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Aetiology
Assessing the
obese patient
Lifestyle changes
Very low energy
diets
Pharmacotherapy
The author
PROFESSOR JOSEPH
PROIETTO,
Sir Edward Dunlop Medical
Research Foundation Professor
of Medicine at the University of
Melbourne and Repatriation
Hospital, Heidelberg, Victoria.
OBESITY in adults
Background
OBESITY is now a major health
issue in Australia and around the
world, and the prevalence of overweight has been rising steadily. Of
great concern is that childhood obe-
sity has now reached alarming rates.
The multiple comorbidities associated with, or caused by, obesity
make the condition an increasing
burden on the health system. Public
Australian Doctor presents
Wealth
Creation
health measures attempted so far
have failed to stem the rise in the
prevalence of obesity, and the longterm outcomes of individualised
treatments are generally poor. Why is
obesity so difficult to treat?
Definition and prevalence
Obesity is a state in which there is
cont’d next page
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HOW TO TREAT Obesity in adults
from previous page
excess storage of fat in the
body. Three measurements
need to be made to make
two complementary assessments of excess weight.
• Weight (kg).
• Height (m), from which
can be calculated the BMI:
weight divided by the
square of the height
2
(kg/m ).
• Waist circumference (cm).
The clinical state defined by
the BMI is shown in table 1.
Excess fat can be deposited
in different areas of the body.
There is almost certainly a
genetic predisposition to
where fat is deposited. A dramatic example of genetic
regional fat distribution is
the large gluteal fat deposit
in people from the Hottentot tribe in Africa. From a
health point of view, two
major types of fat distribution are important — central
abdominal (android) and
gluteal-femoral (gynoid).
It is the central abdominal
obesity that is generally associated with features of the
metabolic syndrome.
The International Diabetes
Federation (IDF) definition
of the metabolic syndrome
places waist circumference as
the essential feature (males
94cm, females 80cm) plus
any two of the following
Table 1: Clinical state according to BMI
BMI (kg/m )
Clinical state
<18
Underweight
18-24.9
Normal weight
25-29.9
Overweight
30-40
Obese
>40
Severely (morbidly) obese
2
Table 2: Prevalence of overweight, obesity, diabetes
and the metabolic syndrome in Australia
Prevalence
Overweight and obesity
(BMI 25kg/m2)
Males: 67.5%
Females: 52.1%
Obesity (BMI ≥30kg/m2)
Males: 19.3%
Females: 22.3%
Diabetes
Adult population (>25
years): 7.2%
four features:
• Triglyceride level ≥ 1.7
mmol/L.
• Reduced HDL-cholesterol
level (<1.03mmol/L in
males and <1.29mmol/L in
females).
• Hypertension (blood pressure >130mmHg systolic
or >85mmHg diastolic or
patient receiving treatment
TO understand the aetiology
of obesity it is necessary to
briefly explain the regulation
of body weight. The central
regulator of weight is the
hypothalamus. The complex
details of how weight is regulated are not within the
scope of this article but there
have been many reviews on
the subject.
Briefly, neurones in the
arcuate nucleus produce
compounds that induce
hunger. These include neuropeptide Y (NPY) and agoutirelated peptide (AGRP).
Adjacent neurones produce
cocaine-and-amphetamineregulated transcript (CART)
and alpha-melanocyte-stimulating hormone (αMSH),
which powerfully inhibit
food intake.
These neurones project to
other areas of the hypothalamus and in turn receive signals from them and from the
brainstem. Overall there is a
mechanism that stimulates
and one that inhibits food
intake. Whether we have the
drive to eat (hunger) or to
Table 3: Hormones involved in regulating body weight
Condition
Metabolic syndrome
Aetiology
Adult population (>25
years): 30.7%
for hypertension).
• Fasting plasma glucose
level ≥5.6 mmol/L or previously diagnosed type 2
diabetes.
The prevalence of these
disorders is rising.
Prevalence of overweight,
obesity, diabetes and metabolic syndrome in Australia
are shown in table 2.
Hormone
Origin
Function
Ghrelin
Stomach
Stimulates hunger
Leptin
Adipose tissue
Inhibits hunger
Cholecystokinin
Upper gut
Induces satiety
Peptide YY
Lower gut
Induces satiety
Glucagon-like peptide 1
Lower gut
Reduces hunger, slows gastric emptying
Oxyntomodulin
Lower gut
Reduces hunger
Amylin
Pancreatic beta cell
Reduces hunger
Pancreatic polypeptide
Islet cell
Reduces hunger
Insulin
Pancreatic beta cell
Reduces hunger
PLEASE REVIEW PRODUCT INFORMATION BEFORE PRESCRIBING. PRODUCT INFORMATION CAN BE FOUND IN THE PRIMARY ADVERTISEMENT IN THIS PUBLICATION.
PBS Information: Restricted benefit. For single maintenance and reliever therapy in a patient who experiences frequent asthma
symptoms while receiving treatment with oral corticosteroids or inhaled corticosteroids or a combination of an inhaled corticosteroid and a long
acting beta-2-agonist (Symbicort 400/12 is not recommended nor PBS subsidised for use in maintenance and reliever therapy).
22
| Australian Doctor | 31 July 2009
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AD_ 0 2 3 _ _ _ J UL 3 1 _ 0 9 . p d f
not eat (anorexia) depends
which of these systems is
dominating at the time.
The balance of this central system is strongly influenced by circulating hormones that originate in fat,
the gut and the pancreas.
These are shown in table 3
and figure 1.
Obesity has a complex
aetiology. Studies in identical
twins raised apart suggest
that about 70% of the variance in body weight is
genetic, while 30% is environmental. This was confirmed by adoption studies
that found no relationship
in body weight between
adopted individuals and that
of their adoptive parents. In
contrast there was a statistically significant relationship
between the body weight of
adopted subjects and that of
their biological parents.
So far, more than five
genes have been identified
that, when mutated, can lead
to massive obesity. These
include:
• Leptin.
• The leptin receptor.
• Pro-opiomelanocortin
(POMC).
• Prohormone convertase
(the enzyme that cleaves
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Table 4: Consequence of obesity and related
conditions
System
Condition
Metabolic
Type 2 diabetes, dyslipidaemia,
hyperuricaemia, insulin resistance
Immunological
Low-grade inflammatory state
Respiratory
Obstructive sleep apnoea,
asthma
Cardiovascular
Increased risk of ischaemic
heart disease, hypertension and
stroke
Figure 1: Weight-regulating mechanisms, with a mouse brain in the background.
Cerebral cortex:
conscious will
Opioids
Dopamine
Endo-cannabinoids
Gastrointestinal
Non-alcoholic steatohepatitis, reflux
oesophagitis, gallstones
Orthopaedic
Back pain, osteoarthritis
Dermatological
Acanthosis nigricans, skin tags,
intertrigo
Arcuate nucleus:
NPY CART
AGRP αMSH
Paraventricular
hypothalamic
nucleus:
Oxytonin CRH
Brainstem
Lateral
hypothalamus:
Orexin MCH
Ghrelin
PYY 3-36
PP
Reproductive
Polycystic ovary syndrome
Renal
Proteinuria
Oncology
Increased risk of cancers of breast
and bowel
Psychosocial
Depression, social discrimination,
social isolation, binge-eating
disorder, bulimia
CCK
Leptin
Insulin
FOOD
INTAKE
Amylin
ENERGY
EXPENDITURE
GLP-1
Oxyntomodulin
POMC to make αMSH).
• The receptor for αMSH,
the melanocortin-4 receptor (MCR4).
AGRP = agouti-related peptide; CART = cocaine-and-amphetamine-regulated transcript;
CCK = cholecystokinin; CRH= corticotropin-releasing hormone; GLP-1 = glucagon-like peptide 1;
MCH = melanin-concentrating hormone; αMSH = alpha-melanocyte-stimulating hormone;
NPY = neuropeptide Y; PP = PP peptide family; PYY3-36 = one of the two major forms of gut peptide YY
Source: Adapted from Proietto J. Why staying lean is not a matter of ethics. Medical Journal of Australia 1999;
171:611-13. ©Copyright 1999. The Medical Journal of Australia — reproduced with permission.
Effects on health
Obesity has many health
consequences that can
impact on different organs
(table 4). The most important of these is type 2 diabetes and its precursor,
insulin resistance. The major
cause of insulin resistance is
excess fat accumulation in
various tissues.
cont’d next page
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31 July 2009 | Australian Doctor |
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HOW TO TREAT Obesity in adults
Assessing the obese patient
expenditure can be calculated.
WHEN a patient presents for management of obesity or indicates, after
your initiative, that they are ready to
attempt to lose weight, the following
structured set of procedures should
be routinely undertaken.
Examination
History
A thorough history should be taken
that documents some of the following
information:
• Age of onset of obesity.
• Precipitating factors (if any).
• Peak weight and lowest adult
weight.
• Previous weight-loss attempts.
• Maximum weight previously lost
and how.
• Previous use of pharmacotherapy
for obesity.
• Past medical history.
• Family history of obesity, diabetes,
cardiovascular disease.
• Systems review:
— cardiovascular system: for
example, chest pain, shortness
of breath, orthopnoea, swelling
of ankles
— respiratory system: especially
symptoms of obstructive sleep
apnoea
— CNS: any headaches
— GI system: reflux oesophagitis
— arthritis
— in females: symptoms and signs
suggestive of polycystic ovary
syndrome (irregular periods,
acne, hirsutism, infertility).
• Social history.
It is my practice not to take a
detailed dietary history. Generally the
information obtained is not accurate.
If a patient has stable weight, caloric
intake equals energy expenditure.
As there is a linear relationship
between weight and energy expenditure, caloric intake can be calculated
from the patient’s weight. There are
tables available from which energy
A targeted examination follows. This
includes:
• Measurement of height and weight,
from which can be calculated BMI.
Measure waist circumference in
men and waist and hip circumference in women.
• Blood pressure after a few minutes’
rest.
• Neck circumference.
• Look for acanthosis nigricans in
hands and neck and for skin tags
on the neck (these are markers of
insulin resistance).
• Examine the heart, with particular
attention to cardiac murmurs, as
previous weight-loss medications
caused valve lesions in some
patients.
• Listen to the lungs.
• Examine the abdomen, with particular attention to the possible
presence of hepatomegaly and a
fatty apron.
• In older patients it is important to
check for peripheral vascular disease.
Investigations
Request investigations. As a matter
of routine these should include:
• Fasting glucose.
• Lipids (total cholesterol, triglycerides and HDL-cholesterol).
• Uric acid.
• LFTs.
• Electrolytes, urea and creatinine.
• Any other investigations suggested
by the history.
Note that endocrine conditions
associated with weight gain, such as
hypothyroidism and Cushing’s syndrome, generally do not result in
marked weight gain, so thyroid function tests and urinary free or salivary
cortisol do not need to be measured
routinely.
Similarly it can be assumed that
all obese patients are insulin resistant,
so measuring insulin levels has limited clinical value.
Management
FOR many years it has been
advocated that weight loss
should be achieved by a
change in lifestyle with a
reduction in caloric intake and
an increase in physical activity. For some time there was
controversy regarding whether
the diet should be high in protein, low in fat or high in complex carbohydrates. However
recent evidence suggests that
the composition of the diet is
not important, provided it
leads to a decrease in caloric
intake.1 There is a large body
of literature suggesting that
group support is important
and that exercise should
always be a component of the
weight loss program. In addition to lifestyle modification
some others have advocated
use of low or very-low-energy
diets and/or pharmacotherapy.
However, the ‘Holy Grail’
of obesity management is not
achieving weight loss but successfully preventing weight
regain. There is overwhelming
evidence that most people who
lose weight eventually regain
it. Some can maintain weight
loss for longer than others,
possibly because of their personality type or their enthusiasm for vigorous exercise.
Nonetheless, if viewed at five
years after the initial weight
loss, most have regained all the
weight lost.
Why would someone who
is very motivated to lose
weight, regain the weight
after working hard to
achieve weight loss?
There is now growing evidence that weight is strongly
defended. In the previous
section, the circulating hormones that influence hunger
were discussed. Table 3
(page 22) shows that the
vast majority of circulating
regulators inhibit food
intake, with only one (ghre-
24
The ‘Holy Grail’
of obesity
management is
not achieving
weight loss
but successfully
preventing
weight regain.
account these facts is destined
to long-term failure.
Thus it does not matter
which type of program is used
to achieve weight loss — commercial weight loss centres,
mixed reduced-calorie diets,
low-carbohydrate diets, diet
plus exercise, diet plus behaviour modification or very-lowenergy diets can all be used to
achieve weight loss, provided
there is a period where energy
intake is less than energy
expenditure. But how do we
prevent weight regain? This is
where we need more assistance and is the area of major
failure.
Lifestyle changes
lin) so far found to stimulate
hunger.
It has been shown that after
weight loss, leptin, insulin and
cholecystokinin levels decrease
while ghrelin level rises, leading to increased drive to eat.
Also, it has been long known
that energy expenditure
decreases after weight loss.
This is due to the combination
of reduced body mass and
reduced metabolic rate, possibly partly due to thyroxine
(T4) being converted to the
inactive reverse triiodothyronine (reverse T3) instead of the
active hormone triiodothyronine (T3).
It is not known if the rate
of weight loss influences these
hormonal adaptations, but
there seems to be no evidence
to indicate that that these hormonal changes can be modulated by type of diet. Any program that does not take into
| Australian Doctor | 31 July 2009
A recent large study has
shown that the type of diet an
individual follows does not
affect the success of achieving
weight loss.1 The important
fact is to reduce energy intake
below energy expenditure; the
larger the gap, the more rapid
the weight loss.
It is useful to discuss with
patients the preferred method
to achieve weight loss. In general, the full range of available
strategies should be given to
patients so they can make the
choice that best fits in with
their lifestyle and their temperament.
Patients who have not made
previous attempts at weight
loss should be advised to
follow a calorie-reduced
lifestyle-change program. In
contrast, a severely obese
patient who has undergone
many cycles of weight loss followed by weight regain may
be best steered towards the
very-low-calorie program
described below.
In general, most doctors are
not qualified to give detailed
dietary advice, so if the patient
chooses a mixed reduced-calorie diet or a low-carbohydrate
diet it is advisable to refer the
patent to a qualified dietitian.
If the patient chooses a verylow-energy diet, dietitian referral is not essential at this stage,
as the diet is very prescriptive;
however, referral will become
important as the patient exits
the rapid-weight-loss phase.
Very low energy diets
Very low energy diets (VLED)
are “shakes” or bars that are
composed of small quantities
of carbohydrate and protein
and contain essential vitamins,
minerals, fatty acids and
amino acids. Generally each
shake or bar has 150-200
calories (600-800 kJ) and
approximately one third of
daily vitamin and mineral
requirements. They are used
to replace two or three meals
per day.
These diets should be considered when:
• There is morbid obesity.
• When there have been multiple previous attempts at
weight loss with conventional diets.
• When it is necessary to have
rapid weight loss.
• In the presence of significant
comorbidities such as
obstructive sleep apnoea or
uncontrolled type 2 diabetes.
• When waiting for surgery
that is conditional on losing
weight.
Contraindications to use of
a VLED approach include:
• Pregnancy.
• Advanced age.
• History of severe psychological disturbance.
• Alcoholism or drug abuse.
• Presence of porphyria.
• Recent MI or unstable
angina.
Starting a patient on a VLED
The overall strategy with these
diets is to have a period of
weight loss (this can last 3-12
months) followed by a vigorous weight maintenance pro-
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gram that includes diet, exercise, lifestyle change and, if
necessary, pharmacotherapy.
The VLED provides the
patient with 3280 kJ (800
calorie) daily energy intake
and ensures intake of all essential vitamins, minerals, essential fatty acids and amino
acids. The diet has a low carbohydrate and fat content.
The low carbohydrate
intake leads to mild ketosis
within a few days. There is
increasing evidence that ketosis
reduces hunger. The mechanisms are not known but it is
known that ketones are easily
metabolised by the brain (and
the heart) and it has been
shown that ketones stimulate
cholecystokinin release.
Provided the patient avoids
carbohydrate intake during
this weight loss phase, they
will not experience hunger
after the first week. It is therefore my view that pharmacotherapy is not necessary
during this phase.
In addition to the three
VLED shakes or bars to
replace each of the three
meals, the patient is advised to
have a bowl of vegetables or a
salad in the evenings to provide roughage and to avoid
constipation. Extra fibre may
be needed if constipation
occurs.
It is essential to use one
tablespoon of oil (preferably
olive oil) on the vegetables to
trigger the gallbladder to
empty once daily. In very large
patients some protein in the
form of meat or fish is advisable once daily in addition to
the VLED and the evening
vegetables.
Some individuals cannot
face the prospect of not having
at least one meal a day. In
these cases, two meals can be
replaced with VLED meal
replacements. To achieve the
ketotic state it is imperative
there is no calorie intake in
between meals, and the one
meal a day must consist of
some protein (meat, fish or
egg) plus vegetables or a salad.
Clearly variations on this
theme are possible, such as
replacing three meals during
the week and having one meal
on weekends or on special
occasions. This is fine provided
the ketosis is not broken by
the ingestion of carbohydrate.
When it has been decided to
start a VLED regimen, the
patient should be given written
instructions and told of the
general strategy of the program. The importance of
achieving mild ketosis to suppress hunger should be
emphasised and patients
encouraged to avoid carbohydrate when hungry. Advise
them to have lean meat or fish
instead in the first week before
the onset of ketosis.
Great care must be taken
when starting diabetic patients
on a VLED if they are on any
insulin-raising therapies such
as sulphonylureas or insulin.
A rule of thumb is to stop the
sulphonylureas but continue
metformin and/or thiazolidenedione. If the patient is on
insulin, reduce the insulin dose
to half and ask the patient to
do more frequent testing for
the first week and to modify
insulin dose accordingly.
Advice from or referral to a
specialised clinic may be advisable for some patients.
Follow-up
After starting on a VLED the
patient should be followed up
every two weeks for advice
and encouragement. Blood
tests should be repeated
midway through the VLED
phase. At the end of the VLED
phase, the patient is started on
a maintenance program (see
below).
cont’d page 26
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HOW TO TREAT Obesity in adults
It is becoming
increasingly clear
that severe
obesity is a
chronic incurable
condition with a
biological basis.
from page 24
Blood tests during a VLED
Careful supervision of patients
on VLED is important because
of the potential for serious
consequences while on these
diets. There have been very
few electrolyte imbalances
using the modern VLED programs. I am aware of three
cases of hyponatremia over the
last 12 years of use, probably
due to the over enthusiasm of
the patients to drink water.
There are many VLED products on the market and not
all are suitable for the complete replacement program
described here.
Baseline blood tests: These
include electrolytes, urea and
creatinine, LFTs, fasting glucose, cholesterol/triglycerides/
HDL-cholesterol, uric acid,
FBC and iron studies.
Follow-up blood tests: Electrolytes should be checked
every 4-6 weeks throughout
the VLED regimen or earlier
if required by the patient’s condition (eg, patients with renal
impairment, because of the
risk of electrolyte imbalance
[in fact patients with severe
renal failure requiring dialysis
should only be treated in specialist units]).
How long should a patient
continue on a VLED?
Usually patients continue on
VLED for at least 12 weeks.
However, this period is variable and depends on the
patient’s ability to tolerate the
VLED. It is not necessary for
patients to get to the goal
weight with one period of
VLED use. They may have
repeated periods of use separated by periods of weight
maintenance. However it is
my experience that it is always
difficult to go back on a
VLED after having been on
one for some time. Hence, if
the patient is willing, it is best
to continue the VLED for as
long as it is successful.
Finishing the VLED
The patient is weaned off the
VLED over a period of two
months. At this time the input
of a dietitian familiar with the
overall strategy is obtained.
The patient is starting to introduce a normal diet and the
type of meals chosen becomes
important. The patient has
two VLED meal replacements
and one specified meal a day
for four weeks, followed by
four weeks of one VLED meal
replacement and two specified
meals a day for two weeks.
After two months the
patient should be following a
diet that is low in fat but is no
longer ketogenic, such as the
CSIRO diet. In addition the
patient is encouraged to undertake as much exercise as he or
she can do. Any exercise is
beneficial to health but to be
sustained it should fit in easily
with the patient’s lifestyle and
preferably be enjoyed by the
patient. The aim in this phase
is weight maintenance, not
26
topiramate are effective long
term. Sibutramine has a twoyear study showing effectiveness at weight maintenance at
two years. At this time, the
sibutramine group had on
average regained 2kg while the
placebo group had regained
10kg.6 Later in 2009 we will
have the results of the Scout
study, a five-year study on the
long-term safety of sibutramine. However this study
was not designed to assess efficacy at weight maintenance.
There are no long-term trial
data on topiramate but the
epilepsy literature may inform
us on both safety and efficacy
as these patients are on this
medication long term.
Surgery
weight loss. If weight loss continues it is a bonus.
Patients are then followed
carefully, initially at monthly
intervals. If the weight loss is
maintained, the lifestyle regimen is continued and gradually the interval between visits
is increased to three monthly.
If the weight is starting to
rise again (1-2kg weight
regain) or the patient reports
difficulty with controlling food
intake, consideration should
be given to starting drug therapy to assist with maintaining
weight loss.
Pharmacotherapy
It is becoming increasingly
clear that severe obesity is a
chronic incurable condition
with a biological basis. As
such it is legitimate to consider
long-term chronic treatment
for the condition. However,
the problem with chronic
treatment is that the long-term
safety of most currently available drugs has not been
proved.
Noradrenergic agonists
Centrally acting adrenergic
agonists
(phentermine
[Duromine] and diethylpropion [Tenuate Dospan]) have
previously been in use for
many years. Diethylpropion is
no longer available in Australia. These agents work by
reducing hunger and possibly
stimulating energy expenditure.
Side effects include hypertension, impaired sleep and
dry mouth. Their long-term
safety has not been tested. Furthermore, when given to
patients taking phentermine,
fenfluramine caused cardiac
valvular abnormalities in some
patients. As a result, fenfluramine and dexfenfluramine
were withdrawn from the
market.
Serotonergic agonists
This class of agents includes
the SSRIs, generally used for
the treatment of depression.
These include fluoxetine, fluvoxamine, paroxetine and sertraline. Of these, studies have
been performed on the weight
loss effects of fluoxetine only.
Overall it can be concluded
that fluoxetine does have an
effect on food intake and
| Australian Doctor | 31 July 2009
weight, but it is more modest
than the effects that were seen
with either dexfenfluramine or
fenfluramine.
Orlistat
This agent’s action is to inhibit
intestinal lipase. It has been
shown that orlistat (Xenical)
reduces fat absorption by
30%. In a one-year clinical
study, weight loss of 9kg was
reported in the orlistat group,
compared with 5-6kg for the
placebo-treated group.2 Both
groups were treated with diet
and exercise in addition to the
tablets.
In a two-year, double- blind,
randomised placebo-controlled
trial conducted in 15 European centres, 743 patients
were randomised to treatment
with orlistat 120mg or placebo
three times daily.3 At one year
there was a significantly higher
degree of weight loss with orlistat compared with placebo.
The orlistat-treated group had
a 10.2% decrease from initial
body weight, compared with
6.1% for placebo. A slight
weight increase occurred in all
groups during the second year,
when physician visits were less
frequent.
The XENDOS (XENical in
the Prevention of Diabetes in
Obese Subjects) study, published in 2004, reported that
orlistat was safe for long-term
use and that at four years, it
reduced the risk of developing
diabetes by 37.3% in the
whole group of study subjects
and by 45% in those who had
impaired glucose tolerance at
the start. At 12 months, subjects randomised to orlistat
had lost 10.6kg compared to
the placebo group who lost
6.2kg (p <0.001). At four
years, the orlistat-treated
group had regained 4.8kg
while the placebo group had
regained 3.2kg.4
As can be expected from an
agent that works to inhibit fat
absorption, orlistat has the
potential to cause steatorrhoea. In clinical trials, most
patients had only one or two
episodes of fatty stool, generally in the early part of treatment. This suggests that the
patients learnt that they developed steatorrhoea if they ate
more than 30g of fat a day.
That patients can recognise if
they have eaten more than 30g
of fat per day is one of the
beneficial effects of this agent.
Another possible side effect
is a deficiency of vitamins. In
two-year studies mean levels
of vitamins A, D, E and K and
of betacarotene all remained
within the normal reference
range in each treatment group,
despite the values being generally marginally lower in the
treatment groups, compared
with placebo. Vitamin supplementation was given to any
patient whose levels were
below the normal range.
Sibutramine
Sibutramine (Reductil) is a tertiary amine whose secondary
and primary amine metabolites inhibit both serotonin and
noradrenaline reuptake. Originally developed as an antidepressant, it was soon noted in
clinical trials that it was more
active in causing weight loss
than in relieving depression.
Because of its dual action,
sibutramine acts like the combination of phentermine (an
adrenergic agonist) and fenfluramine or dexfenfluramine
(serotonin agonists). Animal
studies have shown that activating both adrenergic and
serotinergic neurones has a
more powerful effect to reduce
food intake than each agent
alone.
Controlled studies have
shown that sibutramine produces dose-related weight loss
with optimal doses of 1015mg/day. Weight loss with
sibutramine over six months
is 3-5kg better than with
placebo, an effect that is maintained for at least 12 months.
Because of its adrenergic
action, sibutramine may
increase heart rate and blood
pressure. However, clinical
studies have shown that the
effect on blood pressure is not
marked. Other side effects
include dry mouth, constipation and insomnia.
Sibutramine is a serotonin
and noradrenaline reuptake
inhibitor (SNRI) so it cannot
be used in conjunction with
other SNRIs or SSRIs. It is
theoretically possible that the
combination may increase
serotonin levels, leading to
valve lesions or pulmonary
hypertension.
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However, studies on this
question are needed, as these
agents are reuptake inhibitors
and not stimulators of serotonin release.
Topiramate
Topiramate (Topamax) is an
anti-epileptic drug currently
available in Australia on
authority prescription for difficult-to-control epilepsy and for
migraine prophylaxis. It was
found that the drug has a
powerful effect in suppressing
appetite, with the common
side effect of weight loss. Several studies to assess the use
of topiramate in the management of obesity were undertaken, proving its efficacy;
however, development for this
indication is not proceeding
presently.5
The effective dose for
weight loss seems to be 25100mg/day. Side effects include
depression, difficulty concentrating, closed-angle glaucoma
(rare) and paraesthesia
(common). Suicidality is a concern with agents that can cause
depression, and care must be
taken to assess the patient’s
mood. Topiramate can be considered for use ‘off-label’ in the
management of severely obese
patients in whom sibutramine
is contraindicated (eg, arrhythmia or pulmonary hypertension).
Weight maintenance
It is my view that pharmacotherapy is not necessary for
weight loss but is essential for
weight maintenance after
weight loss, to counter the
physiological adaptations that
occur that lead to weight
regain.
For weight loss all the available agents may have a role if
necessary, but for weight maintenance the only two agents
that should be considered are
sibutramine and topiramate
(off-label use). This is because
there are no data on the longterm safety for phentermine
and diethylpropion, and orlistat does not address the main
reason for pharmacotherapy
— the control of hunger.
It must be stated that while
appetite suppressants are the
appropriate class of agents that
are needed, we still await evidence that sibutramine and
If the above medical approach
fails and the patient has a BMI
>40kg/m 2, or >35kg/m 2 in
conjunction with significant
obesity-related comorbidities,
consideration should be given
to bariatric surgery. In Australia the most common procedure has become laparoscopic
adjustable gastric banding.
The only other procedure
performed routinely is Roux
en Y gastric bypass. This procedure is generally done as an
open operation but in some
experienced centres it is performed laparoscopically. Some
centres are now performing
the sleeve gastrectomy but it
is too early to know the longterm effectiveness of this less
aggressive procedure.
Gastric balloons are available but can only be seen as a
temporary measure, possibly
to achieve enough weight loss
to make the more definitive
procedure safer. This is
because they need to be
removed after six months.
Bariatric procedures are
complex to manage both
before and after surgery and
must be done within a multidisciplinary setting that offers
comprehensive follow-up.
Prevention
Obesity is one condition for
which prevention is better than
cure. Given the growing evidence that weight is defended
by vigorous physiological
mechanisms, it is likely that
secondary prevention will not
be successful. We must therefore focus on primary prevention in children.
Monogenic forms of obesity,
such as leptin deficiency or
melanocortin-4 mutations
cannot be prevented. However,
possible epigenetic obesity precipitated by the intrauterine
environment (maternal malnutrition in the first trimester or
over-nutrition in the last
trimester) or the food that we
feed our babies can all be
modified.
Future research will determine all the genetic and epigenetic mechanisms leading to
obesity. In the meantime, parents can help their children by
encouraging physical activity
(eg, school sport) and avoid
feeding them high-fat/highsugar foods.
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Overall summary
cise should be first attempted for maintenance, but the patient must be monitored
carefully, as significant weight regain is
disheartening.
A weight regain of only 1-2kg should
be the trigger to offer the patient pharmacotherapy to assist with hunger control. The first choice is currently sibutramine and, if contraindicated, the
second choice is topiramate. If medical
therapy fails, bariatric surgery should be
considered.
OBESITY is a chronic organic condition
that, once established, is difficult to
reverse.
There are many roads to weight loss,
including low-fat and low-carbohydrate
diets, commercial weight-loss programs,
doctor-supervised VLED programs and
pharmacotherapy. The best road should
be selected in consultation with the
patient.
When the realistic target is reached,
lifestyle change involving diet and exer-
Practice points
• Have a good set of scales that can accurately measure at least
250kg.
• Have an extra-long tape measure to assess waist circumference.
• Learn about the biology of body weight regulation.
• If you have a practice nurse, train them to weigh the patient and
measure waist circumference.
• Familiarise yourself with the contraindications of sibutramine and
topiramate.
• Do not discharge the patient, as obesity is chronic and requires
long-term follow-up.
What not to miss
Evidence-based practice
forget to stress the role and reason for
the development of ketosis.
• Check if the patient has depression or
is taking antidepressants. If so, consider early referral for bariatric surgery,
especially if there have been many
previous attempts at weight loss.
Sibutramine is contraindicated if the
patient is taking an SNRI or SSRI and
topiramate can cause depression.
• In the clinical assessment, do not fail
to seek evidence of obstructive sleep
apnoea.
• Make sure to ask about previous
weight-loss attempts and outcomes.
• Always assess the patient for diabetes,
dyslipidaemia and hypertension.
• If choosing a VLED or low-carbohydrate diet approach to weight loss, do
not
2-4
• Pharmacological agents can assist with weight loss.
• Twin and adoption studies have concluded that most of the variance
7-9
in body weight in the population can be attributed to genetic factors.
• Very few obese subjects can maintain weight loss for more than 3-5
10
years.
• There are co-ordinated physiological changes that encourage
9-11
weight regain after weight loss.
14
• Bariatric surgery is currently the best therapy for severe obesity.
Author’s case study
MRS AB, 66, was referred to
the weight-control clinic in
February 2007 for management of obesity. She said she
had been obese all her life,
with a gradual increase in
weight.
She had held her presenting
weight for the previous six
years. Her peak weight was
131kg and her lowest weight
as an adult was 100kg. In the
past she had tried various
diets, commercial weight-loss
centres and over-the counter
alternative therapies obtained
from her local pharmacist.
None of these approaches had
been very successful.
She gave a past history of
right knee osteoarthritis and
right hip pain. Both of her
parents and one brother were
obese but there was no
family history of diabetes,
dyslipidaemia, hypertension,
ischaemic heart disease or
stroke.
On systematic questioning
she denied chest pain but had
some shortness of breath on
exertion and possibly some
orthopnoea. She had a history
of swelling of her ankles but
no claudication. She was a
non-smoker.
Surprisingly, there was no
history suggestive of obstructive sleep apnoea. In particular
she gave no history of snoring, frequent waking or excessive daytime somnolence.
There was no history of reflux
oesophagitis or polycystic
ovary syndrome.
She was taking meloxicam
7.5mg for pain and was also
taking ‘metabolism boost’,
fish oil, celery, glucosamine,
calcium and magnesium. She
is a retired nurse, married and
lives with her husband. Examination revealed:
• Weight: 131.7kg.
• Height: 1.66m.
2
• BMI: 47.8kg/m .
• Waist
circumference:
143cm.
• Hip circumference: 148cm.
References
Figure 2: Weight loss rate and long-term maintenance with the assistance of sibutramine.
Dates: 1 = 9/2/2007; 11 = 16/11/2007; 21 = 14/4/2009
Weight loss
140
120
100
80
60
40
20
0
1
3
5
7
9
11
13
15
17
19
21
Visit number
• Pulse: 84 beats per minute
and regular.
• Blood pressure: 138/90
mmHg.
Mrs AB had an android
body shape. Cardiovascular
and respiratory examinations
were normal. Abdominal
examination revealed a fatty
apron but there was no tenderness under the right costal
margin. Organs could not be
palpated.
Peripheral examination was
normal, including examination of her peripheral pulses.
She had evidence of
osteoarthritis in the knees.
Investigations showed:
• Fasting glucose: 5.8mmol/L.
• Total
cholesterol:
6.1mmol/L.
• Triglycerides: 0.8mmolL.
• HDL-cholesterol:
1.74mmol/L.
• LDL-cholesterol:
4.0mmol/L.
• Electrolytes, urea and creatinine: all normal.
• LFTs: all normal.
Because Mrs AB had made
many previous attempts at
losing weight using conventional diets, she was started
on the unit’s VLED program,
as described above.
She was also advised to
start taking fibre, as she had a
tendency to constipation, and
was referred to a respiratory
physician for more careful
assessment of obstructive sleep
apnoea, despite her denial
of symptoms.
Figure 2 shows the rate of
weight loss since her initial
presentation. She achieved
weight loss at a steady rate,
reaching a nadir of 101kg in
May 2008. Sibutramine was
started at visit 16 because she
had a 2kg weight gain and
she reported starting to feel
hungry.
Mrs AB was first seen by
the respiratory physician in
March 2007, when she admitted to snoring and having
fragmented sleep. A sleep
study was organised that con-
A weight regain
of only 1-2kg
should be the
trigger to offer
the patient
pharmacotherapy
to assist with
hunger control.
firmed severe obstructive sleep
apnoea. She was offered treatment with a mandibular
advancement splint or continuous positive airway pressure but she declined.
When reviewed in August
2007, having lost 23kg, she
reported sleeping better. The
plan is to continue lifestyle
changes and sibutramine
indefinitely and to review her
at regular intervals.
www.australiandoctor.com.au
1. Sacks FM, et al. Comparison of weight-loss diets with different
compositions of fat, protein, and carbohydrates. New England
Journal of Medicine 2009; 360:859-73.
2. Finer N, et al. One-year treatment of obesity: a randomized
double-blind, placebo-controlled multicentre study of orlistat, a
gastrointestinal lipase inhibitor. International Journal of Obesity
and Related Metabolic Disorders 2000; 24:306-13.
3. Sjöström L, et al. Randomized placebo-controlled trial of orlistat
for weight loss and prevention of weight regain in obese patients.
European Multicentre Orlistat Study Group. Lancet 1998;
352:167-72.
4. Torgerson JS, et al. XENical in the prevention of diabetes in
obese subjects (XENDOS) study: A randomised study of orlistat
as an adjunct to lifestyle changes for the prevention of type 2
diabetes in obese patients. Diabetes Care 2004; 27:155-61.
5. Astrup A, Toubro S. Topiramate: a new potential
pharmacological treatment for obesity. Obesity Research 2004;
12(Suppl):167S-73S.
6. James WP, et al. Effect of sibutramine on weight maintenance
after weight loss: a randomised trial. STORM Study Group.
Sibutramine Trial of Obesity Reduction and Maintenance.
Lancet 2000; 356:2119-25.
7. Stunkard AJ, et al. The body-mass index of twins who have been
reared apart. New England Journal of Medicine 1990; 322:1483-87.
8. Bouchard C. The response to long-term overfeeding in identical
twins. New England Journal of Medicine 1990; 322:1477-82.
9. Sorensen TI, et al. Correlations of body mass index of adult
adoptees and their biological and adoptive relatives. International
Journal of Obesity and Related Metabolic Disorders 1992; 16:22736.
10. NHMRC Clinical Practice Guidelines for the Management of
Overweight & Obesity in Adults, Children & Adolescents
including a Guide for General Practitioners. 2000.
http://www.nhmrc.gov.au/publications/subjects/clinical.htm
11. Geldszus R, et al. Serum leptin and weight reduction in female
obesity. European Journal of Endocrinology 1996; 135:659-62.
12. Chearskul S, et al. Effect of weight loss and ketosis on
postprandial cholecystokinin and free fatty acid concentrations.
American Journal of Clinical Nutrition 2008; 87:1238-46.
13. Cummings DE, et al. Plasma ghrelin levels after diet-induced
weight loss or gastric bypass surgery. New England Journal of
Medicine 2002; 346:1623-30.
14. O’Brien PE, et al. Treatment of mild to moderate obesity with
laparoscopic adjustable gastric banding or an intensive medical
program: a randomized trial. Annals of Internal Medicine 2006;
144:625-33.
Further reading
• Sumithran P, Proietto J. Safe year-long use of a very-low-calorie
diet for the treatment of severe obesity. Medical Journal of
Australia 2008; 188:366-68.
• Woods SC, et al. Central control of body weight and appetite.
Journal of Clinical Endocrinology and Metabolism 2008; 93:S37S50.
Declaration of a potential conflict of interest
Professor Joseph Proietto is chairman of the Optifast medical
advisory board for Nestlé and a member of the Reductil
medical advisory board for Abbott.
cont’d next page
31 July 2009 | Australian Doctor |
27
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HOW TO TREAT Obesity in adults
GP’s contribution
DR LIZ MARLES
Redfern, NSW
Case study
FOR the past eight years
Jan, 54, has been trying to
lose weight through a succession of diets and regular
walking. The past three
years have been particularly
difficult, as she had an
extended worker’s compensation claim for back pain,
during which time she was
unable to earn any additional overtime in her work
as a welfare officer.
She
became
quite
depressed, and her exercise
program evaporated. After
starting her on escitalopram
her mood improved and she
made a concerted effort to
get back into walking her
dog. Earlier this year she
was diagnosed with type 2
diabetes and at this point
made a decision that she
really needed to address her
weight, suggesting that “perhaps surgery might be the
go”.
This is not the first time
Jan has taken a surgical
approach. Twenty years ago
she had gastric banding surgery and lost 40kg, achieving a weight of 68kg. This
was maintained for about
seven years, but then her
weight started to rise again.
Acknowledging that she
has a stressful job, Jan
describes herself as a “stress
eater”. She is not keen on
attending WeightWatchers,
and has had trouble sticking
to any particular dietary
advice.
In addition to the diabetes
and recurrent back pain, Jan
also suffers from reflux
oesophagitis and possibly
sleep apnoea (although this
has not formally been diagnosed).
Is surgery appropriate, given
her previous history of gastric stapling?
Surgery may now be more
difficult and the risk benefit
ratio would need to be carefully assessed. Referral to an
experienced bariatric surgeon for an opinion is an
option.
At 121kg she has a BMI
of 45kg/m 2. She also has
mildly elevated LFTs and
ultrasound showed a “fatty
liver”.
Questions for the author
What approach would you
take to Jan’s weight loss?
Given that Jan has now
developed significant comorbidities it is important that she
How to Treat Quiz
attempt weight loss again. The
previous surgery may make
further surgery difficult and/or
dangerous.
Considering this past history, I would offer Jan the
approach detailed in the article, with a VLED followed by
lifestyle and pharmacotherapy
if required. Should this
approach fail, a surgical
opinion should be sought.
She was recommended to
lose weight before the gastric stapling — what is the
purpose of this?
It has been shown that 2-4
weeks of a VLED before surgery significantly reduces
liver size and reduces intraabdominal fat, making surgery easier and safer.
General questions for the
author
Is a regular program of brisk
walking for 30 minutes a
day sufficient exercise to
lead to weight loss?
On its own, without concomitant energy restriction,
the impact of this amount of
exercise would be small.
Are there special precautions
in undertaking meal replacement with a product such as
Optifast in patients with type
2 diabetes?
VLEDs can have a dramatic
impact on glycaemia, so any
patient using insulin or sulfonylureas must be warned
about the risk of hypoglycaemia.
My rule of thumb when initiating these diets in someone
with diabetes is to continue
insulin sensitisers (metformin,
thiazolidenediones) or acarbose or insulin-secretion-stimulating compounds that
require elevated glucose levels
to work (sitagliptin, exenatide)
but to stop sulfonyureas.
If a patient is using insulin I
do not stop it completely, as
these patients are often insulin
deficient. I halve the dose and
ask the patient to check their
blood glucose level more often
when they start the diet. The
dose of insulin can then be
adjusted over the next week
based on the patient’s glucose
response to the diet.
INSTRUCTIONS
Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes
by post or fax.
The mark required to obtain points is 80%. Please note that some questions have more than one correct answer.
Obesity in adults — 31 July 2009
1. Which THREE statements about the
prevalence of obesity and related
conditions in Australia are correct?
a) About two-thirds of men are overweight or
obese
b) About one-half of women are overweight or
obese
c) The prevalence of diabetes in adults is
about 7%
d) The prevalence of the metabolic syndrome
in adults is about 15%
2. The International Diabetes Federation
(IDF) criteria for the metabolic syndrome
include central obesity, plus two out of four
additional features. Which THREE of the
following additional features are correct?
a) Triglyceride level ≥1.7mmol/L
b) HDL-cholesterol level of <1.2mmol/L in
males and <1.5mmol/L in females
c) Blood pressure ≥130mmHg systolic or
≥85mmHg diastolic
d) Fasting plasma glucose level ≥5.6mmol/L
3. Which TWO statements about regulation
of body weight are correct?
a) Studies suggest that about 30% of the
variance in body weight is genetic, while
70% is environmental
b) Among the circulating hormones that
influence hunger, only glucagon-like peptide
1 has been found to stimulate hunger
c) After weight loss, changes in circulating
regulatory hormone levels lead to an
increased drive to eat
d) Energy expenditure decreases after weight
loss
4. Which THREE statements about the
clinical assessment of obese adults are
correct?
a) Assessment should include measurement of
height and weight
b) Assessment should include measurement of
waist circumference in men and waist and
hip circumference in women
c) A waist circumference of ≥94cm in men and
≥80cm in women meets the central obesity
criterion for the metabolic syndrome
d) Assessment should include examination for
acanthosis nigricans, which is indicative of
dyslipidaemia
5. Which TWO statements about the
investigation of patients presenting for
management of obesity are correct?
a) Routine investigations should include
electrolytes, urea, creatinine and LFTs
b) Routine investigations should include uric
acid
c) Routine investigations should include
screening for Cushing’s syndrome
d) All obese patients should have their insulin
levels measured
6. Which THREE statements about diet and
lifestyle changes in the management of
obesity are correct?
ONLINE ONLY
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a) Patients who have not made previous
attempts at weight loss should be advised
to follow a calorie-reduced lifestyle-change
program
b) A recent large study has shown that the
type of diet an individual follows does not
affect the success of achieving weight loss
c) It is best for the GP to choose the weightloss strategy for an individual to follow
d) If detailed dietary advice is required, referral
to a dietitian is advisable
7. Which TWO statements about very low
energy diets (VLEDs) are correct?
a) A VLED may be considered when there is
morbid obesity despite multiple previous
weight loss attempts with conventional
diets
b) The VLED provides the patient with a daily
energy intake of 1000 calories
c) After starting on a VLED the patient should
be followed up once monthly
d) Blood tests must be performed at baseline
and electrolytes should be monitored
during the VLED regimen
8. Which TWO statements about the VLED
are correct?
a) Patients are advised to have a bowl of
vegetables or a salad in the evenings while
on the VLED
b) In very large patients some protein in the
form of meat or fish is advisable once daily
in addition to the VLED
c) Patients should avoid all oils while on the
VLED, to maintain a low fat intake
d) If patients feel hungry on the VLED, they
can have a small carbohydrate snack once
a day
9. Which THREE statements about
pharmacotherapy in the management of
obesity are correct?
a) Side effects of centrally acting adrenergic
agonists for the management of obesity
such as phentermine include hypertension
b) Orlistat reduces fat absorption by 50%
c) Sibutramine works by inhibiting both
serotonin and noradrenaline reuptake
d) Long-term safety of most currently
available drugs for the management of
obesity has not been proved
10. Which TWO statements about surgery
in the management of obesity are correct?
a) Bariatric surgery should be considered in
2
patients with a BMI >40kg/m for whom
medical therapy has failed
b) Bariatric surgery should be considered in
2
patients with a BMI >30kg/m in
conjunction with significant obesity-related
comorbidities who have failed medical
therapy
c) In Australia gastric balloons have become
the most common bariatric procedure
d) Patients undergoing bariatric procedures
require management in a multidisciplinary
setting
CPD QUIZ UPDATE
The RACGP now requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2008-10 triennium. You
can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post
or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.
HOW TO TREAT Editor: Dr Wendy Morgan
Co-ordinator: Julian McAllan
Quiz: Dr Wendy Morgan
NEXT WEEK Acute abdominal pain is one of the most common reasons for a child presenting to their GP. Such a visit may challenge even an experienced clinician, especially when dealing with a
distressed preschool-age child accompanied by anxious parents. Next week’s How to Treat looks at the assessment and management of children with acute abdominal pain. The author is
Associate Professor Andrew J A Holland, associate professor of paediatric surgery, the University of Sydney, and consultant paediatric surgeon, The Children’s Hospital at Westmead and Royal
North Shore Hospital, St Leonards, NSW.
28
| Australian Doctor | 31 July 2009
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