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A recent medical article in a national newspaper caused a flurry of
excitement. It was picked up by TV, radio and other newspapers throughout
the country. This was not a breakthrough in asthma, cancer or Alzheimer’s
disease. No, it was a chocoholics dream come true – a pill which may allow
people to eat chocolate without putting on weight, because it reduces the
absorption of fat.

At 9 Calories per gram, fat is the most energy-rich food in our diet. The
new drug, tetrahydrolipstatin (THL) works by blocking the conversion of
triglycerides to fatty acids. Without this step, fat cannot be digested.
Partially digested fats travel through the gut and are excreted, so not all
their calories are taken in.

This marks a new way of treating obesity with drugs. Now being tested on
around 200 seriously overweight people at ‘six secret locations’ in Britain,
THL is at least five years from the market. Yet its safety is already in
dispute. Some scientists believe that it might increase the risk of colonic
cancer and heart attack. It seems that this new generation of diet pills
which prevents absorption of nutrients will prove as controversial as the
present generation which suppress appetite.

But dieting is big business. An estimated 400 000 people are currently
prescribed appetite suppressants on the National Health Service, at an
annual cost to the taxpayer of over £1 million. Many
thousands more dieters are prescribed the drugs by doctors working in
private clinics. The incentive for pharmaceuticals manufacturers to produce
new diet pills is huge.

Throughout the Western world, an obsession with diet and dieting seems to be
coupled with an increase in obesity. The British government’s White Paper
Health of the Nation, published last year, reports that in 1986/7, 8 per
cent of adult men and 12 per cent of adult women were obese. Obesity is
defined by the body mass index (BMI), a measure introduced in 1869, which
divides a person’s weight in kilograms by the square of their height in
metres. Health hazards start to turn up in people with a BMI between 25 and
30 – above 30 they are classified as obese. The White Paper also highlights
the link between obesity and raised blood pressure and plasma cholesterol
levels – both of which seem to increase the risk of coronary heart disease
and stroke. It recommends that almost everyone should eat more starch,
vegetables and fruit, and less fat, sugar and salt.

The best way for an obese person to lose weight and keep it off is to
change the behaviour which caused the problem. This is one approach used by
Weightwatchers, Britain’s biggest dieting organisation, which has around
150 000 members and 3400 meetings each week. Dieters may be asked to list
the food they eat, with a note about their mood at the time, or persuaded to
eat more slowly, taking smaller mouthfuls from a smaller plate. The aim is
to help people change their eating habits by becoming more aware of them.

DESPERATE DIETERS

Andrew Hill, a psychologist at the University of Leeds, says this approach
can work, but is not appropriate for everyone. Desperate dieters, he says,
will try just about anything, from acupuncture to hypnosis. Many turn to
drugs. Over the past fifty years, appetite suppressants have been absorbed
into the medical mainstream, but now their critics are fiercer than ever.
Joe Collier, a consultant pharmacologist at London’s St George’s Hospital,
believes they should be banned. ‘These drugs are useless,’ he says. ‘They
should only ever be used in excessively overweight people and, even so, they
don’t really work. In the whole of St George’s – with 600 medical staff –
they are not used at all. That’s how much we think of them.’

Slimming drugs have a chequered history, dating back to the 19th century
when ephedrine was extracted from the Chinese plant Ephedra sinica, and
taken in tea as a stimulant. Further experimentation with ephedrine-like
compounds produced amphetamines which at the height of their popularity in
the 1960s were used illicitly by around 200 000 people in Britain alone.

The appetite suppressant effect of amphetamines was first reported in the
late 1930s. They act on the paraventricular nucleus of the hypothalamus, the
appetite centre in the of the brain, stimulating the release of
neurotransmitters – noradrenaline, serotonin and dopamine – which remove the
desire to eat. Unfortunately, the direct stimulation of the central nervous
system even with low doses of amphetamine has many adverse effects. These
can include increased irritability, restlessness, insomnia, blurred vision,
increased blood pressure, cardiac palpitations and anxiety. Furthermore,
long-term use can result in dependence, both psychological (because they
induce euphoria) and physiological (withdrawal symptoms include
depression).

Amphetamines can also cause eating disorders because tolerance to the
appetite suppressing effect develops rapidly, and when the drug is withdrawn
there is a rebound effect resulting in increased appetite. In the mid-1960s,
British doctors decided the disadvantages outweighed the benefits, and
voluntarily banned them.

In Britain a handful of drugs are prescribed as appetite suppressants. These
work in one of two ways. Bulk-forming drugs such as methylcellulose swell up
in contact with liquids. They aim to reduce food intake by producing
feelings of satiety. Other appetite suppressants are centrally acting. Some,
such as diethylproprion, phentermine and mazindol act, like amphetamines,
on the appetite centre to reduce the desire to eat. All are much less toxic
than amphetamines and safe in overdose, but they are stimulants and have
some of the same side effects, including dry mouth, headache, insomnia and
nervousness and also a potential for abuse.

Two other centrally acting drugs, fenfluramine and dexfenfluramine, are
chemically related to the amphetamines but do not stimulate the central
nervous system, so do not have the same potential for abuse. They both
increase serotonin transmission in the appetite centre by inhibiting its
uptake into neurons – the mechanism by which it is normally removed from
service. The increase in available serotonin results in a feeling of
satiety, so patients retain the desire to eat but are more easily
satisfied.

Mike Lean, professor of human nutrition at the University of Glasgow,
believes appetite suppressants can benefit some patients if used for a few
weeks or months to give them time to develop healthier eating habits and
take more exercise. He says randomised, placebo-controlled studies have
shown that dexfenfluramine gives, on average, an additional weight loss of
two to three kilograms over a year when coupled with dieting. This may seem
small, but Lean points out that the studies include people who are not
strongly motivated. ‘The range of effect is considerable.’ One-fifth of
people cannot tolerate dexfenfluramine, and of the rest, half do pretty
well. But, as Lean points out: ‘It takes a long time to shift fat. For each
kilogram lost, you have to undereat by 7000 Calories. To lose three
kilograms, that’s 21 000 Calories. It takes six or twelve weeks before you
are sure the drug is working.’

DOCTORS’ DOUBTS

Another advocate of appetite suppressants is Philip James, a government
adviser on nutrition and director of the Rowett Research Institute for
nutritional studies in Aberdeen. He says many doctors do not view obesity as
a medical problem worthy of treatment and are wary of prescribing diet pills
because of doubts about their long-term effects. ‘Doctors are very fond of
giving pills for high blood pressure or diabetes which have to be taken on
a lifelong basis. These therapies were introduced long before the long-term
impact of the drugs on overall health could be evaluated. With obesity,
doctors think it’s simply a behavioural problem which relates to a lack of
resolution. They dispense a diet sheet and tell people to pull themselves
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James does not deny that diet pills have side effects. But he says they
should be offered to many more people than they are at present. With more
information, he argues, patients can make their own decision. ‘People don’t
have to be desperate, it’s simply that one has to balance the risk with the
potential benefit.’

Other doctors are more sceptical about diet pills. John Garrow, professor of
human nutrition at London’s St Bartholomew’s Hospital, believes the drugs
are already being misused. He is particularly concerned about the many
private slimming clubs and clinics where appetite suppressants are
prescribed to people who are not clinically obese. ‘There are doctors around
who are giving them to normal weight people. But there’s nothing we can do
about that.’ Diet pills are only available on prescription and therefore
from registered doctors. ‘If you are on the register,’ says Garrow, ‘it is
assumed that what you do is professionally reasonable. No one is going to
draw up a law to say appetite suppressants must not be given to people with
a BMI less than 30, any more than they’d say you can’t give aspirin unless
joints are swollen by more than 7.3 millimetres.’

Garrow prescribes appetite suppressants only in the rare situation when a
patient has dieted successfully and then decides to give up smoking as well.
A six-week course of drugs can help these people to overcome the oral
craving associated with quitting smoking. But Garrow believes that dieting
is undoubtedly the answer to obesity. He does not question the ability of
appetite suppressants to reduce hunger, but points out that this effect
decreases with time. Furthermore, many people overeat for reasons such as
boredom, against which drugs will have no effect. ‘Dieting,’ says Garrow,
‘is very effective if done properly, but it is hard work and a continuous
strain. I wouldn’t object to an alternative if it would give results without
the inconvenience of dieting. Certainly in my view there isn’t any.’

Garrow’s view seems more in line with the medical establishment. The British
Medical Association, together with the Royal Pharmaceutical Society,
publishes the British National Formulary – the doctors’ reference book for
prescribing. It recommends that appetite suppressants have only a limited
role and should never be used as the sole element of treatment. It
describes centrally acting drugs as of ‘no real value’ because they do not
improve the long-term outlook. Any possible benefits of the
amphetamine-like drugs are, the book claims, ‘outweighed by the risks
involved; abuse, particularly of diethylproprion, is an increasing problem’.
Fenfluramine, it warns, ‘should preferably be avoided’ because withdrawal
can result in depression.

Doctors may soon be prevented from prescribing appetite suppressants on the
NHS, if proposals from the government’s Advisory Committee on NHS Drugs are
approved. The committee’s terms of reference require it to ensure that drugs
to meet all clinical needs are provided as economically as possible under
the NHS. But this move would not, however, stop private prescriptions.

Since appetite suppressants became available, many other compounds have
looked promising but none has yet made it on to the market. A few years ago
a class known as thermogenic drugs caused great excitement and optimism. The
theory was that brown fat cells burn up excess food and stop it
accumulating in the body. These cells, packed with mitochondria, have a high
capacity for generating heat and are activated when people overeat. It is
thought that in obese people the brown fat is probably not so easily
activated. Thermogenic drugs aim to override this sluggish response.

TRIALS ABANDONED

Adrenaline-like hormones speed up the activity of brown fat cells, but they
also make the heart beat faster. Ten years ago, researchers at Beecham
pharmaceuticals discovered so-called beta-3-adrenergic receptors on brown
fat cells – which differ from the beta-1 and beta-2-receptors found on heart
and lung cells. The drugs they developed to target these beta-3-receptors
looked promising. In randomised trials among people on restricted diets,
those taking BRL 26830A lost one and a half times as much as those on
placebo.

But the first generation of thermogenic drugs were associated with side
effects such as tremor. Beecham abandoned research, saying the compound was
only applicable for small numbers of people. But according to Garrow the
drawback was more serious. He says most of the weight lost with thermogenic
drugs was lean rather than fat tissue – normally, weight lost by dieting
will be three-quarters fat and the remainder lean tissue. This assertion is
contested by Michael Stock, professor of physiology at St George’s Hospital
Medical School and a pioneering researcher into brown fat metabolism.

Stock’s view mirrors a resurgence of interest in thermogenic drugs from the
pharmaceuticals industry. Now Beecham has developed a second generation of
thermogenic drugs and clinical trials are about to start. Zeneca and
American Cyanamid are researching similar drugs, but even without hitches,
it will be at least five years before any are available.

The latest drug strategy for tackling obesity – as exemplified by THL – is
to prevent absorption of some of the food consumed. It is based on a theory
that anyone, whether obese or of normal weight, will start craving
high-calorie foods if their eating is severely restricted. So absorption
blockers allow obese people to consume a reasonable amount of food without
absorbing all its calories.

Up to February 1993, preliminary trials of THL had involved 1300 people. The
amount of fat absorption prevented depends on the dose given, and the aim is
to give enough to prevent absorption of 30 per cent. In Britain, the average
daily intake of fat is 90 grams. If THL prevented absorption of about a
third of that, then the 30 grams of fat not absorbed in the small intestine
would pass into the large intestine where it could lead to bowel
incontinence. But there are even more serious concerns. Under normal
circumstances, about 7 grams of fat pass through the large intestine each
day. Garrow is worried about the long-term effect of increasing this to 30
grams. ‘If the bacteria suddenly find their nutrient supply drastically
increased, they will not only change in quantity but also in variety. The
ones that like living in fat will flourish. We have to worry whether it will
affect the predisposition to colonic cancer, which is related in some way to
diet and increases with fat intake in some way.’

Garrow is also concerned that people taking the drug will fail to stick to
their normal diet. ‘People are going to take THL because it’s better than
dieting. If they think there’s no harm in eating fat and they eat 120 grams
a day – which is not unlikely – they are going to be absorbing as much fat
as ever, with huge amounts going through the colon.’ They may even see the
drug as an opportunity to eat more of the most unhealthy foods. ‘If someone
is taking THL because they love animal fats and dairy fats, a higher
proportion of their fat intake will be saturated,’ says Garrow. ‘Ideally,
we get people who are eating 90 grams of fat a day to eat 60 grams by
reducing their saturated fat intake.’ But THL does not distinguish between
saturated and unsaturated fats. If most of the intake is in the form of
saturated fats then most of the fat absorbed will be saturated. This type of
fat is associated with heart disease, so THL could indirectly increase this
risk.

Even if the drug were used under strict supervision, concerns remain. Ian
Baird, medical spokesman for the British Heart Foundation, says preventing
absorption of fat would result in a decreased intake of fat-soluble vitamins
– particularly D and E – as well as essential fatty acids and calcium. ‘It
may not produce serious malabsorption, but in certain conditions like
coeliac disease, a little less calcium, vitamin D and vitamin E can cause
quite serious skeletal changes and other disadvantages in the long term.’ An
operation for obesity, the duodenal bypass – whereby part of the small
intestine is removed to reduce the absorption capacity of the gut – has
been abandoned in recent years for just this reason. Baird believes that it
will take up to two years to discover whether THL causes similar problems.

THL does have its enthusiasts, though. James, who is involved with the
trials, is one. But even he suggests that the body may counter the effects
of THL with some mechanism we do not yet understand. ‘I would not see it as
a magic bullet at all. It’s something that may have a place in treatment,
but the evidence just isn’t there yet.’

Lean believes the answer to obesity lies elsewhere – in improving training
for health professionals and in more effective measures to change
lifestyles. ‘One really valuable thing we can do would be to take the young
relatives of people with heart disease and diabetes and educate them about
their personal risks and the gains from healthy eating. But the only real
way to tackle obesity in the long term will be to find out how to stop
ordinary people getting fat.’

Helen Saul is a freelance journalist specialising in health and medical
issues.

* * *

When fat makes you thin

One approach to reducing fat intake is to substitute it in food. The past
few years have seen the introduction of many low-fat products containing fat
substitutes. But US food manufacturer Procter & Gamble hopes to take this
one step further. Since 1968 it has been working on a nondigestible fat
called Olestra. It is a novel compound, and more controversial by far than
the low-fat alternatives.

Olestra is a fatty acid ester of sucrose – its physical properties are
similar to those of triglycerides. Triglycerides are broken down with the
help of an enzyme called pancreatic lipase. The enzyme cannot get access to
binding sites on Olestra because the molecule is too bulky, so it remains
intact and cannot be absorbed. In early trials, large amounts of fat in the
lower intestine caused problems of anal incontinence and fatty stools, but
these have now been greatly reduced by stiffening the molecule with palm
oil.

During 25 years of trials, Olestra has been tested on seven different
species of animal. It has been tested for toxicity and carcinogenicity, and
taken by more than 5000 adults and children – some for as long as five
years. Some of these trials were assessing taste and texture, others looked
at Olestra’s impact on the intestine. But with around $200 million
already spent on development, the company has yet to get the product on the
market. The US Food and Drug Administration is still considering over 20 000
pages of evidence, but Don Tassone at Procter & Gamble says the company
hopes to receive approval by 1994.

The licence application is for use of Olestra in salted snacks only.
Originally Proctor and Gamble also wanted to use it in fats, shortenings and
oils for home use. But time is not on the company’s side. One patent on
Olestra has already run out in the US and the company has applied for an
extension.

Philip James, a British government adviser on food and nutrition, says the
approval procedure for a product like Olestra is extremely stringent because
it could potentially be used in large quantities by a substantial proportion
of the public. But Sue Dibb of the Food Commission in London believes
Olestra has already passed its sell-by date with increased demand from the
public for more natural foods. ‘Even if Olestra gets approval now, most
people want natural foods not additives. The idea of a chemical taking up a
large part of food isn’t very appealing to people.’

Undeterred by these sentiments and Procter & Gamble’s problems, companies
like Unilever continue with their own research programmes into other
potential fat substitutes. They are relying on the public’s obsession with
body weight to ensure that such products remain attractive commercial
propositions.