CURRENT TOPICS IN DIABETES CARE

Sibutramine update
CAROLINE DAY, CLIFFORD J BAILEY

Abstract

T
he introduction of sibutramine has brought a new therapeutic option for the management of many
overweight and obese patients. To date it has been used by more than eight million patients in over 70
countries. As part of a comprehensive programme that includes diet and lifestyle guidance, the additive effect
of sibutramine (10 or 15 mg/day) facilitates patients to achieve and sustain greater weight loss. Overall weight loss
is typically 510% of starting body weight, and this is almost entirely due to loss of excess adipose tissue.
Commensurate with this level of weight loss, benefits have been noted in comorbidities such as insulin resistance,
type 2 diabetes and dyslipidaemia. Sibutramine is a serotonin-noradrenaline (norepinephrine) re-uptake inhibitor
which acts centrally to induce satiety and maintain thermogenic expenditure. The main side effects are increased
heart rate and blood pressure which are generally small, but require frequent checks.

Key words: sibutramine, obesity, overweight, seratonin noradrenaline re-uptake inhibitors, SNRI.

Introduction
Table 1. Sibutramine at a glance
More than half of the adult population of Europe and north
America is overweight or obese.1 Carrying excess body fat, par- Use Management of excess adiposity
ticularly in the abdomen, incurs a major burden to health, includ- Actions Induces satiety
ing increased risk of type 2 diabetes and many other chronically Maintains energy expenditure
debilitating conditions. Without adequate prevention, the treat- Rx Once-daily capsule (Reductil, Meridia)
ment of overweight and obesity is now a priority. Adjunct to diet, exercise and health education

Sibutramine is a new agent to facilitate weight management. Outcomes Increased weight loss
Sustained weight loss
It enhances the effects of diet, exercise and healthy living advice
by acting centrally to induce premature satiety and maintain Precautions Important exclusions and monitoring must be respected
Monitor blood pressure and heart rate
thermogenic energy expenditure (table 1).

Managing obesity
Effective interventions to treat overweight and obesity ideally
require a comprehensive personalised programme of lifestyle
modifications. These should enable the patient to adopt more
appropriate dietary practices with adequate physical activity.
Where resources permit, an integrated team approach is advo-
cated, in which experienced professionals provide continuing
guidance, support and monitoring. Drug therapy with sibu-
tramine can provide a valuable part of the intervention process
to achieve and sustain greater weight control.2
Achieving greater weight loss
Early trials in obese patients established the efficacy of sibu-
Correspondence to: Dr Caroline Day
Diabetes Group, Pharmaceutical Sciences, Aston University, Birmingham,
B4 7ET, UK.
Tel: +44 (0)121 359 3611; Fax: +44 (0)121 359 0578
Email: cday@mededuk.com
Br J Diabetes Vasc Dis 2002;2:3927
tramine to increase weight loss beyond that attained with diet
and lifestyle advice.3,4 Compared with addition of placebo tablets
in obese patients receiving diet and lifestyle advice, addition of
sibutramine (1015 mg/day for 26 months) achieved:
510 kg average weight loss (versus 24 kg placebo)
> 5% weight loss in 5070% of patients (versus 2530%
placebo)
> 10% weight loss in 3040% of patients (versus < 10%
placebo)
The extra 36 kg of weight loss attributed solely to sibu-
tramine (placebo subtracted) was mostly sustained in trials
extending to one year. These initial trials have been substantiat-
ed by many subsequent studies in a range of ethnic groups using
controlled trials, open label protocols and clinical audits.5-7
Predicting non-responders
When obese patients follow dietary and lifestyle advice with
sibutramine, significant weight loss is usually evident in 24
weeks. Sixty percent of those who lose > 1.8 kg (4 lbs) in this
time are likely to achieve > 5% weight loss in 612 months,

392 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

 CURRENT TOPICS IN DIABETES CARE

Figure 1. Body weight loss with sibutramine (10 mg/day) in obese
patients previously treated for one month with a very-low-
calorie diet (VLCD). At 12 months body weight loss was
-5.2 kg with sibutramine whereas the placebo group had
re-gained weight (+0.5 kg)
Figure 2. Long-term weight reduction and maintenance with
sibutramine. Sibutramine Trial of Obesity Reduction and
Maintenance (STORM). Patients received a 600 kcal/day diet
plus sibutramine (10 mg/day) for six months. Those achieving
> 5% weight loss were then randomised to sibutramine or
placebo

0
Weight loss Weight maintenance
-2 108
106
-4 104
Weight loss (kg)

Placebo (n=78)

Body weight (kg)

-6 102
100
Control
-8 98
96
-10
94
Sibutramine (n=81) Sibutramine
-12 92
90
-14
88
0 2 4 6 8 10 12 14 16 18 20 22 24
-16
Month
-1 0 1 2 3 4 5 6 7 8 9 10 11 12
NB: Same diet and exercise for both sibutramine and control
VLCD Months

Redrawn from the data of Apfelbaum et al. 19999 Reproduced with permission of The Lancet (James et al. 2000)10

compared with only 20% of those who lose < 1.8 kg by four
weeks.
Various definitions of non-responders have been applied to
trial data, such as those who fail to lose 1% of body weight in
four weeks. In most trials < 15% of patients have been consid-
ered as non-responders. Despite extensive analyses, no clear pre-
dictors of responsiveness to sibutramine have emerged.8
For routine clinical use in the UK, patients start with 10 mg/
day sibutramine plus a calorie-reduced diet and lifestyle advice.
Those who do not lose 2 kg by four weeks are titrated up to
15 mg/day. If weight loss is < 2 kg after a further four weeks or
< 5% of starting weight after three months, discontinuation of
the drug is advised.
months. This achieved > 5% weight loss in 467 (77%) of patients
who were then randomised to either continue sibutramine
(n=352) or placebo (n=115) for a further 18 months. Sibutramine
was increased to 20 mg/day if weight regain occurred. Of those
who completed the trial (204 on sibutramine and 57 on placebo),
43% on sibutramine maintained or increased weight loss com-
pared with 16% on placebo (figure 2).10
It may not be necessary to take sibutramine continuously to
maintain the weight loss effect of the drug. A two-year multi-
centre trial in Germany with 1,102 obese patients found that
intermittent use of 15 mg sibutramine (weeks 112, 1930 and
3748) produced similar weight loss (-7.8 kg) to 48 weeks of
continuous therapy (-7.9 kg).11

Maintaining weight loss Sibutramine versus orlistat

Maintaining weight loss is always a problem in the management
of obesity, and the introduction of drug therapy is often a con-
sequence of failure to achieve or sustain reasonable weight loss
with non-pharmacological measures. The ability of sibutramine
to improve long-term weight control in these circumstances has
been demonstrated in several trials.
For example, a multicentre trial in France gave obese patients
a very-low-calorie-diet (VLCD) (220800 kcal/day) for one
month. Those who lost > 6 kg were then randomised to sibu-
tramine (10 mg/day) or placebo and permitted a less rigorous
diet. After one year the sibutramine group sustained an addi-
tional weight loss of > 5 kg whereas the placebo group had
regained 0.5 kg (figure 1).9
The Sibutramine Trial of Obesity Reduction and Maintenance
(STORM), conducted at eight European centres, employed a low-
calorie diet (600 kcal/day) with sibutramine (10 mg/day) for six
The weight reduction reported for trials with sibutramine have
been similar to those reported with the intestinal lipase inhibitor
orlistat. Choice between the two agents is usually determined by
patient suitability and preference of patient and prescriber.
A head-to-head comparison of sibutramine (10 mg b.i.d.)
with orlistat (120 mg t.i.d.) was undertaken in 150 obese
women for six months. Both agents substantially reduced body
mass index (BMI), and a slightly greater reduction was noted
with sibutramine (-13.5%) than orlistat (-9%).12
Sibutramine plus orlistat
Combination of two or more differently acting agents is now
accepted practice to improve control in several disorders such as
hypertension and type 2 diabetes. The potential for combining
sibutramine and orlistat in the treatment of obesity was studied in
34 women who had maintained an average weight loss of 11.6%

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CURRENT TOPICS IN DIABETES CARE
after one year on sibutramine. Addition of orlistat for a further
four months did not produce any additional weight loss.13
Reducing intra-abdominal fat
Although several studies have indicated that body weight loss
associated with sibutramine therapy is specially due to loss of
adipose tissue, recent interest has focused on the need to reduce
intra-abdominal adipose tissue (IAAT). IAAT is highly metaboli-
cally active and constitutes an especially high risk for the devel-
opment of insulin resistance, type 2 diabetes and cardiovascular
disease.
Waist circumference and waist:hip ratio are useful surrogate
measures of IAAT,14 and sibutramine-associated weight loss has
consistently reduced waist measurements (by 310 cm) and
waist:hip ratio (by 0.020.04) more than diet alone. This approx-
imately corresponds with a sibutramine-associated reduction in
IAAT of 0.51 kg. Confirmation has recently been obtained by
direct determination using magnetic resonance imaging and
dual-energy X-ray absorptiometry (DEXA). Patients who lost
weight over six months with a low-calorie diet (600 kcal/day)
plus sibutramine (10 mg/day) showed a proportionally greater
decrease in IAAT than subcutaneous adipose tissue.15
Minor changes in lean body mass during sibutramine thera-
py are similar to those seen with equivalent weight loss by diet
alone.16
Sibutramine and type 2 diabetes
The majority of patients with type 2 diabetes are overweight or
obese and weight loss is known to greatly improve the progno-
sis of these patients. Hence there is broadening debate about
the potential use of anti-obesity agents as either initial
monotherapy or in combination with an antidiabetic agent to
treat the obese type 2 diabetic patient.17
Preliminary observations in overweight and obese type 2 dia-
betic patients suggested that sibutramine improved both weight
loss and glycaemic control when added to concurrent treatment
by diet alone or diet plus a sulphonylurea.18 Subsequent studies,
up to six months, have now affirmed these observations.16,19-21 In
each study sibutramine significantly improved the proportion of
patients who achieved > 5% weight loss, although the extent of
weight loss (typically 24 kg) was usually less than reported for
non-diabetic obese individuals. The improvement in glycaemic
control was generally commensurate with the amount of weight
loss: reductions in HbA1C were mostly < 0.5%, but larger reduc-
tions (sometimes > 1%) occurred in patients achieving substantial
weight loss. A reduction in the dosage of oral antidiabetic thera-
py with a sulphonylurea or metformin was occasionally required.
Consistent with the weight loss, sibutramine therapy in
obese type 2 diabetic patients reduced waist circumference. A
12-week study using DEXA noted that sibutramine (15 mg/day)
decreased total body fat by 1.8 kg and truncal fat by 0.6 kg,
compared with 0.2 and 0.1 kg respectively in the placebo
group.16
Concomitant reductions of plasma glucose and insulin dur-
ing sibutramine treatment indicate a reduction in insulin resis-
394
tance and it is possible that sibutramine metabolites may act
directly on muscle to facilitate insulin-mediated glucose trans-
port.22 Improvements in the lipid profile were also evident during
sibutramine therapy in obese diabetic patients, particularly a
lowering of triglyceride concentrations and in some studies a rise
in high density lipoprotein cholesterol (HDLc).
Sibutramine and dyslipidaemia
Obese individuals commonly exhibit raised circulating triglyc-
erides, especially postprandially, and low HDLc. Reductions in
basal triglycerides have been a consistent feature of sibutramine
therapy, generally exceeding the reductions achieved with non-
pharmacological therapy, even at equivalent levels of weight
loss. Most studies have also noted a greater increase in HDLc
with sibutramine. A recent 24-week study of 322 overweight
and obese patients with dyslipidaemia noted that diet plus sibu-
tramine (20 mg/day), which produced greater weight loss than
diet plus placebo (-4.9 kg versus -0.6 kg) also produced marked-
ly greater benefits to triglycerides and HDLc.23
Reductions of low density lipoprotein cholesterol (LDLc) with
sibutramine have generally been modest and comparable to
non-pharmacological means of weight loss. No consistent
changes in plasma free fatty acids have emerged.
Sibutramine and blood pressure
Obesity is commonly accompanied by raised blood pressure (BP),
and is a well recognised risk factor for cardiovascular disease.
Sibutramine is prone to cause a small increase in BP and heart
rate (HR) attributed to its inhibitory action on neuronal nora-
drenaline re-uptake. Monitoring of BP and HR has been under-
taken during the many clinical trials involving sibutramine. The
average increment in systolic and diastolic BP has been 06
mmHg, with similar results for supine, standing, morning,
evening and 24-hour ambulatory measurements. The average
increase in HR has been 36 beats/minute.
The effects of sibutramine on BP and HR are usually seen
within days and weeks of initiating treatment, and they appear
to be unrelated to weight-lowering efficacy. Hence monitoring
of BP and HR is important during the introduction of sibutramine
to identify and discontinue treatment in individuals who show
clinically significant increases at more than one measurement. In
most trials few patients (usually < 1%) have been withdrawn
due to adverse effects of BP, tachycardia or palpitations. It is like-
ly that small increases in BP are offset by the reduction in BP that
normally accompanies weight loss.24
Although it is emphasised that sibutramine must not be pre-
scribed to patients with uncontrolled hypertension, several studies
have shown that sibutramine can be used without detrimental
cardiovascular effects if the hypertension is well controlled.24-29
Similar observations have been made when sibutramine is used
concurrently with a range of antihypertensive therapies (e.g. beta-
blockers and angiotensin converting enzyme inhibitors, with and
without a thiazide diuretic), and minor adjustments to the antihy-
pertensive therapy may be required. Thus, potential benefits of
sibutramine-assisted weight loss to reduce cardiovascular risk
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
 CURRENT TOPICS IN DIABETES CARE

Figure 3. Sibutramine blocks the re-uptake of serotonin Table 2. Clinical use of sibutramine
(5-hydroxytryptamine) and noradrenaline (norepinephrine)
by neurones
Indications Obesity (BMI > 30 kg/m2)
Overweight (BMI > 27 kg/m2) with associated
RE-UPTAKE co-morbidity e.g. dyslipidaemia, type 2 diabetes
BLOCKED
Pre-treatment Fail to achieve realistic weight reduction after serious
attempt using non-pharmacological measures (e.g.
X diet, exercise, health education) for > three months

Monoamines
Usage Adjunct to non-pharmacological measures
(e.g. serotonin and Receptors
noradrenaline) Capsule strengths 10 mg, 15 mg (5 mg in some countries)
Treatment schedule Start 10 mg o.d. in the mornings; increase to 15 mg
o.d. if weight loss < 2 kg at four weeks. Discontinue
Nerve terminal
if weight loss insignificant at 15 mg (e.g. < 2 kg at
Post-synaptic four weeks; < 5% initial body weight at three
Synapse cell
months; regain > 3 kg of previous weight loss).
Maximum treatment period one year*
Contraindications Inadequately controlled hypertension, severe hepatic
or renal disease, history of serious eating disorders
(e.g. anorexia nervosa) or psychiatric illness, existing
or previous cardiovascular disease, use of a
Figure 4. Sibutramine is metabolised mainly in the liver to two active monoamine oxidase inhibitor, narrow angle
metabolites; Metabolite 1 (M1) is a secondary amine, and glaucoma, hyperthyroidism, previous hypersensitivity
Metabolite 2 (M2) is a primary amine to sibutramine
Side effects Increased blood pressure (BP) and heart rate (HR), dry
CH3 CH3 CH3 mouth, anorexia, constipation, insomnia, asthenia
HC CH3 HC CH3 HC CH3 Cautions Monitor BP and HR frequently (e.g. every two weeks
for first three months). Use not recommended in
CH2 CH2 CH2
children, elderly, pregnancy or lactation, alcohol or
N
CH3
N
CH3
N
H other drug abuse, or history of seizures. Possible
HC HC HC
CH3 H H interactions with erythromycin and ketoconazole+
CI CI CI
* Dose of 20 mg for two years permitted in some countries;
+
Pulmonary hypertension and valvular heart disease reported with
Sibutramine Metabolite 1 Metabolite 2 dexfenfluramine and phentermine have not been found with sibutramine

should not be confused with the contraindication of sibutramine
in patients who already exhibit clinical signs of established heart
disease and occlusive vascular disease.
Mechanism of action
Sibutramine reduces body weight by inducing satiety and
maintaining thermogenic energy expenditure.30 It acts centrally
as a serotonin and noradrenaline (norepinephrine) re-uptake
inhibitor (SNRI), increasing the duration of these transmitters in
the synaptic cleft (figure 3).31 The effects of sibutramine are
mainly mediated via two active hepatic metabolites (M1 and
M2) (figure 4).
The predominantly satiety-inducing (rather than anorectic)
effect of sibutramine involves central actions on alpha-1 and
beta-1 adrenoceptors, and serotonin receptors 5-HT2c and prob-
ably 5-HT2a, increasing the activity of the central satiety path-
ways.32 Reduction in meal size has been confirmed in clinical
studies.33 Unlike anorectic drugs, sibutramine and its metabolites
do not stimulate neurotransmitter release, removing the abuse
potential.31,34
Preclinical studies found that sibutramine causes central activa-
tion of sympathetic pathways that stimulate thermogenic energy
expenditure, particularly via beta-3 adrenoceptors in brown adi-
pose tissue. In man, sibutramine can cause a small acute increase
in basal energy expenditure and diet-induced thermogenesis.35
In the long term, sibutramine does not appear to increase
thermogenesis. However, it partially or totally prevents the adap-
tive reduction in resting energy expenditure that contributes to
the increased metabolic efficiency during weight loss i.e. it helps
to maintain energy expenditure during weight loss.36,37
Starting sibutramine
The clinical use of sibutramine to treat overweight and obesity is
summarised in table 2. It cannot be overstated that sibutramine
should be used as part of a comprehensive weight management
programme with frequently reinforced guidance on diet, exer-
cise and healthy living.2,38 Contraindications, especially uncon-
trolled hypertension, must be respected, and pulse and BP
should be monitored vigilantly.
The pharmacokinetic profile of sibutramine suits convenient
once-daily administration, but metabolism and elimination of
the drug obviates use in patients with severe liver or kidney dis-
ease (table 3). Attention is also drawn to the interaction with
monoamine oxidase inhibitors. While psychiatric disorders and

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CURRENT TOPICS IN DIABETES CARE

Table 3. Pharmacokinetics of sibutramine

Key messages
Bioavailability > 75% absorbed from gastrointestinal tract
Tmax ~1.2 hours (delayed when taken with food)

Metabolism Almost all metabolised, mainly by liver,

Sibutramine can improve and sustain weight loss as part
Firstly to two active metabolites (M1 and M2)
then to two inactive metabolites (M5 and M6) of a comprehensive therapeutic programme for
overweight and obese patients
Plasma concentration M1: Cmax 4 ng/mL; Tmax ~3.5 hours
M2: Cmax 6.5 ng/mL; Tmax ~3.5 hours Sibutramine-assisted weight loss can benefit
Plasma protein bound ~94% comorbidities of overweight and obesity, notably type 2
Elimination Elimination T1/2: M1 ~14 hours; M2 ~16 hours diabetes and dyslipidaemia
Urine >75% (M5 and M6); Faeces <25% Use of sibutramine requires monitoring of blood
pressure and heart rate
Sibutramine reduces body weight by inducing satiety
and maintaining thermogenic energy expenditure
Figure 5. Body Mass Index (BMI): BMI > 27 is overweight, and BMI
> 30 is obese*

Weight (lbs)
110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 abdominal obesity alone also carries a high burden of clinical
62 14 16 17 18 19 21 22 23 24 26 27 28 30 31 32 1.87 risk, and this may be quite gross before overall BMI reaches the
61 15 16 17 18 20 21 22 24 25 26 28 29 30 32 33 1.85 level of obesity. Also, standard BMI is not necessarily appropri-
60 15 16 18 19 20 22 23 24 26 27 29 30 31 33 34 1.83 ate to categorise the increasing prevalence of obesity in children
511 15 17 18 20 21 22 24 25 26 28 30 31 32 33 35 1.80 and adolescents. Due to lack of information to date, sibutramine
510 16 17 19 20 22 23 24 26 27 29 31 32 33 34 36 1.78 is not recommended for this population.
59 16 18 19 21 22 24 25 27 28 30 32 33 34 35 37 1.75
Height (feet and inches)

58 17 18 20 21 23 24 26 27 29 31 33 34 35 36 38 1.73 Safety and tolerability

Long-term treatment trials for obesity are customarily beset by a
Height (metres)

57 17 19 20 22 23 25 27 28 30 32 34 35 36 38 39 1.70

56 18 19 21 23 24 26 27 29 31 33 35 36 37 39 40 1.68
substantial proportion of dropouts and poor compliance. Thus the
relatively high number of completers in the many trials with sibu-
55 18 20 22 23 25 27 28 30 32 34 36 37 38 40 42 1.65
tramine supports claims that this drug is well tolerated. The
54 19 21 22 24 26 27 29 31 33 35 37 38 39 41 43 1.63
requirement for frequent monitoring at the beginning of therapy
53 19 21 23 25 27 28 30 32 34 36 38 39 41 43 44 1.60
provides an opportunity to recognise and deal with side effects, of
52 20 22 24 26 27 29 31 33 35 37 39 40 42 44 46 1.57
which dry mouth is the most often cited.3,6 Questionnaires have
51 20 23 25 26 28 30 32 34 36 38 40 42 43 46 47 1.55
recorded that patients perceive an improved health-related quali-
50 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 1.52
ty of life during sibutramine-assisted weight loss.40
411 22 24 26 28 30 32 34 36 38 40 42 44 47 49 51 1.50 With regard to safety, former anti-obesity drugs that either
410 23 25 27 29 31 33 36 38 40 42 44 46 48 50 52 1.47 stimulate secretion of serotonin (e.g. dexfenfluramine) or nora-
50 55 59 64 68 73 77 82 86 91 95 100 105 109 114
drenaline (e.g. phentermine) were withdrawn following reports of
Weight (kg)
associated cardiac valve disease and pulmonary hypertension.
BMI <27 BMI 2730 BMI >30 * BMI is kg/m2 (weight/height) Doppler and echocardiography investigations with sibutramine
have not shown any evidence of increased valvular heart disease,41
and there have been no associated reports of pulmonary hyper-
tension. In Europe in June 2002 the Committee for Proprietary
eating disorders are contraindications for the use of sibutramine, Medicinal Products re-affirmed its opinion of a favourable risk-
patients who seek treatment for obesity sometimes describe a benefit profile of sibutramine.
history of binge eating, and this has recently been shown to
respond favourably to sibutramine.39 References
The maximum recommended period of treatment with sibu- 1. Kopelman PG. Obesity as a medical problem. Nature 2000;404:635-43.
2. James WP, Finer N. The role of sibutramine in weight management. Int J
tramine in the UK is presently one year, and the likelihood of Obesity 2001;25(suppl 4):S34-38.
weight regain after completion of therapy must be anticipated. 3. Lean MEJ. Sibutramine: a review of clinical efficacy. Int J Obesity 1997;
Thus it is essential that non-pharmacological measures are re- 21(suppl 1):S30-36.
doubled at this time. 4. Bray GA, Blackburn GL, Ferguson GM et al. Sibutramine produces dose-
related weight loss. Obes Res 1999;7:189-98.
Although BMI is the accepted parameter for defining over- 5. Cuellare GE, Ruiz AM, Mousalve MC, Barber A. Six-month treatment of
weight and obesity (figure 5) it is pertinent to remember that obesity with sibutramine 15 mg: a double-blind, placebo controlled

396 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE


monocenter clinical trial in a Hispanic population. Obesity Res 2000;
8:71-82.
6. Finer N. Sibutramine in clinical practice. Int J Obesity 2001;25(suppl 4):
S12-15.
7. Smith IG, Goulder MA. Randomised placebo-controlled trial of long-term
treatment with sibutramine in mild to moderate obesity. J Fam Pract
2001;50:505-12.
8. Hansen D, Astrup A, Toubro S et al. Predictors of weight loss and main-
tenance during 2 years of treatment by sibutramine in obesity. Int J
Obesity 2001;25:496-501.
9. Apfelbaum M, Vague P, Ziegler O et al. Long-term maintenance of
weight loss after a very-low-calorie diet: a randomised blinded trial of the
efficacy and tolerability of sibutramine. Am J Med 1999;106:179-84.
10. James WPT, Astrup A, Finer N et al. Effect of sibutramine on weight
maintenance after weight loss: a randomised trial. Lancet 2000;356:
2119-25.
11. Wirth A, Krause J. Long-term weight loss with sibutramine. A ran-
domised controlled trial. JAMA 2001;286:1331-9.
12. Gokcel A, Gumurdulu Y, Karakose H et al. Evaluation of the safety and
efficacy of sibutramine, orlistat and metformin in the treatment of obe-
sity. Diabetes Obesity Metab 2002;4:49-55.
13. Wadden TA, Berkowitz RI, Womble LG et al. Effects of sibutramine plus
orlistat in obese women following 1 year of treatment by sibutramine
alone: a placebo-controlled trial. Obesity Res 2000;8:431-7.
14. Lean MEJ. The role of central fat accumulation in type 2 diabetes. Br J
Diabetes Vasc Dis 2001;1:115-17.
15. Kamel EG, McNeill G, Van Wijk MC. Change in intra-abdominal adipose
tissue volume during weight loss in obese men and women: correlation
between magnetic resonance imaging and anthropometric measure-
ments. Int J Obesity 2000;24:607-13.
16. Finer N, Bloom SR, Frost GS et al. Sibutramine is effective for weight loss
and diabetic control in obesity with type 2 diabetes: a randomised, dou-
ble-blinded, placebo-controlled study. Diabetes Obesity Metab 2000;2:
105-12.
17. Scheen AJ, Lefebvre PJ. Antiobesity pharmacotherapy in the manage-
ment of type 2 diabetes. Diabetes Metabol Res Rev 2000;16:114-24.
18. McNeely W, Goa KL. Sibutramine. A review of its contribution to the
management of obesity. Drugs 1998;56:1093-124.
19. Fujioka K, Seaton TB, Rowe E et al. Weight loss with sibutramine
improves glycaemic control and other metabolic parameters in obese
patients with type 2 diabetes mellitus. Diabetes Obesity Metab 2000;2:
175-87.
20. Gokcel A, Karakose H, Ertorer EM et al. Effects of sibutramine in obese
female subjects with type 2 diabetes and poor blood glucose control.
Diabetes Care 2001;24:1957-60.
21. Serrano-Rios M, Melchionda N, Moreno-Carretero E. Role of sibutramine
in the treatment of obese type 2 diabetic patients receiving sulphony-
lurea therapy. Diabetic Med 2002;19:119-24.
22. Bailey CJ, Turner SL, Bates SH, Jones RB. Sibutramine metabolites
increase glucose transport by cultured rat muscle cells. Int J Obesity
2001;25:478-85.
23. Dujovne CA, Zavirak JH, Rowe E et al. Effects of sibutramine on body
weight and serum lipids: a double blind, randomised, placebo-controlled
study in 322 overweight and obese patients with dyslipidaemia. Am
Heart J 2001;142:489-97.
VOLUME 2 ISSUE 5 . SEPTEMBER/OCTOBER 2002
CURRENT TOPICS IN DIABETES CARE
24. Sharma AM. Sibutramine in overweight/obese hypertensive patients. Int
J Obesity 2001;25(suppl 4):S20-23.
25. Hazenburg BP. Randomized, double-blind, placebo-controlled, multicen-
ter study of sibutramine in obese hypertensive patients. Cardiology
2000;94:152-8.
26. McMahon FG, Fujioka K, Singh BN et al. Efficacy and safety of sibu-
tramine in obese white and African American patients with hyperten-
sion: a 1-year, double-blind, placebo-controlled, multicenter trial. Arch
Int Med 2000;160:2185-91.
27. Faria AN, Ribeiro Filho FF, Lerarlo DD et al. Effects of sibutramine on the
treatment of obesity in patients with arterial hypertension. Arq Bras
Cardiol 2002;78:172-80.
28. McMahon FG, Weinstein SP, Rowe E et al. Sibutramine is safe and effec-
tive for weight loss in obese patients whose hypertension is well con-
trolled with angiotensin-converting enzyme inhibitors. J Hum Hypertens
2002;16:5-11.
29. Sramek JJ, Leibowitz MT, Weinstein SP et al. Efficacy and safety of sibu-
tramine for weight loss in obese patients with hypertension well con-
trolled by beta-adrenergic blocking agents: a placebo-controlled, double-
blind, randomised trial. J Hum Hypertens 2002;16:13-19.
30. Stock MJ. Sibutramine: a review of the pharmacology of a novel anti-
obesity agent. Int J Obesity 1997;21(suppl 1):S25-29.
31. Heal DJ, Aspley S, Prow MR et al. Sibutramine: a novel anti-obesity drug.
Int J Obesity 1998;22(suppl 1):S18-28.
32. Jackson HC, Bearham MC, Hutchins LJ et al. Investigation of the mech-
anisms underlying the hypophagic effects of the 5-HT and noradrenaline
reuptake inhibitor, sibutramine, in the rat. Br J Pharmacol 1997;121:
1613-18.
33. Rolls BJ, Shide DJ, Thorwatt ML et al. Sibutramine reduces food intake in
non-dieting women with obesity. Obesity Res 1998;6:1-11.
34. Schuh LM, Schuster CR, Hopper JA, Mendel CM. Abuse liability assess-
ment of sibutramine, a novel weight control agent. Psychopharmacology
2000;147:339-46.
35. Hanson DL, Toubro S, Stock et al. Thermogenic effects of sibutramine in
humans. Am J Clin Nutr 1998;68:1180-6.
36. Hansen DL, Toubro S, Stock MJ et al. The effect of sibutramine on ener-
gy expenditure and appetite during chronic treatment without dietary
restriction. Int J Obesity 1999;23:1016-24.
37. Walsh KM, Leen E, Lean MJ. The effect of sibutramine on resting energy
expenditure and adrenaline-induced thermogenesis in obese females. Int
J Obesity 1999;23:1009-15.
38. Berube-parent S, Prudhomme D, St-Pierre S et al. Obesity treatment
with a progressive clinical tri-therapy combining sibutramine and a
supervised diet-exercise intervention. Int J Obesity 2001;25:1144-53.
39. Appolinario JC, Godoy-Matos A, Fontenelle LF et al. An open-label trial
of sibutramine in obese patients with binge-eating disorder. J Clin
Psychiatry 2002;63:28-30.
40. Samsa GP, Kolotkin RL, Williams GR et al. Effect of moderate weight loss
on health-related quality of life: analysis of combined data from 4 ran-
domised trials of sibutramine versus placebo. Am J Manag Care 2001;7:
926-7.
41. Bach DS, Rissanen AM, Mendel CM et al. Absence of cardiac valve dys-
function in obese patients treated with sibutramine. Obesity Res
1999;7:363-9.
397