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Effect of Orlistat on Weight Regain and
Cardiovascular Risk Factors Following a
Very-Low-Energy Diet in Abdominally
Obese Patients
A 3-year randomized, placebo-controlled study
BJØRN RICHELSEN,
MD, PHD
1
SERENA TONSTAD,
MD, PHD
2
STEPHAN R¨OSSNER,
MD, PHD
3
SØREN TOUBRO,
MD
4
LEO NISKANEN,
MD, PHD
5
STEEN MADSBAD,
MD, PHD
6
PERTTI MUSTAJOKI,
MD
7
AILA RISSANEN,
MD, PHD
8
OBJECTIVE — To investigate the efficacy of orlistat on the maintenance of weight loss over
3 years following a major weight loss induced by very-low-energy diet (VLED) in obese patients
with metabolic risk factors such as dyslipidemia, impaired fasting glucose, and diet-treated type
2 diabetes.
RESEARCH DESIGN AND METHODS — Initially, weight loss was induced by an
8-week VLED (600–800 kcal/day) in 383 patients with a mean BMI of 37.5 kg/m
2
(range
30.0–45.2). Those who lost ⱖ5% of their body weight (309 of 383 patients) were then ran-
domized to receive lifestyle counseling for 3 years together with either orlistat 120 mg t.i.d. or
matching placebo capsules. Primary end points were the maintenance of ⱖ5% weight loss after
3 years. Additionally, differences in the development of type 2 diabetes between orlistat and
placebo were analyzed.
RESULTS — The VLED induced a mean weight loss of 14.4 ⫾2..0 kg among the subse-
quently randomized patients. The mean weight gain after 3 years was lower with orlistat than
with placebo (4.6 ⫾8.6 vs. 7.0 ⫾7.1 kg; P⬍0.02). The number of participants who achieved
ⱖ5% weight loss also favored orlistat (67 vs. 56%; P⫽0.037). Waist circumference was
significantly more reduced in the orlistat group (P⬍0.05), but no other differences in the risk
factors were observed between the two groups. The incidences of new cases of type 2 diabetes
were significantly reduced in the orlistat group (8 cases out of 153 subjects) versus placebo (17
cases out of 156 subjects) (P⫽0.041).
CONCLUSIONS — The addition of orlistat to lifestyle intervention was associated with
maintenance of an extra 2.4 kg weight loss after VLED for up to 3 years in obese subjects. The
combination of orlistat and lifestyle intervention was associated with a reduced occurrence of
type 2 diabetes.
Diabetes Care 30:27–32, 2007
T
he relation between obesity and sev-
eral of its comorbidities, such as
type 2 diabetes and premature ath-
erosclerosis, seems to be mediated by risk
factors characterized by the metabolic
syndrome (1,2). The metabolic syndrome
is closely associated with abdominal obe-
sity (3–6). Weight loss and increased
physical activity are the cornerstones in
the treatment of the metabolic syndrome.
Treatment success defined as clinically
meaningful weight loss that can be main-
tained for longer periods is, however, lim-
ited (7–9).
The lipase inhibitor orlistat (Xenical)
has been shown to promote additional
weight loss compared with lifestyle mod-
ifications alone (10,11). Moreover, stud-
ies (12,13) have shown improvement in
insulin sensitivity and glucose homeosta-
sis with orlistat treatment in both diabetic
and nondiabetic obese patients. Recently,
the XENDOS (XENical in the Prevention
of Diabetes in Obese Subjects) Study has
indicated that the additional weight loss
induced by orlistat reduced the develop-
ment of type 2 diabetes by 37% during the
4-year study in obese patients (14).
Very-low-energy diets (VLEDs; 400–
800 kcal/day) containing a high amount
of protein may induce major short-term
weight loss. However, the long-term
maintenance of this weight is generally
disappointing (15). Accordingly, we ex-
amined the effect of orlistat on long-term
weight regain after weight loss induced by
a VLED in obese subjects with metabolic
risk factors. Our research question was
whether treatment with orlistat in addi-
tion to lifestyle change maintains weight
loss after a VLED better compared with
lifestyle modifications alone. Thus, in this
study major weight loss was induced by
VLED and then followed by randomized,
double-blind treatment with orlistat or
placebo for 3 years. Additionally, we an-
alyzed the changes in the metabolic risk
profile and the development of type 2 di-
abetes during the study.
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
From the
1
Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus, Denmark;
the
2
Clinic for Preventive Medicine, Ullevål Hospital, Oslo, Norway; the
3
Department of Obesity, University
Clinic, Huddinge Hospital, Huddinge, Sweden; the
4
Institute of Human Nutrition, Copenhagen, Denmark;
the
5
Department of Medicine, Kuopio University Hospital, Kuopio, Finland; the
6
Department of Endocri-
nology, Hvidovre Hospital, Hvidovre, Denmark; the
7
Peijas Hospital, Helsinki University Central Hospital,
Helsinki, Finland; and the
8
Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland.
Address correspondence and reprint requests to Bjørn Richelsen, MD, Professor, Department of Endo-
crinology and Metabolism C, Aarhus University Hospital, Aarhus Sygehus, Tage Hansensgade 2, DK-8000
Aarhus C, Denmark. E-mail: bjoern.richelsen@as.aaa.dk.
Received for publication 24 February 2006 and accepted in revised form 29 September 2006.
Abbreviations: VLED, very-low-energy diet; XENDOS, XENical in the Prevention of Diabetes in Obese
Subjects.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
DOI: 10.2337/dc06-0210
© 2007 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Clinical Care/Education/Nutrition
ORIGINAL ARTICLE
DIABETES CARE,VOLUME 30, NUMBER 1, JANUARY 2007 27
RESEARCH DESIGN AND
METHODS — Eligible subjects were
men and women (in ratio 1:1) aged
18– 65 years with abdominal obesity de-
fined as a BMI between 30 and 45 kg/m
2
and a waist circumference ⱖ102 cm
(men) or ⱖ92 cm (women). Further-
more, participants were required to have
one or more of the following risk factors:
impaired fasting glucose (plasma glucose
ⱖ6.1 mmol/l), diet-treated type 2 diabe-
tes (plasma glucose ⱖ7.0 mmol/l) or dys-
lipidemia (HDL cholesterol ⱕ0.9 mmol/l
[men] or ⱕ1.1 [women]), and/or serum
triglycerides ⱖ2.0 mmol/l but ⬍10.0
mmol/l.
The patients were recruited at nine
clinical research centers in Scandinavia.
All provided written, informed consent.
The study was conducted according to
the Helsinki Declaration and was ap-
proved by the ethical committees in each
of the four countries. After screening, 383
participants were prescribed a VLED
(Modifast; Novartis, Basel, Switzerland or
Nutrilett; Nycomed Pharma, Oslo, Nor-
way) of 600– 800 kcal/day for 8 weeks.
During the 8 weeks, the patients were fol-
lowed weekly by registered dietitians. A
body weight loss of ⱖ5% during the
VLED period was a prerequisite for ran-
domization into the 3-year weight main-
tenance period. The number of par-
ticipants obtaining at least 5% weight loss
after the VLED was 309, or 80.7%, of the
total that started in the study. These sub-
jects were randomly assigned to 3 years of
treatment with either orlistat capsules
(120 mg t.i.d.) or matching placebo cap-
sules. At randomization, the population
was stratified according to sex, center,
and the degree of weight loss after VLED.
The patients were randomly assigned in
equal numbers to each group using a min-
imization algorithm. A central random-
ization was used.
After the VLED, the participants were
instructed to follow a standard energy-
restricted diet (600 kcal daily deficit)
during the following 3 years of the inter-
vention. Patients were monitored every
month for the first 18 months and then at
3-month intervals. A dietitian provided
dietary and lifestyle counseling at each
visit, and the dietitians were instructed to
give the same advice at all centers. Pa-
tients were advised to reduce fat to ⬃30%
of total energy, in particular saturated fat
by limiting dairy fats and oils and substi-
tuting poultry, fish, and lean meats for
fatty meats and increasing the intake of
fruits and vegetables and limiting sweets,
cookies, and desserts. Advice to increase
daily physical activity was also given. The
patients completed weighed dietary
records by describing and weighing all
food and beverages that were consumed
for 3 consecutive days 1 month and 1 year
after the VLED. The study medication re-
turned by the patients at clinic visits was
counted.
If glucose control deteriorated in pa-
tients with type 2 diabetes, metformin
was started according to a predetermined
plan. If the A1C level exceeded 10% after
maximal metformin treatment (2 g daily),
the subject should be withdrawn from the
study. Medication for high blood pressure
was allowed. At inclusion, lipid-lowering
drugs were not allowed but treatment
with statins for hyperlipidemia was al-
lowed, if deemed necessary according to
the judgment of the investigator. Almost
two-thirds of the randomized participants
(200 of 309) completed the 3-year study.
The body weight (with a calibrated
scale at each center and with the patients
in underwear without shoes), waist cir-
cumference (measured midway between
lower costa and crista), and blood pres-
sure were determined. Adverse events
and changes of medication were recorded
at every visit. Fasting plasma glucose; in-
sulin; C-peptide; A1C; total, HDL, and
LDL cholesterol; and triglycerides were
measured at a certified central laboratory
(Medi-Lab, Copenhagen, Denmark).
Outcome measures
The primary objective was to demonstrate
the effect of orlistat on the prevention of
body weight regain after an initial weight
loss induced by VLED. This was obtained
by determining the change in body
weight after 36 months of treatment and
counting the number of patients who
were able to obtain a weight loss of ⬎5%
after 36 months. Secondary efficacy vari-
ables included changes in waist circum-
ference and metabolic profile. We also
analyzed the development of new cases of
type 2 diabetes during the study. The de-
velopment of diabetes was based on
changes in fasting glucose from normal or
from impaired fasting glucose levels to
fasting glucose levels ⬎7.0 mmol/l at two
consecutive determinations. The defini-
tion also included subjects without a
medical history of diabetes who started
antidiabetes drug treatment during the
study.
Statistical analysis
The data were primarily analyzed in the
intention-to-treat population, consisting
of all randomized patients who received
at least one dose of study drug and had at
least one follow-up assessment using the
last-observation-carried-forward ap-
proach. The analysis of all longitudinal
data (such as weight, vital signs, efficacy,
etc.) was performed using ANCOVA,
with the screening/baseline values as the
covariate. The 95% CIs for treatment dif-
ferences were estimated using LSMeans.
Interaction effect between treatment and
specific subgroups was also defined in the
model. The analysis of primary end point,
the treatment success rate, was performed
with the Cochran-Mantel-Haenszel test,
with all the stratification variables in-
cluded one at the time. The analysis of the
new cases of diabetes was performed us-
ing the hazard ratio. The 0.05 level of sig-
nificance was used for all analyses.
RESULTS — A total of 383 obese men
and women met the eligibility criteria and
started the VLED treatment. Of these, 309
patients (152 men and 157 women) who
achieved ⱖ5% weight loss after 8 weeks
of VLED treatment were randomized in
the double-blind, placebo-controlled
phase of the investigation. Seventy-four
patients (19.3%) who were unable to lose
5% of their body weight during the VLED
were excluded. The randomized groups
were comparable in regard to age and
baseline anthropometric measurements
(Table 1). Mean body weight at screening
was similar in the two groups. The num-
ber of participants with risk factors was
not different between the two groups (Ta-
ble 1).
Weight loss
The weight loss after 8 weeks’ VLED was
14.3 ⫾2.0 kg in those who were random-
ized to orlistat and 14.5 ⫾2.1 kg in those
who were randomized to placebo (Fig. 1).
The gain in body weight after VLED to
month 36 was significantly less in the or-
listat group compared with placebo treat-
ment (4.6 ⫾8.6 vs. 7.0 ⫾7.1 kg; P⬍
0.02). From before VLED (month ⫽⫺2)
to month 36, the mean weight loss was
9.4 kg (8.3%) after orlistat treatment
compared with 7.2 kg (6.4%) after pla-
cebo (P⬍0.05). Treatment success rate
predefined as losing at least 5% of initial
body weight was 85% in the orlistat group
and 72% in the placebo group after 1 year
(P⬍0.001) and 67 vs. 56%, respectively,
after 3 years (P⬍0.05). Weight loss after
Long-term weight loss maintenance by orlistat
28 DIABETES CARE,VOLUME 30, NUMBER 1, JANUARY 2007
3 years at the level of ⱖ10% was obtained
in 34% (orlistat) and 29% (placebo) (NS).
Waist circumference was significantly re-
duced in the orlistat group by 7.7 cm
compared with 5.4 cm in the placebo
group (P⬍0.05) after 3 years (Table 2).
For completers, the weight regain 3 years
after VLED was 5.4 kg in the orlistat
group and 8.6 kg after placebo (P⬍
0.01), which was similar to the intent-to-
treat population. Baseline characteristics
for completers and noncompleters were
similar (data not shown).
Sex differences. In predetermined anal-
yses according to sex, the absolute weight
loss in women during 3 years was signif-
icantly higher in the orlistat group com-
pared with placebo (9.7 kg [8.4%] vs. 6.3
kg [5.3%] weight loss; P⬍0.02), whereas
in men the effect of orlistat compared
with placebo was less (8.9 kg [8.3%] vs.
8.1 kg [7.5%] weight loss; NS).
Diet
From the dietary records, it was found
that the fat content was reduced to a sim-
ilar degree in the orlistat group (by 19%)
and the placebo group (by 22%) (from
⬃35% of the total energy intake to ⬃28%
in both groups; NS).
Changes in risk factors
As shown in Table 2, all risk factors were
significantly (P⬍0.05) improved after
the mean weight loss of 14 kg induced by
8 weeks of VLED treatment. Hereafter, a
gradual increment was observed for all
the risk factors. With regard to glucose,
insulin, C-peptide, and A1C, a tendency
to more pronounced reduction in all these
parameters was observed after 3 years of
orlistat treatment compared with pla-
cebo, but these differences did not reach
statistical significance for any of the pa-
rameters (Table 2).
After VLED, a significant reduction in
total cholesterol was observed (20% re-
duction). Moreover, a pronounced reduc-
tion in blood pressure was observed after
VLED with a reduction of 12.5 mmHg in
systolic blood pressure and a reduction of
7.4 mmHg in diastolic blood pressure.
However, after 3 years, there were no dif-
ferences in total, LDL, or HDL cholesterol
and triglycerides between the two treat-
ment groups, but the lipids (except HDL
cholesterol) were, however, still signifi-
cantly lower after 3 years in both groups
compared with the initial levels (Table 2).
The number of patients who started
with medications with statins, metformin,
and medication for high blood pressure
during the trial was similar in the two
groups. The number of patients treated
with metformin was 13 and 18, with
statins 11 and 11, and with antihyperten-
sive medication 84 and 90 in the orlistat
group and placebo group, respectively.
None were withdrawn from the study be-
cause of high A1C (⬎10%).
Changes in the development of type
2 diabetes
New cases of diabetes were recorded, and
significantly more patients in the placebo
group developed type 2 diabetes (17 sub-
jects [10.9%]) compared with the orlistat
Figure 1. —Body weight changes during the study. Absolute body weight changes from screening
where t⫽0 is at randomization after 8 weeks of VLED. The mean weight loss after VLED in the
two groups was 14.4 kg. Means ⫾SE for the intent-to-treat population. Comparison of weight
changes from t⫽0to36;P⫽0.0125. E, Xenical; F, placebo.
Table 1—Patient characteristics at screening
Orlistat Placebo
n153 156
Women 77 (50.3) 80 (51.3)
Age (years) 47.2 (20–64) 46.7 (19–63)
Weight (kg) 110 (75–162) 112 (78–152)
BMI (kg/m²) 37.4 (30.1–45.2) 37.6 (30.0–45.0)
Waist (cm) 119 (92–168) 119 (92–144)
Impaired fastin glucose 38 (24.8) 45 (28.8)
Diabetes 38 (24.8) 31 (19.9)
Low HDL 69 (45.1) 65 (41.6)
High triglycerides 91 (59.5) 92 (50.9)
Data are n(%) or mean (range). There were no significant differences between the two groups. Low HDL
cholesterol ⱕ0.9/1.1 (mmol/l). High triglycerides ⬎2.0 mmol/l.
Richelsen and Associates
DIABETES CARE,VOLUME 30, NUMBER 1, JANUARY 2007 29
treatment (8 subjects [5.2%]) during the
3-year study (P⫽0.041).
Safety data
Premature withdrawals were similar in
the orlistat (33.3%) and the placebo
group (37.2%) during the 3-year trial.
The withdrawals due to adverse events
were 5% in both groups, while the re-
mainder of the withdrawals were due to
protocol violation (not enough time, etc.).
The only differences in adverse events be-
tween the two groups were due to the ex-
pected increase in gastrointestinal
complications in the orlistat group com-
pared with placebo. These included fatty/
oily stool (23 vs. 2.5%), oily spotting
(17.5 vs. 0%), abdominal pain (21.5 vs.
16%), and fecal urgency (8.5 vs. 5%) in
the orlistat and placebo groups, respec-
tively. In total, 88% in the orlistat group
experienced one or more gastrointestinal
events (minor, moderate, or severe) dur-
ing the study compared with 63% in the
placebo group (P⬍0.01). There were 18
subjects in the orlistat group and 28 sub-
jects in the placebo group that experi-
enced a serious adverse event (NS).
CONCLUSIONS — In the present
study, we found that the lipase inhibitor
orlistat was superior to placebo in main-
taining an initial weight loss induced by a
VLED for 3 years in subjects who were at
high risk of cardiovascular diseases due to
abdominal obesity and impaired fasting
glucose/diabetes or dyslipidemia. This ex-
tra weight loss maintenance obtained
with orlistat was associated with reduced
development of type 2 diabetes. The
VLED effectively induced a major weight
loss of ⬃14 kg after 8 weeks, and this
weight loss was associated with pro-
nounced improvements in all metabolic
risk factors.
The absolute difference in body
weight between the orlistat and placebo
groups was ⬃2.2 kg (i.e., a total of a
9.4-kg weight loss in the orlistat group
versus a 7.2-kg weight loss in the placebo
group after 3 years’ follow-up). Treatment
success, as defined as losing at least 5% of
initial body weight, was achieved by 67%
in the orlistat group compared with 56%
in the placebo group after 3 years. The
waist circumference was reduced 2–3 cm
more in the orlistat group compared with
placebo after 3 years (P⬍0.05).This de-
gree of weight loss after prolonged fol-
low-up has only rarely been observed in
the field of obesity, and we believe that
the present findings underscore the im-
portance of an initial large weight loss fol-
lowed by intensive, frequent, and
prolonged behavioral therapy.
Only very few long-term (⬎2 years)
intervention studies have been performed
with regard to the pharmacological treat-
ment of obesity. Recently, the 4-year
study of the effect of Xenical on weight
loss and development of diabetes was
published (14). This extra weight loss ob-
tained with orlistat in this trial was rather
similar to the results obtained in the
present study after 3 years. Moreover, re-
cent systematic reviews of pharmacother-
apy for weight loss including obese
patients and obese patients with type 2
diabetes—without an initial VLED—
show that the additional weight loss in-
duced by orlistat was from 2.6 to 3.2 kg
after 1 year of treatment (13,16,17).
With regard to changes in metabolic
risk factors, the orlistat group had a
nonsignificant tendency to better out-
Table 2—Changes in weight and risk factors during the study
Time ⫺2 months 0 months 18 months 36 months Pvalue
Weight (kg) P 111.9 ⫾16.0 ⫺14.3 (⫺12) ⫺9.6 (8.4) ⫺7.2 (⫺6.3) 0.028
O 110.7 ⫾17.9 ⫺14.5 (⫺13) ⫺11.7 (10.4) ⫺9.4 (⫺8.3)
Waist circumference (cm) P 119 ⫾10.9 ⫺12 ⫺9⫺5.4 0.032
O 119 ⫾12.1 ⫺12 ⫺12 ⫺7.7
A1C (%) P 6.28 ⫾0.64 ⫺0.48 ⫺0.34 ⫺0.51 NS
O 6.32 ⫾0.93 ⫺0.54 ⫺0.43 ⫺0.69
Fasting glucose (mmol/l) P 6.27 ⫾1.54 ⫺0.95 ⫺0.45 ⫺0.32 NS
O 6.44 ⫾1.83 ⫺1.1 ⫺0.67 ⫺0.49
Fasting insulin (pmol/l) P 114 ⫾58.3 ⫺45 ⫺28 ⫺12 NS
O 116 ⫾65.3 ⫺48 ⫺35 ⫺26
C-peptid (nmnol/l) P 1.02 ⫾0.39 ⫺0.19 ⫺0.03 ⫹0.16 0.09
O 1.10 ⫾0.43 ⫺0.21 ⫺0.1 ⫹0.05
Total cholesterol (mmol/l) P 6.02 ⫾1.08 ⫺1.2 ⫺0.13 ⫺0.46 NS
O 5.91 ⫾1.26 ⫺1.2 ⫺0.36 ⫺0.46
LDL cholesterol (mmol/l) P 3.77 ⫾0.94 ⫺0.80 ⫺0.12 ⫺0.38 NS
O 3.71 ⫾1.04 ⫺0.75 ⫺0.29 ⫺0.34
HDL cholesterol (mmol/l) P 1.15 ⫾0.26 ⫺0.07 ⫹0.11 ⫹0.06 NS
O 1.13 ⫾0.26 ⫺0.05 ⫹0.06 ⫹0.04
Triglycerides (mmol/l) P 2.50 ⫾1.41 ⫺0.94 ⫺0.34 ⫺0.43 NS
O 2.36 ⫾1.24 ⫺0.89 ⫺0.32 ⫺0.38
BT sys (mmHg) P 144 ⫾17.3 ⫺12 ⫺7.2 ⫺8.2 NS
O 144 ⫾19.3 ⫺13 ⫺8.2 ⫺7.8
BT dia (mmHg) P 90.7 ⫾10.4 ⫺7.6 ⫺4.8 ⫺4.7 NS
O 90.8 ⫾11.6 ⫺7.2 ⫺5.1 ⫺3.7
Data are n(%) or means ⫾SD. The abdominally obese subjects were randomised after 2 months of VLED (from month ⫺2 to month 0) to receive either orlistat (O)
or placebo (P). Values at the various times are absolute changes from initial values (month ⫺2) calculated from the intention-to-treat population. Minus indicates
reduction from initial values and plus increment. Body weight changes are also given in percentage (in parentheses). Pvalues are given for the absolute changes after
36 months between orlistat and placebo. The time effect at 36 months versus 0 month is significant for all parameters (P⬍0.001).
Long-term weight loss maintenance by orlistat
30 DIABETES CARE,VOLUME 30, NUMBER 1, JANUARY 2007
comes in relation to glucose-insulin ho-
meostasis than placebo during 3 years,
but very similar effects between the two
groups were observed concerning
changes in lipids and blood pressure
(Table 2). Total and LDL cholesterol
plus triglycerides were significantly re-
duced after the VLED-induced major
weight loss, but in contrast to several
other studies of orlistat (18) there were
no additional effects of orlistat on these
lipids in the present study. Thus, the
effects of orlistat on risk factors seemed
to be less pronounced than shown in
several other studies (10,18–20). Be-
cause we allowed supplementary treat-
ment with antidiabetes medications,
statins, and antihypertensive medica-
tions, it could be suggested that this co-
medication may have influenced the
result. This possibility cannot com-
pletely be excluded, but the number of
subjects who were on medication for
these risk factors was similar between
the two groups during the study. An-
other explanation could be that the im-
provement in all risk factors induced
after the VLED treatment was so pro-
nounced that the possible specific ben-
eficial effect of orlistat observed in many
other studies might be somehow ob-
scured by these initial large weight loss.
Finally, compared with several other
placebo-controlled studies (21–23), the
lifestyle intervention alone plus placebo
was markedly effective in the present
study.
Although the specific effects of or-
listat on risk factors were modest or lack-
ing on some risk factors, orlistat treatment
for 3 years was associated with a signifi-
cant reduction of the development of type
2 diabetes. It was not possible to clarify
from the present study whether this is a
specific effect of orlistat or whether it is
due to the extra 2.2- to 2.4-kg weight loss
maintenance induced by orlistat. How-
ever, these findings are in accordance
with the 4-year XENDOS Study, in which
the development of type 2 diabetes was
reduced by 37% in the orlistat group
compared with the placebo group (14).
That orlistat may reduce the development
of diabetes and can improve glucose-
insulin homeostasis has also been shown
by others (13). Other lifestyle interven-
tions with focus on weight loss also have
shown reduced development of type 2 di-
abetes in association with moderate
weight loss (24,25).
Our study is one of the few studies of
obesity to achieve an approximately equal
sex distribution. In the subgroup analysis,
the differences in weight loss between or-
listat and placebo were more pronounced
in women compared with men. The rea-
son for this sex-specific effect might be
influenced by the fact that women on pla-
cebo were not able to maintain their body
weight loss as well as men (only 5.3%
weight loss in women versus 7.5% in
men). These sex differences should, how-
ever, be investigated in more detail in fu-
ture studies.
The absolute amount of weight loss
obtained in the present study is quite pro-
nounced compared with several other
pharmacotherapy and lifestyle interven-
tions with maintained weight loss of 9.6
kg after 1.5 years and of 7.3 kg after 3
years in the lifestyle alone plus placebo
group and losses of 11.7 kg after 1.5 years
and of 9.3 kg after 3 years in the lifestyle
plus orlistat group. There may be more
reasons for these findings, but the most
important may be that in our study design
we selected only those participants for
randomization who were able to lose at
least 5% of their weight during the
8-week VLED, which was ⬃80% of all
who started VLED. Thereby, we have se-
lected the most compliant obese patients
for the study, which will result in better
weight loss results than if all participants
were included. This kind of program
might, however, be well suitable for most
treatment settings. As a lipase inhibitor,
orlistat may theoretically compromise the
uptake of fat soluble vitamins. In the
XENDOS Study, a significant decrease in
the level of fat soluble vitamins was found
in the orlistat group after 4 years but the
mean level remained within its reference
range for all the vitamins during the 4
years (14). These findings, however, indi-
cate that it is rational to give a vitamin
supplement together with orlistat.
In conclusion, we found that 3 years
of treatment with the lipase inhibitor or-
listat modestly reduces weight regain after
a major initial VLED-induced weight loss
in abdominally obese subjects. Notably, a
significant reduction in the development
of type 2 diabetes was observed during 3
years of orlistat treatment compared with
placebo. Thus, orlistat may be a useful
adjunct to conventional dietary and life-
style treatment of high-risk obese sub-
jects. Lastly, this study indicates that an
initial VLED treatment is very efficacious
when incorporated into a more general
strategy in the treatment of obesity. This
approach seems to result in large and
rapid weight losses leading to pro-
nounced improvements in the metabolic
risk factors.
Acknowledgments— This clinical trial was
investigator initiated and sponsored by Roche
Scandinavia.
Dr. David Laaksonen and his team at the
Department of Medicine, Kuopio University
Hospital, Kuopio, Finland, are thanked for
their valuable contribution. We are very in-
debted to the staff at each of the nine involved
clinical centers and to Fredrik Hansson, MSc,
for statistical support.
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