Summary amd Introduction
Summary
Rimonabant is the first drug to target the endocannabinoid (CB) pathway by inhibiting the actions of anandamide and 2-archidonyl-glycerol on CB1 receptors. This review gives an overview of rimonabant and the CB system and how this system relates to obesity. Rimonabant blocks the central effects of this neurotransmitter pathway involved in obesity and weight control and also blocks the direct effects of CBs on adipocyte and hepatocyte metabolism. Blockade of CB1 receptors leads to a decrease in appetite and also has direct actions in adipose tissue and the liver to improve glucose, fat and cholesterol metabolism so improving insulin resistance, triglycerides and high-density lipoprotein cholesterol (HDL-C) and in some patients, blood pressure. The Rimonabant in Obesity (RIO) trials have shown that rimonabant induces weight loss >5% in 3040% of patients and >10% in 1020% above both a dietary run-in and long-term hypocaloric management over a 2 year period with a low level of drug-related side effects. Rimonabant therapy is associated with an extra 810% increase in HDL-C and a 1030% reduction in triglycerides and improvements in insulin resistance, glycaemic control in patients with diabetes and also adipokines and cytokines including C-reactive protein over hypocaloric diet therapy. In addition rimonabant abolishes the weight gain associated with smoking cessation and improves the chances of quitting smoking. Thus rimonabant has major effects on both the metabolic syndrome and cardiovascular risk factors thus has the potential to reduce the risks of type 2 diabetes and cardiovascular disease associated with the cardiometabolic phenotype.
What is Known About the Subject
The prevalence of obesity is increasing rapidly.
Current weight loss therapies have significant limitations.
The endocannabinoid system is involved in the regulation of appetite and metabolism.
What Does This Article Add?
The endocannabinoid system is a new target for obesity and metabolic syndrome therapies.
Rimonabant is the first CB1 receptor blocker to reach clinical practice.
Clinical trials in man have shown that rimonabant has consistent effects in reducing weight, abdominal obesity in patients with obesity, obesity with dyslipidaemia and obesity and concurrent type 2 diabetes.
Review Criteria
This review was compiled using data from PubMed identified using the search terms cannabinoid, endocannabinoid; drug treatment added to obesity and the drug names rimonabant and SR141716A. Additional data was sourced from conference abstracts, clinical trials databases and press releases of the American Heart and Diabetes Societies.
For The Clinic
Rimonabant is a new anti-obesity drug acting on the endocannabinoid system.
It delivers a consistent 5 kg of weight loss.
It has a secondary beneficial effect on lipids, glucose and neutral effects on blood pressure.
It has a generally good tolerability profile.
Introduction
An epidemic of obesity is occurring in the developed and developing world. As gross obesity becomes commoner, milder degrees of obesity remain unnoticed as they are the norm. It is already accepted that patients recruited for phase I drug trials in the USA should average a body mass index (BMI) of 30 kg/m. Yet the cardiometabolic consequences of mild obesity are likely to be more severe. Gross morbid obesity with its osteological and physiological problems is associated with an increased risk of mortality and with a 9 years reduction in life expectancy. Beneficial trends have been evident for 20 years in some cardiovascular disease and diabetes risk factors including smoking, relative saturated fat intakes and cholesterol levels. However, these are counterbalanced and may be overwhelmed by adverse trends in increased carbohydrate intakes, increased food calorie densities and especially reduced exercise resulting in obesity and rises in the prevalence of obesity-associated cardiometabolic risk factors.