Govern well thy appetite, lest Sin surprise thee, and her black attendant Death
- Paradise Lost, John Milton
Every so often a drug comes along that is touted by doctors and, more loudly, by its manufacturers as the 'next big thing'. Such drugs invariably receive coverage in the general media to a far greater extent than is usually afforded to a new drug, news of which is usually restricted to specialist publications.
In June, 2006, the drug rimonabant1 was approved for doctors in the UK to prescribe, and other countries in the European Union followed suit, although rimonabant was never approved in the USA. This news made British newspapers such as The Times. Even before the drug was approved, stories were starting to appear in places such as The Guardian newspaper and the BBC news website. Coverage of this sort is usually reserved for the latest cancer drug but, in the early 21st Century, obesity is such an enormous health issue that a drug that can stop people from over-eating and help them to shed weight is newsworthy indeed. For a while, it looked as though rimonabant, which does precisely that, was going to make a name for itself in the fight against obesity.
So How Does it Work?
The story of rimonabant begins, not in a laboratory, but in student bedrooms, hippie communes and the more relaxed type of cafeteria. It begins with cannabis2. As anyone who has ever used cannabis will know, a common side effect is 'the munchies' - a craving for food. Research in animals showed that this effect is largely the result of the effects of cannabis on proteins called 'endocannabinoid (EC) receptors' in the brain. Cannabis stimulates these receptors, leading to the feelings of hunger. So, if activating the receptors makes you hungry, perhaps blocking the same receptors can stop you feeling hungry...
Rimonabant acts by blocking a particular type of EC receptor (EC1) that is found in the brain, as well as in other tissues involved in appetite and metabolism, including adipose (fat) tissue, liver, muscle and the digestive tract. Further studies in rodents fed a high-fat diet showed that blocking EC1 receptors caused animals to lose weight, and also had beneficial effects to reduce levels of the so-called 'bad' cholesterol3 without affecting levels of 'good' cholesterol4, and to improve glucose and insulin levels. A further effect of rimonabant was to increase levels of the hormone adiponectin. This hormone, which is decreased in obese people and animals, is believed to be involved in the prevention of atherosclerosis - the process that leads to blocking of arteries.
That's Fine if You're a Rat, but...
...does it work in humans? The data seemed to show that it does. The effects of rimonabant were tested in a series of large clinical trials known as the 'RIO' (Rimonabant In Obesity) programme. The first of these to be published5 was carried out in Europe and involved people who were obese, or who were overweight and had risk-factors for heart disease such as high blood pressure or high cholesterol levels. The participants in the study were placed on a strict diet, and were randomised to receive one of two doses of rimonabant or a placebo - the study was 'double blind', so neither the doctors nor the patients knew who was receiving which treatment.
The results from the study showed that the patients taking the higher dose of rimonabant lost more weight after one year than those who had taken a placebo. As in the animal studies, rimonabant also improved 'good' cholesterol levels, 'insulin resistance' - a risk factor for developing diabetes - and reduced waist circumference, showing that the weight had been lost from the abdomen, where fat may be more harmful.
Two other studies in the RIO programme were also been published, one carried out in North America, and one specifically looking at patients with high cholesterol levels6. These studies showed similar results to the European study, with patients taking rimonabant losing more weight than those taking placebo and improving their cholesterol and insulin levels.
Why Would I Want to Take it?
Obesity - which is defined by the World Health Organisation as a body mass index7 of more than 30kg/m2 - is rapidly becoming a serious health problem in industrialised countries. An increase in consumption of junk food, coupled with sedentary lifestyles and lack of exercise, has meant that the incidence of obesity has increased dramatically in the last 20 - 25 years. In the UK, for example, it is estimated that 20% of adults, 17% of 15-year-olds and 10% of six-year-olds are clinically obese. In the USA, the Centres For Disease Control and Prevention estimate that nine of the US states8 have an obesity prevalence of more than 25%, while back in 1991, none of the 50 states had a prevalence above 20%. Importantly, obesity is a cause of diabetes and heart disease, and is also linked with an increase in the risk of some types of cancer, notably breast and colon cancer. If current trends continue, obesity will soon become the UK's leading cause of death.
The licence for rimonabant in Europe allowed it to be prescribed only to obese individuals, or overweight individuals who also had important risk factors for heart disease. The rimonabant 'Summary of Product Characteristics' also specified that it should be used only as an 'add-on' to diet and exercise programmes - any patient who approached their GP for drugs to help them lose weight would have been asked to demonstrate first that they could lose some weight without them. Rimonabant was not a 'magic' weight-loss pill, whatever the media hype would have had us believe, but a drug designed for people whose health was in serious danger as a result of their weight.
The End of Rimonabant
In the short-term trials in which rimonabant was initially studied, the main side effects seemed to be nausea or diarrhoea in some patients, and, because it affects the brain, some patients experienced anxiety or insomnia. Sadly, further studies, together with careful monitoring of patients who were prescribed rimonabant, showed that there was a greatly increased risk of psychiatric disorders, and even suicide, in patients taking the drug. Because of this, rimonabant was withdrawn by the manufacturers in October, 2008.