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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