The drug rimbonabant helped to substantially reduce the bodyweight, waist circumference, and risk factors for heart disease in obese people, according to results of a phase III randomised trial presented at the Scientific Sessions of the American College of Cardiology in Orlando, Florida in March and published in The Lancet (15/4/04): ‘Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients.’ (The first-year results of the RIO-Europe study were presented at the European Society of Cardiology meeting in August 2004).
The RIO-Europe two-year phase III study of rimonabant involved 1,507 people from Europe and the USA, and was led by principal investigator Luc Van Gaal MD, Professor of Diabetology, Metabolism and Clinical Nutrition, and colleagues at the University Hospital Antwerp, Belgium. ‘The RIO-Europe findings demonstrated that in addition to maintaining body weight loss, two-year treatment with rimonabant 20 mg/day compared with placebo reduced waist circumference improved metabolic profile and reduced the number of patients meeting the National Cholesterol Education Programme (NCEP) criteria for metabolic syndrome, thus diminishing cardiovascular risk factors in patients studied,’ Professor Van Gaal concluded.
In an accompanying comment in The Lancet, Uberto Pagotto and Renato Pasquali, of the Department of Internal Medicine and Gastroenterology, Sant Orsola-Malpighi Hospital, Bologna, Italy, wrote: ‘These data, and those from the other ongoing clinical trials with rimonabant, might presumably help us to better tackle obesity and related metabolic and cardiovascular disease. When additional drugs are available, we will also have the possibility to individually target the therapeutic strategies according to phenotype characteristics and to the pathophysiological mechanism inducing the disease.
The RIO-Europe two-year phase III study of rimonabant (see page 1), led by principal investigator Luc Van Gaal MD, Professor of Diabetology, Metabolism and Clinical Nutrition, and colleagues at the University Hospital Antwerp, Belgium, involved 1,507 people from Europe and the USA.
Participants had a body mass index (BMI) of 30 kg/m2 or greater, or a BMI greater than 27 kg/m2 with abnormal blood fat levels, high blood pressure, or both. They were randomly assigned 5mg or 20mg of a drug called rimonabant, rimonabant (the first in a new class of therapeutic agents called selective CB Blockers) or a placebo once daily, in addition to a calorie controlled diet. The treatment groups had similar characteristics. 920 patients (61%) completed the one-year follow-up: 379 in the rimonabant 5mg group, 363 in the rimonabant 20mg group and 178 in the placebo group. Weight loss at one year was greater in patients treated with 5 mg or 20 mg of rimonabant compared with placebo. More than 67% of patients who completed treatment with 20mg of rimonabant achieved 5% or more weight loss, and 39% achieved 10 % or more weight loss.
Patients on 20 mg of rimonabant had greater improvements than placebo in waist circumference (average reduction of four cm), and cardiovascular risk factors including cholesterol, insulin resistance and prevalence of metabolic syndrome. The pattern of weight loss seen with rimonabant was sustained for around 36-40 weeks.
Side effects - The most common side effects leading to study discontinuation were depressed mood disorders in all treatment groups; withdrawals due to nausea, vomiting, diarrhoea, headache, dizziness, and anxiety were more frequent in the rimonabant 20 mg group than in other groups. Serious adverse events did not occur more frequently in patients treated with the drug than in those on placebo.
The trials were funded by the Paris-based pharmaceutical company Sanofi-Aventis, where researchers had worked on the premise that, because cannabis smokers experience extreme hunger bouts, cannabinoids stimulate appetite, a means of blocking the brain’s central cannabinoid (CB1) receptors could reduce hunger. The researchers cloned the human cannabinoid receptor then expressed this in cells. Compounds with potential inhibitory activity against this receptor were then screened for inhibitory activity, and rimonabant was identified as a CB1 receptor antagonist. Pre-clinical animal studies later indicated that rimonabant reduced consumption of fats and sugars.