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Sibutramine update


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.

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 tramine to increase weight loss beyond that attained with diet
require a comprehensive personalised programme of lifestyle and lifestyle advice.3,4 Compared with addition of placebo tablets
modifications. These should enable the patient to adopt more in obese patients receiving diet and lifestyle advice, addition of
appropriate dietary practices with adequate physical activity. sibutramine (1015 mg/day for 26 months) achieved:
Where resources permit, an integrated team approach is advo- 510 kg average weight loss (versus 24 kg placebo)
cated, in which experienced professionals provide continuing > 5% weight loss in 5070% of patients (versus 2530%
guidance, support and monitoring. Drug therapy with sibu- placebo)
tramine can provide a valuable part of the intervention process > 10% weight loss in 3040% of patients (versus < 10%
to achieve and sustain greater weight control.2 placebo)
The extra 36 kg of weight loss attributed solely to sibu-
Achieving greater weight loss tramine (placebo subtracted) was mostly sustained in trials
Early trials in obese patients established the efficacy of sibu- 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
Correspondence to: Dr Caroline Day
Diabetes Group, Pharmaceutical Sciences, Aston University, Birmingham, Predicting non-responders
B4 7ET, UK.
When obese patients follow dietary and lifestyle advice with
Tel: +44 (0)121 359 3611; Fax: +44 (0)121 359 0578
Email: sibutramine, significant weight loss is usually evident in 24
Br J Diabetes Vasc Dis 2002;2:3927 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,



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

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

Placebo (n=78)

Body weight (kg)

-6 102
-8 98
Sibutramine (n=81) Sibutramine
-12 92
0 2 4 6 8 10 12 14 16 18 20 22 24
-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 months. This achieved > 5% weight loss in 467 (77%) of patients
weeks. who were then randomised to either continue sibutramine
Various definitions of non-responders have been applied to (n=352) or placebo (n=115) for a further 18 months. Sibutramine
trial data, such as those who fail to lose 1% of body weight in was increased to 20 mg/day if weight regain occurred. Of those
four weeks. In most trials < 15% of patients have been consid- who completed the trial (204 on sibutramine and 57 on placebo),
ered as non-responders. Despite extensive analyses, no clear pre- 43% on sibutramine maintained or increased weight loss com-
dictors of responsiveness to sibutramine have emerged.8 pared with 16% on placebo (figure 2).10
For routine clinical use in the UK, patients start with 10 mg/ It may not be necessary to take sibutramine continuously to
day sibutramine plus a calorie-reduced diet and lifestyle advice. maintain the weight loss effect of the drug. A two-year multi-
Those who do not lose 2 kg by four weeks are titrated up to centre trial in Germany with 1,102 obese patients found that
15 mg/day. If weight loss is < 2 kg after a further four weeks or intermittent use of 15 mg sibutramine (weeks 112, 1930 and
< 5% of starting weight after three months, discontinuation of 3748) produced similar weight loss (-7.8 kg) to 48 weeks of
the drug is advised. continuous therapy (-7.9 kg).11

Maintaining weight loss Sibutramine versus orlistat

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



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



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
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

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
children, elderly, pregnancy or lactation, alcohol or
H other drug abuse, or history of seizures. Possible
CH3 H H interactions with erythromycin and ketoconazole+
* 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 expenditure, particularly via beta-3 adrenoceptors in brown adi-
in patients who already exhibit clinical signs of established heart pose tissue. In man, sibutramine can cause a small acute increase
disease and occlusive vascular disease. in basal energy expenditure and diet-induced thermogenesis.35
In the long term, sibutramine does not appear to increase
Mechanism of action thermogenesis. However, it partially or totally prevents the adap-
Sibutramine reduces body weight by inducing satiety and tive reduction in resting energy expenditure that contributes to
maintaining thermogenic energy expenditure.30 It acts centrally the increased metabolic efficiency during weight loss i.e. it helps
as a serotonin and noradrenaline (norepinephrine) re-uptake to maintain energy expenditure during weight loss.36,37
inhibitor (SNRI), increasing the duration of these transmitters in
the synaptic cleft (figure 3).31 The effects of sibutramine are Starting sibutramine
mainly mediated via two active hepatic metabolites (M1 and The clinical use of sibutramine to treat overweight and obesity is
M2) (figure 4). summarised in table 2. It cannot be overstated that sibutramine
The predominantly satiety-inducing (rather than anorectic) should be used as part of a comprehensive weight management
effect of sibutramine involves central actions on alpha-1 and programme with frequently reinforced guidance on diet, exer-
beta-1 adrenoceptors, and serotonin receptors 5-HT2c and prob- cise and healthy living.2,38 Contraindications, especially uncon-
ably 5-HT2a, increasing the activity of the central satiety path- trolled hypertension, must be respected, and pulse and BP
ways.32 Reduction in meal size has been confirmed in clinical should be monitored vigilantly.
studies.33 Unlike anorectic drugs, sibutramine and its metabolites The pharmacokinetic profile of sibutramine suits convenient
do not stimulate neurotransmitter release, removing the abuse once-daily administration, but metabolism and elimination of
potential.31,34 the drug obviates use in patients with severe liver or kidney dis-
Preclinical studies found that sibutramine causes central activa- ease (table 3). Attention is also drawn to the interaction with
tion of sympathetic pathways that stimulate thermogenic energy monoamine oxidase inhibitors. While psychiatric disorders and



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
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