Rimonabant appears to be very promising, especially for the treatment of patients with abdominal obesity

Oct 30 2005

Overweight or obese people who are stout around the waist and abdomen are particularly at high risk for developing type 2 diabetes and high blood pressure.

The most effective way to reduce blood pressure and the risk for secondary diseases is to reduce weight. But most patients do not succeed in losing weight and keeping it off. A possible alternative could be an entirely new substance group which simultaneously blocks feelings of hunger and reduces blood lipid levels, thereby reducing the risk for cardiovascular diseases and type 2 diabetes.

The new drug, called Rimonabant, has been tested in clinical trials for over two years in Europe and the USA. The European Director of the clinical trials, Professor Luc Van Gaal of the University Hospital in Antwerp, Belgium, presented results of this study at the 4th International Symposium on Obesity and Hypertension at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch.

Lose weight and, most importantly, get rid of abdominal fat – that is what doctors recommend. However, most patients are unable to either lose weight or to keep lost weight off on a permanent basis, regaining the pounds that took them such an effort to loose. Professor Sharma defends the patients: “It is too simple to make the patients alone responsible for this lack of success. Genetic factors play a role in the regulation of bodyweight, as do the fat cells themselves. Frequently, too, medications for blood pressure and diabetes make losing weight more difficult.”

A possible alternative could be an entirely new substance group which simultaneously blocks feelings of hunger and reduces blood lipid levels, thereby reducing the risk for cardiovascular diseases and type 2 diabetes. The new drug, called rimonabant, has few side effects. It intervenes exactly where the body controls the hunger feeling, namely in the endocannabinoid system (ECS). Endocannabinoids are the body’s own substances similar to cannabis (hashish), which are released upon feelings of stress, hunger, and pain, as Vincenzo di Marzo explained in Berlin. He is a professor at the Institute for Biomolecular Chemistry of the Italian Research Council in Pozzuoli. Endocannabinoids also play a role in the intricate regulation of the cardiovascular system.

Up to now, particularly two endocannabinoids were known – one of them is anandamide. The name originates from Sanskrit and means “bliss”. According to Vincenzo di Marzo, the system was discovered during research on how cannabis (hashish) works, which gave the system its name. When hungry, the organism releases increased amounts of anandamide, he continued. This is in line with the known fact that hashish users frequently have attacks of the “munchies”.

Endocannabinoids bind and activate two cannabinoid receptors. In particular, cannabinoid receptor1 (CB1) is of great interest to research and medical practice. CB1 is mainly found in the brain, in different organs, and in fatty tissue. According to Professor di Marzo “[CB1] is obviously primarily responsible for food intake after a starvation period. It sees to it that fat is deposited in the fat cells.” This is how the body creates fat reserves in order to survive hunger periods better.

Experiments with obese lab rats have shown that, the more they eat, the more endocannabinoids bind to the CB1-receptor, which is hyperactive in these animals. The result: The binding of endocannabinoids to CB1 increases appetite, Professor George Kunos demonstrated. He is from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which is part of the National Institutes of Health (NIH) in Bethesda, Maryland, USA. Furthermore, Professor Kunos, who was unable to attend the Berlin meeting, showed in experiments with mice that blocking this receptor with the substance rimonabant reduces appetite. The animals become thin and stay that way despite being offered an overabundance of food. And rimonabant not only reduces the animals’ weight but also their blood pressure.

For over two years, rimonabant has been tested in clinical trials. Director of the RIO (Rimonabant in Obesity) clinical trial in Europe is the diabetologist and metabolism expert Professor Van Gaal. Included in the trial are 1,507 patients from 60 clinics in Belgium, Germany, Finland, Sweden, the Netherlands, and the US with a Body Mass Index (BMI)* of over 30 kg/m2 and of over 27 kg/m2 who additionally have high blood pressure and elevated blood lipid levels. The RIO trial is one of a total of four Phase III trials (testing effects and side effects in a larger number of patients) with 6,600 patients. The patients were put on a diet and also had to complete an exercise program. They were divided into three groups: the first group received 20 mg of rimonabant daily, the second group received 5 mg, a day and the third group received a placebo.

Reduces Bodyweight and Improves Metabolic Parameters As Professor Van Gaal reported in Berlin, one year later, patients who had received daily doses of 20 mg of rimonabant had lost 6.6 kg on average; patients who took the lesser dose of 5 mg lost an average of 3.4 kg; patients who received the placebo lost only an average of 1.8 kg. The group of patients with a daily dosage of 20 mg of rimonabant not only lost the most weight of all of the trial participants, but they lost it in the critical places of abdomen and waist. It is remarkable, according to Prof. Van Gaal, that in these patients, the risk factors for metabolic syndrome and cardiovascular diseases were reduced more than could be expected from mere loss of weight. He estimates that 50 percent of this effect is due to rimonabant. The reason: while patients who received the 5 mg dose of rimonabant clearly lost weight, their blood lipid levels were not as improved as in patients with the higher dose.

Exhibited side effects were nausea, diarrhea, and dizziness, but according to Professor Van Gaal, they were mild and transient. “According to current findings, rimonabant appears to be very promising, especially for the treatment of patients with abdominal obesity,” Professor Van Gaal said in Berlin. The two-year study has now been concluded, and it is anticipated that the findings will be published next year.