VOLUME 18 NUMBER 5

The drug management of obesity

SUMMARY

This Bulletin focuses on the drug management of overweight and obesity in adults, based
largely on the National Institute for Health and Clinical Excellence (NICE) guidance published
in 2006. Particular attention is given to the evidence supporting each drug, along with some
important safety considerations.

• Lifestyle changes, mainly based around improvements in diet and physical activity, are the
mainstay of obesity management. These should be continued even when drugs are
prescribed. Lifestyle changes should be tailored to the individual. Encouraging people to Lifestyle changes
make small, manageable changes to their lifestyles by moving a little more and eating a are the mainstay
little less may be more helpful than attempts to radically alter diet and physical activity of obesity
initially. management.
These should be
• Drugs should be prescribed only as part of an overall plan for managing obesity. continued even
when drugs are
• Adding drug treatment to lifestyle approaches may be considered for patients who have not prescribed
reached their target weight loss, or for those who have reached a plateau with dietary,
physical activity and behavioural changes alone. Generally, drug treatment may be
considered for overweight or obese people who have co-morbidities or for obese people
without co-morbidities who have a BMI > 35kg/m2 (i.e. obesity class II).

• Orlistat, sibutramine and rimonabantq are currently available to manage overweight and
obesity. When used with a hypocaloric diet and exercise advice, these drugs seem to have
a modest effect leading to, on average, around a 3 to 5kg greater weight loss than placebo
at one year. Some people will lose more weight than this, whilst some may not lose any
weight at all or might even gain weight. Treatment may also be used to help maintain the
Visit the obesity
weight lost.
floor on NPCi
(www.npci.org.uk)
• There are data showing that, compared with lifestyle changes alone, orlistat plus lifestyle
where further
changes reduces the incidence of type 2 diabetes in people with impaired glucose tolerance
materials are
at four years. However, we do not know yet if this reduces the likelihood of morbidity and
available on this
mortality in the longer-term. Sibutramine is not licensed for use beyond a year and the
topic
product licence for rimonabantq states that its safety and efficacy have not been evaluated
beyond two years.

• NICE recommends that treatment with orlistat or sibutramine for longer than three months
should be considered only if the person has lost at least 5% of their initial body weight since
starting drug treatment. Orlistat may be continued for longer than a year only after
discussing its risks and benefits with the patient.

• The Medicines and Healthcare products Regulatory Agency (MHRA) has reported that
sibutramine can increase pulse rate and blood pressure. The MHRA also reported that
around one in 10 people taking rimonabantq may experience psychiatric side effects and
around 1 in 100 may experience suicidal thoughts. About one in four patients taking orlistat
experience gastrointestinal side effects.

• The choice of drug should be based on careful consideration of the potential risks and
benefits of each agent in individual patients. Considering each drug in terms of its Safety,
This publication was
Tolerability, Efficacy, Price and Simplicity of use (STEPS) can help prescribers to make an
correct at the time of
informed decision around which agent to use (Table, page 8).
preparation:
April 2008

This MeReC Publication is produced by the NHS for the NHS

MeReC Bulletin Volume 18, Number 5 1

 The drug management of obesity
Introduction
The detrimental effects of obesity on health are
well known, yet its incidence is continuing to
rise. Nearly a quarter of all adults in England are
Anti-obesity obese and the government has predicted that
drugs should be 33% of men and 28% of women will be obese
considered only by 2010.1, 2 Obesity has also reached ‘epidemic’
after dietary, proportions in children. This is particularly
exercise and concerning, especially as excess weight in the
behavioural early years has been associated with obesity in
approaches have adulthood.3 In England, nearly a third of children
been started and aged two to 15 years are either overweight or
evaluated obese.1
Obesity occurs when a person gains weight to
the point that it seriously endangers their
health.4 Body mass index (BMI) is usually used
for defining overweight or obesity in adults
(Panel, page 3).5 However, BMI needs to be
interpreted with caution as it is not a direct
measure of adiposity. For adults, assessment of
the health risks associated with being
overweight and obese should be based on a
combination of BMI and waist circumference.
The National Institute for Health and Clinical
Excellence (NICE) obesity clinical guideline
contains a useful risk assessment table that can
be used when advising patients on the impact
these measurements have on their risk of
developing long-term health problems (Panel,
page 3).5
Several causes of overweight and obesity have
been suggested from observational studies
(e.g. sedentary lifestyle, consumption of
energy-dense foods, marketing of fast-food
outlets, adverse socioeconomic conditions,
etc.).3 As a result, the government has
developed a programme of initiatives to
address various social, behavioural and
societal issues.3 Even so, it should not be
forgotten that, fundamentally, being overweight
and obese is caused by consuming more
calories than are expended.4
Why lose weight?
Everyone should aim to maintain or achieve a
Adding drug healthy weight to reduce their risk of diseases
treatment to associated with overweight or obesity, such as
lifestyle coronary heart disease (CHD), type 2 diabetes,
approaches can osteoarthritis and some cancers.5,6 It is
be considered for important to remember, however, that the risks
patients who have of specific diseases from being overweight or
not reached their obese will depend on individual factors, such as
target weight loss, co-morbidities, age, sex, smoking, muscular
or for those whose build, ethnic origin, etc.5,7 For example, an
weight has analysis of 3,457 patients from the Framingham
reached a plateau Heart Study found that, at age 40, obese female
on dietary, smokers lost 13.3 years of life expectancy and
physical activity obese male smokers lost 13.7 years, compared
and behavioural with normal-weight non-smokers.7 At the same
interventions age, obese female non-smokers lost 7.1 years
alone and obese male non-smokers lost 5.8 years
compared with normal weight non-smokers.7
Healthcare professionals should use their
2 MeReC Bulletin Volume 18, Number 5
clinical judgement to decide when to measure
someone’s height and weight, and when
considering risk factors in certain people.5 The
psychological and social burdens of obesity
should also not be underestimated. Low self
esteem, reduced mobility and, generally, a
poorer quality of life are common experiences
of obese people.4
What is the best way to lose weight?
NICE emphasises the importance of adopting an
individualised approach to weight loss. The
approach taken should take into account
patients’ preferences, their social circumstances,
previous treatments tried, and their risk of
disease along with any co-morbidities already
present. Lifestyle changes, mainly based around
improvements in diet and physical activity, are
the mainstay of obesity management, and these
should be continued even when drugs are
required (Panel, page 3).5 From a public health
perspective, it may be helpful to encourage
people to start making small manageable
changes to their lifestyles by moving a little more
and eating a little less.8 This may be more helpful
than attempting to radically change diet and
exercise initially.
Realistic targets for adults who wish to lose
weight are usually to aim to lose 5–10% of their
original weight, with a maximum weekly weight
loss of 0.5 to 1 kg. To lose weight, total energy
intake should be less than expenditure. For
sustainable weight loss, diets with a 600kcal/day
deficit or those that reduce calories by lowering
fat content, in combination with expert support
and intensive follow-up, are recommended.
Adults should also be encouraged to undertake
at least 30 minutes of at least moderate-intensity
physical activity on five or more days a week.
Weight management programmes to improve
people’s lifestyles should be based on several
interventions and include strategies to change
behaviour. The NICE clinical guideline on obesity
contains more information about such lifestyle
and behavioural approaches to weight loss,
including what to tell patients, and best practice
standards for weight loss programmes and
diets.5 In addition, it might be helpful to refer to
the NICE public health guidance on methods to
increase physical activity.9
When should drugs be used?
Anti-obesity drugs should be considered only
after dietary, exercise and behavioural
approaches have been started and evaluated.5
Adding drug treatment to lifestyle approaches
can be considered for patients who have not
reached their target weight loss, or for those
whose weight has reached a plateau after
dietary, physical activity and behavioural
changes alone.5 Generally, drug treatment may
be considered for overweight or obese people
who have co-morbidities (e.g. type 2 diabetes)
and for obese people without co-morbidities who
 The drug management of obesity

have a BMI >35kg/m2 (i.e. obesity class II) Panel: The health risks and management of overweight and
(Panel). However, individual agents should be obesity according to BMI and waist circumference.
given within their licensed indications,5 which Adapted from the NICE obesity guideline.5
differ slightly from this (see below). Referral to a
specialist might be necessary for certain patients Assessment of the health risks
e.g. if BMI >50kg/m2 or if the underlying causes
of obesity need to be assessed (see NICE Assessment of the health risks associated with overweight and obesity in adults
guideline for further details on who to refer).5 should be based on BMI and waist circumference as follows:
None of the drugs has been studied sufficiently in
children or elderly patients.10–12 NICE has given Waist circumference
BMI BMI
guidance on the cautious use of orlistat and classification (kg/m2)
sibutramine in certain children aged >12 years Low High Very high
within a specialist paediatric setting.5 However,
these drugs are specifically not indicated for Increased
Overweight 25–29.9 No increased risk High risk
children in their product licenses.10,11 risk

Orlistat, sibutramine and rimonabantq are

currently available for treating overweight and Obesity I 30–34.9 Increased risk High risk Very high risk
obesity. Orlistat is a gastrointestinal (GI) lipase
inhibitor which prevents absorption of around
30% of dietary fat.10,13 Sibutramine, a For men, waist circumference of less than 94cm (37inches) is low, 94–102cm
monoamine-reuptake inhibitor, suppresses (37–40inches) is high and more than 102cm (40inches) is very high.
appetite by inhibiting serotonin and For women, waist circumference of less than 80cm (32inches) is low, 80–88cm
noradrenaline uptake.11,13 Rimonabantq, which (32–35inches) is high and more than 88cm (35inches) is very high.
was launched in 2006, is a selective cannabinoid
(CB1) receptor blocker.12,13 The endocannabinoid Management
system is associated with energy balance,
Waist circumference
glucose and lipid metabolism, body weight, and Obesity BMI Comorbidities
intake of palatable, sweet or fatty foods.12 Classification (kg/m2) present
Low High Very high
Orlistat, sibutramine and rimonabant are q
Healthy
licensed for use in obese adults who have a BMI 18.5–24.9
weight
of 30 kg/m2 or more; and in overweight adults
with associated risk factors (e.g. type 2 diabetes Overweight 25–29.9
or dyslipidaemia) who have a BMI of 28kg/m2 or
more (orlistat), or a BMI of 27kg/m2 or more
(sibutramine), or a BMI more than 27kg/m2 Obesity I 30–34.9
(rimonabantq).5,10–12
Obesity II 35–39.9
Use of orlistat and sibutramine is discussed in
the NICE clinical guideline on obesity that was
Obesity III >40
published in 2006.5 Guidance on the use of
rimonabantq is being addressed by a NICE
technology appraisal that is underway and is due Key
to be published in May 2008 (see
www.nice.org.uk). General advice on healthy weight and lifestyle

About one million prescription items for obesity
were dispensed in 2007, more than eight times
the amount prescribed in 1999.1,14 Orlistat
accounted for about 67% of prescriptions,
sibutramine for 24% and rimonabantq for 9%.14
How effective are these drugs?
In clinical trials, patients taking drug therapy in
addition to lifestyle changes (which includes a
hypocaloric diet) lose an average of about 3 to
5kg more weight than with placebo in the first
year.15 Some people will lose more weight than
this, whilst some may not lose any weight at all or
might even gain weight. When treatment is
continued during the second year, drug
treatment can help to maintain the initial weight
loss seen, even if patients regain some weight.15
However, obesity is a long-term problem. We are
not aware of any strong evidence showing that
Diet and physical activity
Diet and physical activity; consider drugs
Diet and physical activity; consider drugs; consider surgery
NB The level of intervention should be higher for patients with co-morbidities
(e.g. type 2 diabetes, cardiovascular disease) regardless of their waist
circumference. This approach should be adjusted as needed, depending on
the patient’s clinical need and potential to benefit from losing weight.
continued treatment with anti-obesity drugs over several years leads to
additional weight loss beyond that seen in the first year. For rimonabantq
and sibutramine, the longest duration of fully published randomised
controlled trials (RCTs) is currently only two years, and for orlistat, it is four
years.15,16 In addition, treatment with sibutramine is not recommended
beyond the licensed duration of one year.5,11 The product licence for
rimonabantq states that the safety and efficacy of rimonabantq have not
been evaluated beyond two years.12 A maximum duration of treatment with
orlistat is not specified.10

MeReC Bulletin Volume 18, Number 5 3

 The drug management of obesity
Unfortunately, RCTs of anti-obesity drugs
commonly have dropout rates of 30 to 40%.15 In
addition, published long-term morbidity and
mortality studies are lacking for anti-obesity
drugs. However, there is RCT evidence showing
that orlistat reduces the incidence of type 2
In clinical trials, diabetes (see details of the XENDOS trial
patients taking below17) and outcome studies are underway for
drug therapy in both sibutramine and rimonabantq (see
addition to below).18,19
lifestyle changes
(which includes a Most RCTs of anti-obesity drugs have assessed
hypocaloric diet) weight loss as the primary outcome and various
lose an average of cardiovascular (CV) risk factors, such as
about 3 to 5kg changes in blood lipids, blood pressure (BP),
more weight glycosylated haemoglobin (HbA1c), waist
than placebo in circumference, etc. as secondary outcomes.15
the first year The weight loss figures quoted earlier relate to
the average weight loss. The European
Medicines Agency (EMEA) recommends that the
primary outcome of anti-obesity drug studies
should include at least a 10% reduction of
baseline weight, which is also statistically
significantly greater than that associated with
placebo.20 It also suggests that a further end-
point may be the proportion of people who have
more than 10% weight loss at 12 months.20
These figures are more helpful than looking at
the average weight loss as they tell us the
proportion of people likely to benefit, given that
some people will not lose any additional weight
at all with these drugs. These data are now
available from more recent meta-analyses, as
discussed below.
Several meta-analyses of anti-obesity drugs in
overweight and obesity have been published.
The most recent was published in the BMJ and
included RCTs that compared anti-obesity drugs
with placebo in patients who were overweight or
obese (mean BMI 35 to 36 kg/m2 i.e. class II
obesity) for between one and four years.15 In
most studies, patients in both the active and
The XENDOS placebo groups were allocated to a standardised
study has found low fat, hypocaloric (low energy) diet and
that orlistat plus encouraged to exercise. It is important to note
lifestyle changes that, in addition to the high dropout rates, most
produces a greater studies did not describe the randomisation
reduction in the process or mention whether or not allocation was
incidence of type concealed. In addition, none of the studies
2 diabetes than mentioned blinding of the outcome assessors
lifestyle changes and secondary outcomes were inconsistently
alone reported.15 These shortcomings increase the
possibility of bias.
Orlistat
The BMJ meta-analysis assessed sixteen RCTs
(n=10,631) of orlistat. Nine of these included
only high-risk patients (four RCTs were in people
with type 2 diabetes; and five RCTs included
obese patients with at least one CV risk factor).
At one year, patients in the orlistat group lost
2.9kg more of their bodyweight (95% CI 2.5 to
3.2kg) than those on placebo. Also, compared
with placebo, 12% (95% CI 9% to 14%; this was
an absolute increase) more patients in the
orlistat group achieved >10% weight loss.15 This
4 MeReC Bulletin Volume 18, Number 5
translates into a number needed to treat (NNT)
of eight. i.e. eight patients would need to be
treated with orlistat plus lifestyle changes for one
year instead of lifestyle changes alone, for one
additional patient to lose at least 10% of their
baseline bodyweight. Four RCTs looked at
weight maintenance in the second year and
found that the initial difference in weight loss
between orlistat and placebo was maintained,
although both groups regained the same
amount of weight.15 These results are consistent
with those from previous meta-analyses of
orlistat.6,21
When the meta-analysis looked at secondary
endpoint data, it found that taking orlistat was
associated with statistically significant reductions
in total cholesterol, low density lipoprotein (LDL)
cholesterol, BP, fasting plasma glucose, HbA1C,
BMI and waist circumference, although
concentrations of high density lipoprotein (HDL)
cholesterol were slightly lowered (which is less
desirable).15 It is important to remember that
these are all disease-oriented outcomes and
may not necessarily translate into an effect on
patient-oriented outcomes i.e. showing whether
patients will live longer or better.
The XENDOS study has found that orlistat plus
lifestyle changes produces a greater reduction
in the incidence of type 2 diabetes than lifestyle
changes alone.17 In this RCT, 3,305 patients with
a BMI >30kg/m2 (mean BMI 37, mean age 43
years, 79% with normal glucose tolerance and
21% with impaired glucose tolerance [IGT])
were randomised to lifestyle changes plus either
orlistat or placebo for four years. However, only
52% of the orlistat group and 34% of the placebo
group completed treatment. Using an intention
to treat analysis, the mean weight loss was
5.8kg with orlistat and 3.0kg with placebo
(P<0.001) after four years. At the end of the
study, the incidence of type 2 diabetes was 9.0%
in the placebo group and 6.2% in the orlistat
group (hazard ratio 0.63; 95% CI 0.46 to 0.86;
NNT 36). This reduction was primarily due to
benefits in the population of patients with IGT.17
We do not know yet if this reduces the likelihood
of morbidity and mortality in the longer-term.
To put the XENDOS study into context, lifestyle
changes alone can be particularly effective in
reducing the incidence of type 2 diabetes in
overweight people with IGT. In one RCT, 522
overweight people with IGT (mean age 55 years,
mean BMI 31kg/m2) were assigned to
individualised lifestyle counselling aimed at
reducing weight, improving diet and increasing
exercise, or a control group given general
lifestyle advice.22 Individualised lifestyle
counselling reduced the proportion of people
who progressed from IGT to type 2 diabetes (3%
per year in the intervention group vs. 6% per year
in the control group), with a strong inverse
relationship being seen between the incidence of
type 2 diabetes and the achievement of lifestyle
goals, such as >5% weight reduction. After four

years, the cumulative incidence of type 2
diabetes was 11% (95% CI 6% to 15%) in the
intervention group and 23% (95% CI 17% to
29%) in the control group. In absolute terms, the
NNT was eight i.e. eight overweight people with
IGT would need to undergo individualised
lifestyle counselling for four years, to prevent one
additional case of type 2 diabetes.22
Sibutramine
The BMJ meta-analysis assessed 10 RCTs
(n=2,623) of sibutramine, two of which were in
patients with controlled hypertension, and three
of which were in patients with type 2 diabetes.15
Seven RCTs looked at the effects of sibutramine
on weight loss at one year and found that
patients lost 4.2kg (95% CI 3.6 to 4.7kg) more
than those taking placebo. This is similar to the
weight loss seen in previous meta-analyses of
sibutramine.6,16 An additional 18% (95% CI 11%
to 25% of patients achieved >10% weight loss at
one year compared with placebo (NNT 6).15
Three RCTs assessed the effects of sibutramine
in maintaining weight loss for up to 18 months.
The authors found that between 10% and 30%
more patients on sibutramine than placebo
maintained at least 80% of their initial weight loss
(p<0.05 compared with placebo in all three
studies). However, it was not possible to
combine data from the studies because the
definitions of weight maintenance differed.15
With regard to secondary endpoint data,
sibutramine was associated with statistically
significant reductions in BMI, waist
circumference and triglyceride concentrations,
and increased concentrations of HDL
cholesterol.15 There are currently no fully
published RCTs of sibutramine on obesity-
related morbidity and mortality. However, the
Sibutramine Cardiovascular OUTcomes Trial
(SCOUT) is underway and is expected to report
sometime during 2008. This is a three-year
multicentre, double-blind, placebo-controlled trial
designed to evaluate the potential benefits of
weight management with sibutramine on CV
outcomes in overweight and obese patients who
are at high risk of CV events.18
Rimonabantq
Four RCTs (n=6,635) of rimonabantq in
overweight and obesity have been fully published
and were included in the BMJ meta-analysis.15 Of
these, one was in patients with dyslipidaemia,
one in patients with type 2 diabetes and the other
two included patients with dyslipidaemia or
hypertension. All the trials assessed the effects of
rimonabantq on weight loss at one year and
found that, compared with placebo, patients
allocated to rimonabantq lost 4.7kg more body
weight (95% CI 4.1 to 5.3kg). Also, compared
with placebo, an additional 19% (95% CI 15% to
23% of patients achieved >10% weight loss (NNT
5).15 A similar weight loss was reported in another
meta-analysis of rimonabantq that was published
around the same time.23
MeReC Bulletin Volume 18, Number 5
The drug management of obesity
One RCT (in patients with dyslipidaemia or
hypertension) looked at the effects of
rimonabantq on weight maintenance at two
years and found that, compared with placebo,
rimonabantq maintained the weight lost in the
first year.15
Looking at secondary endpoint data, taking There are no
rimonabantq is associated with statistically published RCTs of
significant reductions in waist circumference, BP sibutramine on
and triglyceride concentrations; as well as obesity-related
increases in HDL cholesterol. Statistically morbidity and
significant reductions in fasting blood glucose mortality
and HbA1C concentrations were also seen in the
RCT of patients with type 2 diabetes.15
There are currently no published studies of
rimonabantq looking at whether patients are
likely to live longer or better with the drug, but the
ongoing CRESCENDO study is looking at its
effects on myocardial infarction, stroke and CV
death over five years. This is due to complete in
2010.19
What are the safety and side effect data?
As might be expected by its mechanism of
action, the most troublesome adverse effects
associated with orlistat are GI-related. About
one in four patients taking orlistat are likely to
experience GI side effects and around one in 50
patients are likely to discontinue treatment
because of them.15 Fatty/oily stools, faecal
urgency and oily spotting are the most common
GI adverse events; with 15 to 30% of patients
experiencing each of these effects in most
studies.15 Orlistat should be avoided by patients
with cholestasis and chronic malabsorption
syndrome, and it is advisable to warn patients
There are
that the GI adverse effects will increase if the fat
content of their diet increases.10 Patients may currently no
wish to try a vitamin supplement (especially of published studies
vitamin D) if there is concern that they might of rimonabant
have a deficiency of fat-soluble vitamins.24 looking at whether
patients are likely
Reported systemic adverse effects with orlistat to live longer
are minimal.13 However, taking orlistat can or better with
occasionally lead to an increased or unbalanced the drug
anticoagulant effect in people taking warfarin. It
also reduces the absorption of amiodarone and
ciclosporin.10 Unlike sibutramine and
rimonabantq, there have been no Medicines and
Healthcare products Regulatory Agency (MHRA)
safety warnings about orlistat to date.
Insomnia, nausea, dry mouth and constipation
have been reported in 7–20% of patients who
take sibutramine in RCTs.15 However, of a
potentially more serious nature, sibutramine is
associated with increases in heart rate and
BP.11,15,16 Therefore, it should be avoided in CV
disease, uncontrolled hypertension and
tachycardia,11 which may limit its use in many
obese patients. The BMJ meta-analysis
reported a mean increase in systolic BP of
1.7mmHg, in diastolic BP of 2.4mmHg and in
pulse rate of 4.5 beats per minute at one year.15
5
 The drug management of obesity
However, BP can increase up to 3mmHg and
pulse rate up to 7 beats per minute, and even
greater increases cannot be excluded in
isolated cases.11 The long-term consequences
of these effects on obese patients who are
already at increased CV risk are unclear,
although sibutramine is currently not licensed
for use beyond a year. Publication of the three-
year data from SCOUT may help to provide
more clarification on this.18
Sibutramine is In 2003, the Committee on Safety of Medicines
associated with recommended that, for patients taking
increases in heart sibutramine, BP and pulse should be monitored
rate and blood every two weeks in the first three months,
pressure monthly for another three months, and at least
every three months thereafter.25 This includes
measuring BP and pulse before starting
treatment. Sibutramine should be stopped if the
resting pulse rises by 10 beats per minute or
more, or if blood pressure rises by 10 mmHg or
more during the treatment period on two
consecutive visits.11,25 In addition, patients
should be told to consult a doctor urgently if
symptoms such as progressive dyspnoea,
chest pain or ankle oedema occur.25
Because sibutramine acts on the serotonin
system, monoamine oxidase inhibitors and
serotonergic drugs (e.g. serotonin-reuptake
inhibitors) should be avoided in patients taking
this drug.11,13 This might be important when
considering several over-the-counter (OTC)
products (e.g. St John’s Wort).
In RCTs, almost 16% of patients taking
rimonabantq stopped treatment because of
adverse events, the most common of which
were nausea, mood alteration with depressive
symptoms, depressive disorders, anxiety and
dizziness.12 Concern over the risk of psychiatric
adverse effects has led to a recent warning from
the MHRA, followed by updates to rimonabant’s
summary of product characteristics (SPC)12,26 In
addition, a meta-analysis of the four fully
published RCTs has attempted to analyse the
The MHRA risk of such adverse effects with rimonabantq.23
reported that
around one in 10 The meta-analysis found that, at one year, more
people taking people taking rimonabantq than placebo
rimonabant may experienced adverse events (odds ratio [OR]
experience 1.4, P=0.0007). The number needed to harm
psychiatric side [NNH] for adverse events was 25, and for
effects serious adverse events (not defined) it was 59
(OR 1.4, P=0.03). If 100 people took
rimonabantq (under the same conditions as the
studies included in the meta-analysis) four
people would experience adverse events (and
two of those four people would experience
serious adverse events) who would not have
done if all had taken placebo. Further analysis
found that withdrawals from the study due to
depression or anxiety were more likely in
patients receiving rimonabantq than placebo
(depression: OR 2.5, P=0.01, NNH 49; anxiety:
OR 3.0, P=0.03, NNH 166).23
6 MeReC Bulletin Volume 18, Number 5
The BMJ meta-analysis reported similar results
with regard to safety, concluding that
rimonabantq caused significantly more general
and serious adverse effects than placebo,
especially of nervous system, psychiatric or GI
origins.15
It is possible that these meta-analyses do not
represent the true risk of psychiatric adverse
effects with rimonabantq because trials did not
report detailed data on the rates of psychiatric
adverse effects experienced by participants.
Also, obese people often suffer from
depression,23 but patients with clinically
significant psychiatric disease or psychological
illness were specifically excluded from most of
the rimonabantq RCTs.27,28
In July 2007, the MHRA reported that around
one in 10 people taking rimonabantq may
experience psychiatric side effects and around 1
in 100 may experience suicidal thoughts. The
MHRA warned that rimonabantq must not be
used by patients with major depression or those
being treated with antidepressants, because of
the risk of psychiatric side effects.26 In addition,
patients should be told about the need to look
out for such symptoms and to seek medical
advice immediately if they occur.12 Since
rimonabant is a black triangle q drug, all
suspected adverse reactions should be reported
to the MHRA through its Yellow Card Scheme.
How should anti-obesity drugs be used?
NICE emphasises that drugs should be
prescribed only as part of an overall plan for
managing obesity. This includes having
arrangements in place to provide patients with
information, support and counselling on
additional diet, physical activity and behavioural
strategies. Treatment should be reviewed
regularly to monitor for effectiveness, adverse
effects and adherence, and lifestyle advice
should be reinforced at the same time.5
NICE recommends that treatment with orlistat or
sibutramine for longer than three months should
be considered only if the person has lost at least
5% of their initial body weight since starting drug
treatment.5 Orlistat may be continued for longer
than a year, but only after discussing its risks
and benefits with the patient. However,
sibutramine treatment is not recommended
beyond the licensed duration of a year.5
Rimonabant’s safety and efficacy has not been
established beyond its licensed duration of two
years.12 The NICE technology appraisal (in
progress) will provide more guidance on how
rimonabantq should be used.
Support should be given to patients who
withdraw from treatment as they may have low
self-confidence, especially if they did not reach
their target weight. People with type 2 diabetes
may lose weight more slowly and so less strict
goals may need to be agreed. It should be
 The drug management of obesity

remembered that drug treatment can be used to
help maintain weight loss as well as to help
people to continue to lose weight.5 Patients may
regain weight once anti-obesity drugs are
stopped.
For more comprehensive information on the
prescribing details for each drug, including
contraindications, precautions, drug interactions
and adverse effects, please refer to their
individual SPCs.10,11,12
Conclusion — which drug should be used?
Lifestyle changes are the mainstay of obesity
management. For population benefits, it is worth
encouraging people to eat a little less and move
a little more. When anti-obesity drugs are used in
addition to lifestyle measures, they seem to have
a modest effect, leading on average to about a 3
to 5kg greater weight loss than placebo plus
lifestyle measures at one year. However, obesity
is a long-term problem and long-term morbidity
and mortality data on these agents are currently
limited. Also, no drug is ideal in terms of its
safety/tolerability profile. Therefore, the choice of
drug used for managing overweight and obesity
should be based on a careful consideration of the
potential risks and benefits of each agent in
individual patients — bearing in mind important Considering each
safety concerns from the MHRA, NICE drug in terms of
guidance, and the licensed recommendations for its Safety,
each drug. Considering each drug in terms of its Tolerability,
Safety, Tolerability, Efficacy, Price and Simplicity Efficacy, Price and
of use (STEPS) can help prescribers to make an Simplicity of use
informed decision around which one to use (STEPS) can help
(Table). The results from long-term morbidity and prescribers to
mortality studies of sibutramine and make an informed
rimonabantq, and fully published guidance from decision around
NICE on rimonabantq, are awaited and may which one to use
further help to determine the place of each agent
in the management of overweight and obesity.

Table. A summary of the anti-obesity drugs10–12,15–17,23,25,26,29

Price
Safety Tolerability Efficacy Simplicity of use
28 days
Orlistat 4-year RCTs Poor Type 2 diabetes £33.58 Oral – take three times a
One in four people prevented day
Licensed duration Reported serious have GI side-effects (9%vs 6.2%17)
unlimited adverse events Must take with meals
minimal or rare (<0.1% Weight loss 2.9kg (< 1hr after)
of patients) at 1 year
Additional contraceptive
NNT for 10% recommended if severe
weight loss at diarrhoea and using an
1 year = 8 oral contraceptive
(95% CI, 7–11)
Sibutramine 2-year RCTs Insomnia, nausea, dry Weight loss 4.2kg £25.00 Oral – take once daily
mouth and constipation at 1 yr
Licensed up to one MHRA warning on in 7–20% of patients Monitor BP and pulse at
year increased BP and NNT for 10% baseline and at least
heart rate weight loss at every three months
1 year = 6 (more frequently for first
(95% CI, 4–9) six months).

Rimonabantq 2-year RCTs Almost 16% of patients Weight loss £44.00 Oral – take once daily
stopped rimonabant 4.7kg at 1 yr
Licence states safety MHRA warning 1 in due to adverse events Monitor for psychiatric
and efficacy have not 10 people may have (most commonly NNT for 10% adverse effects
been evaluated psychiatric adverse nausea, mood weight loss at
beyond two years effects NNH 10 alteration with 1 year = 5
depressive symptoms, (95% CI, 4–7)
depressive disorders,
anxiety and dizziness).

Adverse events NNH

25

Serious adverse
events NNH 59

NB The data within each section are not always directly comparable. For example the NNTs for 10% weight loss are not taken from
RCTs directly comparing one agent with another. Therefore, the populations and trial conditions are likely to have varied between
the different trials. Similarly the tolerability data have been expressed in different ways in the trials.

MeReC Bulletin Volume 18, Number 5 7

 The drug management of obesity

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