0·05) 0·0014 ⫺4·57 (1·72) ⫺12·7 (1·63) 0·0007
4·99 (2·11) 4·02 (2·09) 0·7450 1·80 (0·13) 1·48 (0·12) 0·0770 16·6 (6·01) 2·95 (5·68) 0·1000
Other biochemistry
⫺1·02 (0·54) ⫺3·15 (0·54) 0·0053 6·08 (0·08) 5·82 (0·08) 0·0260 2·33 (1·07) ⫺0·92 (1·02) 0·0290
7·61 (4·57) ⫺1·54 (4·38) 0·1493 104 (5·62) 83·4 (5·3) 0·0073 19·1 (5·28) ⫺5·05 (4·97) 0·0010
Blood pressure (mm Hg)
1·18 (0·55) ⫺0·57 (0·55) 0·0256 130 (1·19) 129 (1·12) 0·5188 2·30(0·93) 1·08 (0·87) 0·3406
0·64 (0·54) ⫺1·74 (0·54) 0·0019 83·6 (0·82) 82·7 (0·77) 0·4098 1·95 (1·04) 0·78 (0·98) 0·4103

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 low-
energy 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
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 1 Year 2
Placebo Orlistat Placebo/placebo Orlistat/placebo Placebo/orlistat Orlistat/orlistat
(n=340) (n=343) (n=123) (n=138) (n=125) (n=133)
Overall adverse events 279 (82%) 322 (94%) 90 (73%) 109 (79%) 109 (87%) 102 (77%)
Gastrointestinal system
Fatty/oily stool 17 (5%) 106 (31%) 1 (1%) 3 (2%) 38 (30%) 11 (8%)
Increased defecation 25 (7%) 69 (20%) 2 (2%) 2 (1%) 12 (10%) 2 (2%)
Oily spotting 4 (1%) 60 (18%) 1 (1%) 1 (1%) 13 (10%) 8 (6%)
Soft stool 30 (9%) 52 (15%) 3 (2%) 9 (7%) 14 (11%) 8 (6%)
Liquid stools 34 (10%) 45 (13%) 6 (5%) 3 (2%) 17 (14%) 11 (8%)
Abdominal pain 30 (9%) 25 (7%) 8 (7%) 7 (5%) 10 (8%) 9 (7%)
Faecal urgency 11 (3%) 33 (10%) 2 (2%) 1 (1%) 10 (8%) 4 (3%)
Flatulence 9 (3%) 24 (7%) 3 (2%) 3 (2%) 5 (4%) 4 (3%)
Flatus with discharge 0 24 (7%) 0 1 (1%) 14 (11%) 1 (1%)
Faecal incontinence 0 24 (7%) 0 0 6 (5%) 3 (2%)
Oily evacuation 2 (1%) 21 (6%) 0 0 5 (4%) 6 (5%)
Central nervous system
Headache 15 (4%) 19 (6%) 4 (3%) 1 (1%) 2 (2%) 2 (2%)
Two consecutive low values
␤-carotene 0·3% 1·2% 0·8% 0% 5·8% 2·4%
Vitamin A 0·6% 0·3% 0·8% 0% 0·8% 0%
Vitamin D 0·6% 5·1% 0·8% 2·3% 5·0% 3·1%
Vitamin E 0·9% 4·6% 0% 0% 3·3% 1·6%
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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ARTICLES
Gastrointestinal Other adverse
adverse events events
Year 1
Placebo (n=343) 2 (0·6%) 7 (2·0%)
Orlistat (n=345) 12 (3·5%) 11 (3·2%)
Year 2
Placebo/placebo (n=126) 2 (1·6%) 1 (0·8%)
Placebo/orlistat (n=127) 5 (3·9%) 1 (0·8%)
Orlistat/placebo (n=138) 0 4 (2·9%)
Orlistat/orlistat (n=135) 2 (1·5%) 1 (0·7%)
*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.
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.
Contributors
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.
European Multicentre Investigators
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.
172
Other reasons* Acknowledgments
This study was supported by a research grant from F Hoffman-La Roche
(Basel, Switzerland).
74 (21·6%)
38 (11·0%) References
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