OBESITY AND THE PHARMACEUTICAL INDUSTRY

Obesity is not an exclusively modern phenomenon, and the quest for remedies that could banish it, such as slimming pills, is equally long-standing. By the end of the 19th century, newspapers in Britain, the USA, Australia and other countries were carrying advertisements for remedies such as 'Allan's Anti-Fat' ('composed of purely vegetable ingredients'), 'Dr Gordon's Elegant Pills' and 'Kellogg's Safe Fat Reducer', which contained an extract of animal thyroid glands, offering rapid weight loss as their claimed effect. These competed with a wide array of laxatives and other much-promoted 'remedies' designed to slim those who wanted to lose weight.

While the fashion for 'purely vegetable ingredients' has not abated since those days, chemically created remedies were also popular. First described in 1887, amphetamine was introduced to medical use in the 1900s and was soon noted to have an appetite-suppressing effect. Related to the naturally-occurring stimulant ephedrine found in some Chinese herbal medicines, amphetamine is effective in reducing appetite, but induces tolerance, requiring everlarger doses, and is addictive. Heart, kidney and other problems may develop from prolonged use. Related compounds (fenfluramine, phentermine and dexfenfluramine) were introduced after amphetamine to control appetite, but these were subsequently withdrawn, following reports in some people of high blood pressure in the circulation through the lungs and damage to heart valves.

Current medicines for obesity

Three medicines are currently authorised in the UK for use as an aid to weight loss in obesity. These are orlistat (Roche), sibutramine (Abbott), and rimonabant (sanofi-aventis). Weight-loss medicines are prescribed as part of an overall treatment plan that includes a lower calorie intake and increased physical exercise. They are used in people with a body mass index greater than 30, or 27 where risk factors such as type 2 diabetes or raised lipid levels in the blood are present (28 in the case of orlistat). Current guidelines recommend that dietary, exercise and behavioural treatments should have been started and evaluated before treatment with medication is considered. Medication is not recommended for those with a lesser degree of overweight, or in children or adolescents, other than in restricted or exceptional circumstances.

Orlistat is an inhibitor of gastric and pancreatic lipase enzymes that control the uptake (absorption) of fat from triglycerides in food through the wall of the intestine. It is usually taken three times a day, before main meals, unless the meal contains no fat. Orlistat is not absorbed into the body; instead, it acts locally on the lipases within the intestine. Blocking the action of lipases reduces absorption of dietary fat, which passes down the intestine and is excreted instead. This extra fat in the intestine may lead to abdominal pain, wind, oily stools and faecal incontinence, especially when the fat content of the food is high and especially at the start of treatment. Absorption of fat-soluble vitamins (A, D, E and K) may be reduced, and a diet rich in fruit and vegetables that contain adequate amounts of such vitamins is advised, but any reduction is not usually significant.

In one clinical trial, about 60 per cent of those given orlistat lost at least 5 per cent of their starting weight after 12 weeks of treatment, as compared with people given an inactive substance (a placebo). After one year of treatment, 41 per cent of people treated with orlistat had lost more than 10 per cent of their starting body weight. Of those who had not lost more than 5 per cent of their weight after 12 weeks, only 5 per cent had lost more than 10 per cent after one year, and treatment with orlistat is therefore usually stopped if a 5 per cent weight loss has not been achieved after 12 weeks. Weight loss may be slower in obese people who also have type 2 diabetes.

In a number of studies, people who had lost weight on orlistat treatment were found to have significantly improved blood pressure, lower levels of LDL cholesterol ('bad' cholesterol) in the blood, lower fasting blood glucose and insulin levels and less insulin resistance. In addition, results from a four-year study suggested that orlistat delayed the development of type 2 diabetes, especially in those with impaired glucose tolerance.

Sibutramine acts in a quite different way from orlistat. It inhibits reuptake of the neurotransmitters serotonin (5HT) and noradrenaline (NA) in the brain, increasing feelings of fullness after eating. It may also lessen the decline in resting metabolic rate that usually occurs on losing weight. Treatment with sibutramine has been shown to improve lipid balance in people with raised lipid levels in the blood and to improve glycaemic control in people with type 2 diabetes. It is taken once a day, in the morning.

Common side-effects of sibutramine include constipation, dry mouth, headache and raised blood pressure and/or heart rate. They are most marked during the first four weeks of treatment and lessen over time. Sibutramine is not normally given to people with bipolar disorder, or with known cardiovascular disease.

Weight loss with sibutramine is affected by changes in diet and lifestyle. In one trial, people with an initial BMI of 30-40 who had lost weight when given sibutramine for an initial four weeks continued to lose weight when given a further 44 weeks of sibutramine treatment. A standardised diet and exercise programme was not used in this trial; people were simply offered 'GP's usual advice'. However, in a more recent study, a much higher weight loss was achieved in one group of people by combining sibutramine treatment with an extended (30 session) programme of group lifestyle-modification counselling. Those given sibutramine alone lost an average of 5kg after a year, while the combination of sibutramine and group counselling produced a weight loss of 12.1kg.

Rimonabant also acts on the brain, but affects different processes from sibutramine. It is a selective inhibitor of cannabinoid type-1 (CB-1) receptors, which are widely distributed in the brain and in some tissues outside the brain, including on fat cells. These receptors play a role in energy balance, glucose and lipid metabolism and body weight regulation and the intake of highly palatable, sweet or fatty foods. Rimonabant is usually taken as a single dose before breakfast.

In four clinical trials in people with initial BMI values of 34-38, treatment with rimonabant led to a significantly greater weight loss after one year than that seen in patients given placebo. There was also a significant increase in HDL-cholesterol ('good' cholesterol) in the blood and a decrease in triglycerides and fasting insulin levels. One trial which included obese people with type 2 diabetes also showed a significant improvement in blood glucose levels, indicating better control of the disease. Continuation of rimonabant treatment for a second year in another of these four studies showed maintenance of weight loss, but those switched onto placebo regained most of the weight they had lost in the first year. The most common side-effects that led to people stopping taking rimonabant in clinical trials were nausea, mood alteration with depressive symptoms, depressive disorders, anxiety and dizziness. A possible increase in suicidal thoughts during rimonabant treatment is being investigated further.