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Efficacy and safety comparative evaluation of orlistat and
sibutramine treatment in hypertensive obese patients
G. Derosa,1 A. F. G. Cicero,2 G. Murdolo,3 M. N. Piccinni,1 E. Fogari,1 G. Bertone,1
L. Ciccarelli1 and R. Fogari1
1Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy2‘G. Descovich’ Atherosclerosis Study Center, ‘D. Campanacci’ Department of Clinical Medicine and Applied Biotechnology,
University of Bologna, Bologna, Italy3Department of Internal Medicine, Section of Nutrition and Metabolism, University of Perugia, Perugia, Italy
Aim: The aim of our study was to comparatively evaluate the efficacy and safety of orlistat and sibutramine treatment
in obese hypertensive patients, with a specific attention to cardiovascular effects and to side effects because of this
treatment.
Methods: Patients were enrolled, evaluated and followed at three Italian Centres of Internal Medicine. We evaluated
115 obese and hypertensive patients. (55 males and 60 females; 26 males and 29 females, aged 50� 4 with orlistat; 28
males and 30 females, aged 51� 5 with sibutramine). All patients took antihypertensive therapy for at least 6months
before the study. We administered orlistat or sibutramine in a randomized, controlled, double-blind clinical study. We
evaluated anthropometric variables, blood pressure and heart rate (HR) during 12months of this treatment.
Results: A total of 113 completed the 4weeks with controlled energy diet and were randomized to double-blind
treatment with orlistat (n¼ 55) or sibutramine (n¼ 58). Significant body mass index (BMI) improvement was present
after 6 (p< 0.05), 9 (p< 0.02), and 12 (p< 0.01) months in both groups, and body weight (BW) improvement was
obtained after 9 (p< 0.05) and 12 (p< 0.02) months in both groups. Significant waist circumference (WC), hip
circumference (HC) and waist/hip ratio (W/H ratio) improvement was observed after 12months (p< 0.05, respect-
ively) in both groups. Significant systolic blood pressure (SBP) and diastolic blood pressure (DBP) improvement
(p< 0.05) was present in orlistat group after 12months. Lipid profile [total cholesterol (TC), low-density lipoprotein-
cholesterol (LDL-C) and triglycerides] reduction (p< 0.05, respectively) was observed in orlistat group and triglyceride
reduction (p< 0.05) in sibutramine group after 12months. No significant change was observed in sibutramine group
during the study. No significant HR variation was obtained during the study in both groups. Of the 109 patients who
completed the study, 48.1% of patients in the orlistat group and 17.5% of patients in the sibutramine group had side
effects (p< 0.05 vs. orlistat group). Side-effect profiles were different in the two treatment groups. All orlistat side
effects were gastrointestinal events. Sibutramine caused an increase in blood pressure (both SBP and DBP) in two
patients, but it has been controlled by antihypertensive treatment. The vitamin changes were small and all mean
vitamin and b-carotene values stayed within reference ranges. No patients required vitamin supplementation.
Conclusions: Both orlistat and sibutramine are effective on anthropometric variables during the 12-month treatment;
in our sample, orlistat has been associated to a mild reduction in blood pressure, while sibutramine assumption has
not be associated to any cardiovascular effect and was generically better tolerated than orlistat.
Keywords: hypertension, obesity, orlistat, safety, sibutramine
Received 14 January 2004; returned for revision 9 March 2004; revised version accepted 9 March 2004
Correspondence:
Giuseppe Derosa, MD, PhD, Department of Internal Medicine and Therapeutics, University of Pavia, P.le C. Golgi, 2-27100 Pavia,
Italy.
E-mail:
giuderosa@tin.it
OR I G I N A L A R T I C L E doi: 10.1111/j.1463–1326.2004.00372.x
# 2004 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 7, 2005, 47–55 47
Introduction
The prevalence of obesity is increasing rapidly in all age
groups in the United States and inmost EU-countries and is
one of the fastest growing epidemics, now affecting 10–40%
of the adult population. Obesity increases the risk of serious
comorbidity such as type 2 diabetes, cardiovascular disease,
certain cancers and reduced life expectancy, and these com-
plications may account for 5–10% of all health costs in
Western countries [1]. Of course, dietary modifications and
physical activity increase are the first (and the most cost-
effective) approach to the treatment of obesity [2]; however,
in many cases, a pharmacological treatment would help
patients to loose weight and to reinforce their motivation
in dietary protocol prosecution [3]. The US Food and Drug
Administration approves for long-term use of only two anti-
obesity drugs: orlistat, a lipase inhibitor that inhibits absorp-
tion of dietary fat by approximately 30%, and sibutramine, a
centrally acting agent which enhances satiety and thermo-
genesis by inhibiting serotonin and noradrenaline
re-uptake [4]. Both drugs are able to induce a significant
weight loss compared to life-changes alone, to maintain
the weight loss after 2 years of treatment and to improve
metabolic pattern of both diabetic and hyperlipoprotein-
aemic patients [5]. Orlistat has mainly mild to moderate
gastrointestinal side effects that usually attenuate with
the prosecution of the treatment but often not acceptable
from the patients [6] and some pharmacokinetic inter-
actions that are rare but potentially relevant, with cyclo-
sporin [7] and warfarin [8]. Sibutramine is also well
tolerated, although it may cause dry mouth, anorexia
and insomnia, while recently some concerns have been
raised about its safety in patients at risk of cardiovascular
disease [9]. However, actually, results from clinical trials
give contrasting results about the sibutramine effect on
heart rate and blood pressure. Although there are studies
in which orlistat and sibutramine demonstrated their
effectiveness on body weight reduction and on some
metabolic parameters, no studies compared orlistat and
sibutramine in the same trial.
The aim of our study was to comparatively evaluate
the efficacy and safety of orlistat and sibutramine treat-
ment in obese hypertensive patients, with a specific
attention to cardiovascular effects and to side effects
because of these treatment.
Materials and Methods
Patients
Obese patients of either sex (age more than 18 years)
were eligible for inclusion in the study, if they had a
body mass index (BMI)> 30 kg/m2 and were on an anti-
hypertensive drug therapy for at least 6months before
the study, according to World Health Organization cri-
teria [10]. Suitable subjects, identified from review of
case notes and/or computerized clinic registers were
contacted personally or by telephone. Exclusion criteria
comprised the following: current or previous evidence
of ischaemic heart disease, heart failure or stroke;
seated pulse rate �100 bpm; systolic blood pressure
�150mmHg and diastolic blood pressure �100mmHg;
weight change >3kg during the preceding 3months;
malignancy and significant neurological or psychiatric
disturbances, including alcohol or drug abuse. Other
exclusion criteria included any clinical condition that
might affect study end points, including renal, hepatic,
endocrine (included diabetes mellitus) or gastrointes-
tinal disorders. Excluded medications (within the
previous 3months) were anorectic agents, laxatives,
b-agonists (other than inhalers), cyproheptadine,
antidepressants, anti-serotoninergics, phenothiazines,
barbiturates, oral corticosteroids and antipsychotics.
Women who were pregnant, lactating or of child-bearing
potential, while not taking adequate contraceptive pre-
cautions, were also excluded.
Participants comprised 54 men (47.8%) and 59
women (52.2%) aged 46–56years. There were no signifi-
cant differences between centres in sex distribution and
in age. At entry, 53 subjects (46.9%) were taking two
antihypertensive drugs [17 subjects, angiotensin-
convertingenzyme(ACE)inhibitorsþ calciumantagonists
(37.2%); 15 subjects, ACE inhibitorsþdiuretics (29.4%);
10 subjects, ACE inhibitorsþ a antagonists (19.6%)
and nine subjects, angiotensin receptor blockers
(ARBs)þdiuretics (16.9%)] and 60 subjects (53.1%)
were taking one antihypertensive drug [22 subjects,
ACE-inhibitors (37.9%); 15 subjects, calcium-antagonists
(25.9%); 10 subjects, ARBs (17.2%); eight subjects, diure-
tics (13.3%) and five subjects, a-antagonists (8.3%)].
Antihypertensive therapy did not change during all
the phases of the study.
Study Design
This multicentre, double-blind, randomized, controlled
trial was conducted in the Department of Internal Medi-
cine and Therapeutics at University of Pavia, in the
‘G. Descovich’ Atherosclerosis Study Center, at Univer-
sity of Bologna, and in the Section of Nutrition and
Metabolism, at University of Perugia. Subjects began a
4-week controlled energy diet (near 600 kCal daily defi-
cit) containing 28% of calories as fat (6% saturated),
52% as carbohydrates, 20% proteins, with a maximum
48 Diabetes, Obesity and Metabolism, 7, 2005, 47–55 # 2004 Blackwell Publishing Ltd
OA Evaluation of orlistat and sibutramine treatment G. Derosa et al.
cholesterol content of 300mg/day, and 35 g of fibre. Each
centre’s standard diet advice was given by a dietitian
and/or specialist doctor. Eligible patients returned
within 4weeks for random allocation to orlistat or
sibutramine (figure 1). Dietitians and/or specialist
doctors periodically provided instruction on dietary
intake recording procedures as part of a behaviour
modification program and then later used the subject’s
food diaries for counselling. During the study, there
were one behaviour modification session on weight-
loss strategies (at baseline), one at 6months and four
seminars with all patients at 3, 6, 9 and 12months. For
each individual, there was a one-on-one behaviour
modification session with a dietitian or specialist doctor,
at baseline and 6months. At 3, 6, 9 and 12months, each
individual attended a group behaviour modification ses-
sion. Individuals were also encouraged to increase their
physical activity by walking briskly for 20–30min, 3–5
times per week, or by cycle. The recommended changes
in physical activity throughout the study were not
assessed. All vitamin and mineral preparations were
discontinued 4weeks prior to randomization.
Subjects were randomized for 1 year of study to
receive orlistat, 360mg/day, or sibutramine, 10mg/day.
They took three capsules daily (one immediately after
breakfast, one immediately after lunch and one immedi-
ately after dinner). Each capsule contained 120mg
orlistat (three times a day) or 10mg sibutramine (three
times a day, one capsule of 10mg and two capsules of
placebo). Randomization was done using a drawing of
envelopes containing randomization codes prepared by
a statistician. A copy of the code was provided only to
the responsible person performing the statistical analy-
sis. The code was only broken after database lock but
115 subjects enrolled into the study
2 withdrawn(protocol violation)
113 randomized subjectsplus controlled energy diet
Orlistat (55 subjects) Sibutramine (58 subjects)
3 months
2withdrawn(1 protocol violation, 1 administrative) 0 withdrawn
6 months1 withdrawn(loss to follow-up)
0 withdrawn
9 months0 withdrawn1 withdrawn
(refused treatment)
12 months
Orlistat subjects52completed study
(25 subjects with side effects)
Sibutramine subjects57 completed study
(10 subjects with side effects)
109 randomized subjects completed study
4 weeks with controlled energy diet
Fig. 1 Flow and disposition of patients
entered into the study. Subjects
received orlistat, 360mg/day, or
sibutramine, 10mg/day.
# 2004 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 7, 2005, 47–55 49
G. Derosa et al. Evaluation of orlistat and sibutramine treatment OA
could have been broken for individual subjects in cases
of an emergency. Medication compliance was assessed
by counting the number of pills returned at the time of
specified clinic visits. Orlistat and sibutramine were
supplied as matching opaque white capsules in coded
bottles to ensure the double-blind status of the study.
We gave three bottles to each patient: one bottle with
treatment A, one bottle with treatment B and one bottle
with treatment C. If patients were randomized to orlistat,
they took one capsule by treatment A (after breakfast),
one capsule by treatment B (after lunch) and one capsule
by treatment C (after dinner). If patients were random-
ized to sibutramine, two treatments of three contained
placebo. Sibutramine was present in one of these treat-
ments (and patients could take it after breakfast or after
lunch or after dinner). Bottles were prepared by the
hospital pharmacy; investigators collected the bottles
from the pharmacy and dispensed them to patients.
At baseline, we weighed participants and gave them a
bottle containing a supply of study medication for at
least 100days. At baseline, participants were weighed
and a bottle containing medication for at least 100days
was given. Throughout the study, we instructed patients
to take their first dose of newmedication on the day after
they were given the study medication. A bottle contain-
ing the new study medication for the next treatment
period was given to participants on the first day of the
new quarter. At the same time, all unused medication
was retrieved for inventory. All medications were pro-
vided free of charge.
The study protocol was approved at each site by institu-
tional review boards and was conducted in accordance
with the Declaration of Helsinki. All patients provided
written informed consent.
Assessments
Before starting the study, all patients underwent an
initial screening assessment that included a medical
history, physical examination, vital signs, a 12-lead elec-
trocardiogram, measurements of height, body weight
(BW), BMI, waist and hip circumference, lipid profile,
blood pressure and heart rate. BMI was calculated as
weight in kilograms divided by the square of height in
meters; waist circumference was measured midway
between the lateral lower rib margin and the iliac crest.
Total cholesterol and triglyceride levels were deter-
mined using fully enzymatic techniques [11,12] on a
clinical chemistry analyzer (HITACHI 737; Hitachi,
Tokyo, Japan); intra-assay and interassay CsV were 1.0
and 2.1 for TC measurement, and 0.9 and 2.4 for
triglyceride measurement, respectively. High-density
lipoprotein-cholesterol (HDL-C) level was measured
after precipitation of plasma apo B-containing lipopro-
teins with phosphotungstic acid [13]; intra-assay and
interassay CsV were 1.0 and 1.9, respectively; LDL-C
level was calculated by the Friedewald formula [14].
Blood pressure measurements were obtained from
each patient (right arm) in the seated position, by using
a standard mercury (Erkameter 3000, ERKA, Bad Tolz,
Germany) sphygmomanometer (Korotkoff I and V) with a
cuff of appropriate size. Measurements were always
taken by the same investigator in the morning before
daily drug intake (i.e. approximately 24h after dosing)
and after the subject had rested 10min in a quiet room.
Three successive blood pressure readings were obtained
at 1 minute intervals and averaged.
BW, BMI, WC, HC, W/H ratio, TC, LDL-C, HDL-C,
triglyceride, SBP, DBP and HR were evaluated at base-
line and after 3, 6, 9 and 12months. Fat-soluble vitamins
A (retinol), D (measured as 25-oh vitamin D) and E
(a-tocopherol), prothrombin time (PT) (used as an
index of vitamin K status) and b-carotene were moni-
tored regularly and analysed at a central laboratory (in
the Department of Internal Medicine and Therapeutics
at University of Pavia). Investigators were promptly noti-
fied, if plasma levels of vitamins A, D or E, PT or
b-carotene were below the reference range but were
blinded to the actual values. Additional diet counselling
and a standardized commercially available vitamin sup-
plement were provided when necessary, if two consecu-
tive vitamin measurements were below the reference
range. In order to evaluate the tolerability assessments,
all adverse events were recorded.
Statistical Analysis
An intent-to-treat analysis was conducted in patients
who had received at least one dose of study medication
and had a subsequent efficacy observation. Patients were
included in the safety analysis, if they had received one
dose of trial medication after randomization and had a
subsequent safety observation. The null hypothesis that
the expected mean weight change from baseline to the
end of 12months of double-blind treatment did not dif-
fer significantly between orlistat and sibutramine treat-
ments was tested using a three-way ANOVA and analysis
of covariance (ANCOVA) models [15]. Similar analyses
were applied to the other parameters. The statistical
significance of the independent effects of treatments
and weight loss on the other parameters was determined
by ANCOVA, using weight loss as the covariate. Statistical
analysis of data was performed by means of the SPSS
statistical software package for Window (version 11.0;
50 Diabetes, Obesity and Metabolism, 7, 2005, 47–55 # 2004 Blackwell Publishing Ltd
OA Evaluation of orlistat and sibutramine treatment G. Derosa et al.
Chicago); data are presented as mean�SD. For all statis-
tical analysis, p< 0.05 was considered statistically
significant.
Results
Study Sample
A total of 115 patients were enrolled in the trial. Of
these, 113 completed the 4week with controlled energy
diet and were randomized to double-blind treatment
with orlistat (n¼ 55) or sibutramine (n¼ 58) (figure 1).
There were 109 patients who completed the study
(47.7% in the orlistat group and 52.3% in the sibutra-
mine group). The reasons for premature withdrawal dur-
ing the double-blind treatment period included protocol
violation, administrative, loss to follow-up and non-
compliance. The characteristics of the patient popula-
tion at study entry, summarized in table 1, were similar
in the two treatment groups (table 1).
Anthropometric Variables
No BMI change was observed after 3months in both
groups. Significant BMI improvement was present after
6 (p< 0.05), 9 (p< 0.02) and 12 (p< 0.01) months in both
groups. Significant BW improvement was obtained only
at 9 (p< 0.05) and 12 (p< 0.02) months in both groups
(figure 2). No significant WC, HC and W/C ratio change
was present at 3, 6 and 9months in both groups, while
significant improvement was observed after 12months
(p< 0.05, respectively) in both groups (tables 2 and 3).
Results are reported in details in tables 2 and 3.
Blood Pressure and Heart Rate
No SBP and DBP change was obtained in orlistat group
after 3, 6 and 9months, and in particular, no significant
change was observed in sibutramine group at the same
time of observation. Significant SBP and DBP improve-
ment (p< 0.05, respectively) was present in orlistat
group after 12months and compared to sibutramine
group (p< 0.05) in SBP only (figure 3).
After 12months, we did not observe any SBP and DBP
significant variation in the sibutramine group. No sig-
nificant HR variation was obtained during the study in
both groups (tables 2 and 3). Results are reported in
details n tables 2 and 3.
Safety
Of the 109 patients who completed the study, 48.1%
(25/52) of patients in the orlistat group and 17.5%
(10/57) of patients in the sibutramine group had side
effects (p< 0.05 vs. sibutramine group). Side-effect
profiles were different in the two treatment groups. All
orlistat side effects were gastrointestinal events (table 4).
Gastrointestinal events occurred early during treatment
were mild to moderate in intensity, were generally
transient and resolved spontaneously. No patients with-
drew because of gastrointestinal events.
Sibutramine caused an increase in blood pressure
(both SBP and DBP) in two patients, but it has been
controlled by antihypertensive treatment. Other side
effects (table 4) were mild, transient and occurred during
Table 1 Demographic, anthropometric and clinical data of
subjects at recruitment (week 4)
Orlistat Sibutramine
n 57 58
Sex (M/F) 28/29 28/30
Age (years) 50� 4 51� 5
Height (m) 170�6 171� 4
Weight (kg) 95.6� 5.9 97.9� 6.0
BMI (kg/m2) 33.1� 1.9 33.5� 1.8
WC (cm) 104�7 103� 5
HC (cm) 116�7 117� 7
W/H ratio 0.90� 0.2 0.88� 0.1
SBP (mmHg) 145�3 146� 3
DBP (mmHg) 96� 4 96� 5
HR (bpm) 73� 8 72� 6
TC (mg/dl) 194�20 198� 22
LDL-C (mg/dl) 124�14 127� 15
HDL-C (mg/dl) 47� 6 46� 5
Triglyceride (mg/dl) 152�39 159� 41
BMI, body mass index; DBP, diastolic blood pressure; HC, hip
circumference; HDL-C, high-density lipoprotein-cholesterol; HR,
heart rate; LDL-C, low-density lipoprotein-cholesterol; SBP, systolic
blood pressure; TC, total cholesterol; WC, waist circumference. Data
are mean�SD; all group differences are non-significant.
Bod
y w
eigh
t (K
g)
Orlistat
Sibutramine–12
–10
–8
–6
–4
–2
0
∗∗ ∗∗
Fig. 2 Body weight change from baseline to the end of the study.
Values are mean�SD. **p< 0.02, change from baseline.
# 2004 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 7, 2005, 47–55 51
G. Derosa et al. Evaluation of orlistat and sibutramine treatment OA
Table 2 Anthropometric and clinical subject characteristics at 3, 6, 9 and 12 months
Orlistat Sibutramine
Baseline 3 months 6 months 9 months 12 months Baseline 3 months 6 months 9 months 12 months
BW (kg) 94.5�5.7 89.9�5.1 89.0�4.6 87.9�4.0* 86.1� 3.4y 96.6� 5.9 92.1�5.3 91.2� 4.8 90.1� 4.2* 88.3�3.5yBMI (kg/m2) 32.7�1.8 31.1�1.5 30.8�1.4* 30.4�1.3y 29.8� 1.3z 33.0� 1.7 31.5�1.6 31.2� 1.5* 30.8� 1.5y 30.2�1.4zWC (cm) 103� 6 102�6 101� 5 100� 4 98� 3* 102�5 101� 5 100�4 98� 4 97�3*
HC (cm) 115� 7 114�6 113� 5 112� 5 111�4* 116�8 115� 7 114�6 113� 5 112� 5*
W/H ratio 0.90�0.1 0.89�0.2 0.89�0.1 0.89�0.05 0.88� 0.05y 0.88� 0.2 0.87�0.2 0.87� 0.1 0.86� 0.1 0.86�0.05*
SBP (mmHg) 144� 3 142�4 142� 3 141� 4 140�3*§ 145�4 144� 3 145�4 144� 4 145� 3
DBP (mmHg) 96�3 95�4 94�4 94�3 93� 3* 95� 4 95�3 94� 3 95� 3 95�4
HR (bpm) 72�6 72�8 71�7 71�6 72� 7 70� 5 72�6 72� 7 72� 7 71�6
TC (mg/dl) 192� 19 186�17 183� 17 179� 16 176�15* 195�21 193� 20 190�19 189� 18 186� 18
LDL-C (mg/dl) 121� 14 118�13 116� 13 114� 12 113�11* 125�14 123� 15 122�15 121� 14 119� 13
HDL-C (mg/dl) 47�5 46�5 45�6 44�6 45� 5 47� 6 45�5 46� 6 45� 7 46�6
Triglyceride (mg/dl) 143� 37 138�35 135� 34 119� 27 106�25* 141�38 136� 37 127�35 122� 34 115� 31*
BMI, body mass index; BW, body weight; DBP, diastolic blood pressure; HC, hip circumference; HDL-C, high-density lipoprotein-cholesterol;
HR, heart rate; LDL-C, low-density lipoprotein-cholesterol; SBP, systolic blood pressure; TC, total cholesterol; WC, waist circumference. Data
are means�SD.
*p< 0.05 vs. baseline.
yp<0.02 vs. baseline.
zp<0.01 vs. baseline.
§p< 0.05 vs. sibutramine group.
Table 3 Overall effects on anthropometric and clinical characteristics in groups treated with orlistat or sibutramine
Change % of change 95% CI of change
Orlistat Sibutramine Orlistat Sibutramine Orlistat Sibutramine
BW
3�m �4.6� 1.8 �4.5�1.5 �4.9�1.9 �4.7� 1.6 �5.9 to 4.9 �5.8 to 5.2
6�m �5.5� 2.1 �5.4�1.9 �5.8�2.4 �5.6� 2.0 �7.1 to 5.8 �6.4 to 6.3
9�m �6.6� 2.8* �6.5�2.2* �7.0�3.1* �6.7� 2.3* �9.1 to �3.4 �8.2 to �3.5
12�m �8.4� 3.6y �8.3�3.2y �8.9�3.3y �2.6� 3.1y �11.8 to �5.2 �10.2 to �5.4
BMI
3�m �1.6� 0.6 �1.5�0.2 �4.9�1.6 �4.5� 1.3 �3.1 to 0.4 �2.9 to 0.6
6�m �1.9� 0.8* �1.8�0.4* �5.8�1.7* �5.5� 1.5* �3.6 to �1.2 �3.4 to �1.0
9�m �2.3� 1.0y �2.2�0.4y �7.0�1.1y �6.7� 1.6y �4.6 to �1.8 �4.5 to �1.5
12�m �2.9� 1.0z �2.8�0.6z �8.9�1.4z �8.5� 1.9z �5.1 to �2.0 �4.9 to �1.9
WC
3�m �1.0� 0.4 �1.0�0.3 �1.0�0.4 �1.0� 0.5 �3.6 to 4.1 �3.8 to 5.0
6�m �2.0� 0.9 �2.0�0.8 �1.9�0.7 �2.0� 0.8 �5.2 to 5.4 �4.3 to 5.1
9�m �3.0� 1.2 �4.0�1.1 �2.9�1.2 �3.9� 1.8 �6.1 to 5.8 �7.0 to 6.1
12�m �5.0� 1.9* �5.0�2.0* �4.9�1.6* �4.9� 1.7* �9.0 to �2.1 �9.4 to �3.3
HC
3�m �1.0� 0.5 �1.0�0.6 �0.9�0.2 �0.9� 0.3 �3.1 to 3.5 �3.2 to 3.7
6�m �2.0� 0.8 �2.0�0.8 �1.7�0.6 �1.7� 0.7 �4.3 to 4.7 �4.6 to 3.8
9�m �3.0� 1.4 �3.0�1.3 �2.6�1.1 �2.6� 1.0 �6.1 to 5.4 �6.4 to 6.3
12�m �4.0� 1.6* �4.0�1.7* �3.5�1.3* �3.4� 1.1* �8.4 to �1.2 �8.3 to �2.0
W/C ratio
3�m �0.01� 0.003 �0.01�0.003 �1.11�0.03 �1.13� 0.05 �0.05 to 0.33 �0.04 to 0.26
6�m �0.01� 0.003 �0.01�0.004 �1.11�0.03 �1.13� 0.06 �0.05 to 0.35 �0.04 to 0.28
9�m �0.01� 0.004 �0.02�0.005 �1.11�0.04 �2.27� 0.16 �0.04 to 0.38 �0.05 to 0.32
12�m �0.02� 0.006* �0.02�0.006* �2.22�0.13* �2.27� 0.17* �0.04 to �0.01 �0.04 to �0.01
SBP
3�m �2.0� 1.0 �1.0�0.5 �1.4�0.5 �0.7� 0.1 �4.3 to 3.2 �4.0 to 2.0
6�m �2.0� 1.0 0 �1.4�0.5 0 �4.2 to 4.3 0
9�m �3.0� 2.0 �1.0�0.5 �2.1�0.9 �0.7� 0.1 �5.1 to 6.7 �4.3 to 2.2
52 Diabetes, Obesity and Metabolism, 7, 2005, 47–55 # 2004 Blackwell Publishing Ltd
OA Evaluation of orlistat and sibutramine treatment G. Derosa et al.
the early phase of treatment and more than 75% of
patients reported only a single episode.
Orlistat’s mechanism of action may affect levels of fat-
soluble vitamins. Although vitamin D and E levels
decreased more in the orlistat group compared with
sibutramine, the changes were small and all mean
vitamin and b-carotene values stayed within reference
ranges. No patients required vitamin supplementation.
Discussion
Approximately, 300 000 deaths a year are currently asso-
ciated with overweight and obesity, second only to
cigarette smoking as a leading cause of preventable
death in the United States [16]. The first complication
of obesity are cardiovascular diseases, especially when
obesity is associated to other risk factors such as hyper-
tension, diabetes and hyperlipoproteinemias, as for
instance, in the X-Metabolic Syndrome Syndrome X
[17].
Several studies have shown that pharmacologically
induced weight reduction with orlistat or sibutramine
can likewise be beneficial in the management of obese
hypertensive patients [18].
Our patients obtained a body weight reduction of
8.9% in orlistat group and 8.6% in sibutramine group
at the end of the study according to Davidson’s and Bay’s
studies [19,20]. In particular, we had no patients who
gained body weight and all patients responded to treat-
ment compared to Bay’s study.
12�m �4.0�2.0*§ 0 �2.8� 1.1*§ 0 �8.1 to �2.4 0
DBP
3�m �1.0�0.4 0 �1.0�0.3 0 �3.1 to 2.0 0
6�m �2.0�1.0 �1.0�0.5 �2.1�0.8 �1.1� 0.4 �5.6 to 3.4 �3.4 to 2.8
9�m �2.0�1.0 0 �2.1�0.9 0 �5.5 to 3.6 0
12�m �3.0�1.5* 0 �3.1�1.5* 0 �7.0 to �1.2 0
HR
3�m 0 2.0�1.0 0 2.9� 1.6 0 4.3 to �3.4
6�m �1.0�0.5 2.0�1.0 �1.4�0.7 2.9� 1.5 �2.8 to 2.6 4.1 to �2.6
9�m �1.0�0.4 2.0�1.0 �1.4�0.7 2.9� 1.6 �3.1 to 2.8 4.5 to �3.8
12�m 0 1.0�0.6 0 1.4� 0.8 0 3.2 to �1.1
TC
3�m �6.0�4.0 �2.0�0.5 �3.1�1.4 �1.0�0.5 �8.5–4.3 �4.1 to 2.9
6�m �9.0�5.0 �5.0�2.0 �4.7�1.8 �2.6�1.2 �14.3–5.8 �7.2 to 4.3
9�m �13.0� 7.0 �6.0�3.0 �6.8�2.9 �3.1�1.5 �20.1–7.4 �9.1 to 6.4
12�m �16.0� 9.0* �9.0�4.0 �7.4�3.1* �4.6�1.9 �24.4 to-11.8 �14.2 to 9.3
LDL-C
3�m �3.0�1.0 �2.0�0.5 �2.5�1.3 �1.6�0.5 �6.4 to 2.3 �3.9 to 1.9
6�m �5.0�2.0 �3.0�1.0 �4.1�2.5 �2.4�1.5 �7.1 to 3.4 �5.8 to 3.4
9�m �7.0�3.0 �4.0�2.0 �5.8�2.9 �3.2�1.9 �10.2 to 5.6 �7.1 to 4.3
12�m �8.0�4.0* �6.0�3.0 �6.6�3.2* �4.8�2.4 �13.1 to �3.4 �9.4 to 5.2
HDL-C
3�m �1.0�0.3 �2.0�1.0 �2.1�1.1 �4.3�1.7 �3.4 to 1.5 �5.4 to 2.6
6�m �2.0�1.0 �1.0�0.3 �4.3�1.8 �2.1�0.5 �5.1 to 2.8 �3.3 to 1.3
9�m �3.0�1.0 �2.0�1.0 �6.4�2.8 �4.3�1.6 �7.3 to 3.4 �5.2 to 2.7
12�m �2.0�1.0 �1.0�0.4 �4.3�1.9 �2.1�0.6 �5.1 to 2.8 �3.4 to 1.4
Triglyceride
3�m �5.0�3.0 �5.0�2.5 �3.5� 1.6 �3.5�1.5 �7.3 to 3.4 �7.5 to 3.8
6�m �8.0�4.5 �14.0�6.0 �5.6� 2.4 �9.9�3.4 �10.2 to 5.7 �18.3 to 4.1
9�m �24.0� 10.5 �19.0�8.0 �16.8�8.3 �13.5� 5.2 �23.3 to 15.4 �24.9 to 6.4
12�m �37.0� 18.0* �26.0�11.0* �25.9�11.4* �18.4� 6.9* �44.1 to �30.4 �33.8 to �20.5
BMI, body mass index; BW, body weight; DBP, diastolic blood pressure; HC, hip circumference; HDL-C, high-density lipoprotein-cholesterol;
HR, heart rate; LDL-C, low-density lipoprotein-cholesterol; SBP, systolic blood pressure; TC, total cholesterol; WC, waist circumference. Data
are means�SD.
*p< 0.05 vs. baseline.
yp< 0.02 vs. baseline.
zp< 0.01 vs. baseline.
§p< 0.05 vs. sibutramine group.
# 2004 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 7, 2005, 47–55 53
G. Derosa et al. Evaluation of orlistat and sibutramine treatment OA
A previous comparative study carried out on female
patients, after 6months of treatment, both sibutramine
and orlistat induced a significant reduction in BMI
(13.57 and 9.06%, respectively), waist circumference
(10.43 and 6.64%, respectively), fasting and postprandial
blood glucose levels, insulin resistance as assessed by the
homeostasis model for assessment of insulin resistance
(HOMA) (38.63 and 32.73%, respectively), levels of
LDL-cholesterol, triglycerides, lipoprotein (a) and apo-
lipoprotein B, uric acid level, pulse rate and systolic and
diastolic blood pressure, with a consequent reduction of
the cardiovascular disease risk profile [21].
In our previous studies [22,23], we demonstrated that
orlistat in hypercholesterolaemic and obese patients
gave TC, LDL-C and triglyceride significant reduction,
after 1 year therapy. In the first (in the orlistat arm), we
obtained a reduction of 15.0, 19.0 and 26.5%, respect-
ively; in the second (in the orlistat arm), we obtained a
reduction of 13.3, 16.9 and 29.9%, respectively. In this
study, we observed a reduction of TC, LDL-C and trigly-
ceride in orlistat (p< 0.05) compared to sibutramine
group (8.3, 6.6 and 25.9%; 4.6, 4.8 and 18.4%, respect-
ively). Although this lipid profile change was signifi-
cant, the reduction percent was lower, possibly because
we treated patients with normal lipid profile values.
A recent meta-analysis shows that 1-year treatment
with orlistat is associated to a mild but significant
decrease of blood pressure and heart rate in obese
uncontrolled hypertensive subjects [24].
Our results are in agreement with that reported by
Bakris and colleagues [25] that observed a significant
improvement in blood pressure control without any sig-
nificant change in heart rate.
As it regards sibutramine, some authors find that the
use of these drugs could be dangerous for patients at
high cardiovascular disease risk, because of the possibil-
ity that it could rise blood pressure and induce arrhyth-
mias in some patients [26], maybe due to a paradoxical
effect on the autonomic system [27]. However, in the
most part of cases, patients who lose 5% or more of
initial body weight have a reduction in blood pressure,
which correlates with the degree of weight loss [28].
In our patient sample, we did not observe a significant
increase in systolic nor diastolic blood pressure during
12months of treatment with sibutramine. No patient
experienced changes in heart rate as well. These
results agree with those reported in two recent clinical
trials where sibutramine treatment do not impair
blood pressure control in patients with hypertension
well controlled by treatment with b-adrenergic blocking
agents [29] or angiotensin-converting enzyme inhibitors
[30].
Beyond the cardiovascular effects, the 17.5% of our
patients treated with sibutramine developed side effects
against the 48.1% of those treated with orlistat. In all
cases, they were mild, but patients treated with orlistat
were more keen to complain about the side effect. Even
these data are in agreement with those reported in
literature [31].
In conclusion, both orlistat and sibutramine are effect-
ive on anthropometric variables during the 12-month
treatment; in our sample, orlistat has been associated to
a mild reduction in blood pressure, while sibutramine
assumption has not been associated to any cardiovascu-
lar effect and was generically better tolerated than orli-
stat. Long-term studies will be required to verify these
potential benefits.
Table 4 Patient side effects that completed the study
Orlistat
Number of patients 25/52*
Abdominal pain 6
Fatty/oily evacuation 12
Flatulence 10
Increased defecation 5
Faecal urgency 4
Sibutramine
Number of patients 10/57
Headache 5
Insomnia 4
Constipation 1
Dry mouth 3
Increased blood pressure 2
Increased heart rate –
*p< 0.05 vs. sibutramine group.
–7
–6
–5
–4
–3
–2
–1
0
Blo
od p
ress
ure
(mm
Hg)
OrlistatSibutramine
* †
*
SBP DBP
Fig. 3 Blood pressure change from baseline to the end of the
study. Values are mean�SD. *p< 0.05, change from baseline;
yp<0.05, between treatments. DBP, diastolic blood pressure;
SBP, systolic blood pressure.
54 Diabetes, Obesity and Metabolism, 7, 2005, 47–55 # 2004 Blackwell Publishing Ltd
OA Evaluation of orlistat and sibutramine treatment G. Derosa et al.
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