Rimonabant: Endocannabinoid Inhibition for the Metabolic Syndrome

Comparison With Other Agents

Rimonabant is a new agent and thus long-term safety data applicable to rare side effects is not yet available. However, it is possible to compare rimonabant with the other drugs used to treat obesity[15,17] ( Table 2 ). Orlistat is well established as a weight loss agent and is considered pharmacologically safe enough that in the USA it may become available over-the-counter. However, in clinical practice a meta-analysis of 29 orlistat studies showed a 2.89 kg (2.27-3.51) weight loss in patients with an initial BMI of 36.7 kg/m2.[15] Orlistat therapy was associated with a 3.4-fold increase in diarrhoea, 3.1-fold in flatulence and 1.48-fold in dyspepsia.[15] Clinical trial data from the XENDOS and other studies shows that therapy over 2 years with % losing >5% of body weight and % losing >10%. In parallel to these changes in weight orlistat reduces triglycerides by 15-20% though it has a little effect on HDL-C or blood pressure. Only 70% of patients comply either because of poor adherence to trial protocols, which is a common problem in obesity trials or because of side effects. The main side effects of orlistat are explosive diarrhoea and bloating on consumption of fat (especially saturated fat). Thus this agent has low patient acceptance. In addition, many obese patients especially from ethnic minorities do not consume diets rich in saturated fat but vast quantities of carbohydrates. In these groups orlistat has limited efficacy.

Sibutramine has less end-point data than orlistat though 2 year studies recruiting on the basis of BMI have been performed of sibutramine added to −500 kCal/day[18] and −1200 kCal/day diets.[64] In weight loss studies it induces an average 4.45 kg (3.62-5.29) weight loss with 19-34% achieving >5% and 12-31% achieving >10% weight loss respectively.[17] In a meta-analysis, sibutramine reduced triglycerides by 0.04 mmol/l HbA1c by 0.3%, and raised HDL-C by 0.05 mmol/l.[17] Its blood pressure effects were variable with long-term trials showing a 4.6/2.8 mmHg increase. There are no data on its effectiveness in preventing diabetes or cardiovascular disease as yet though the Sibutramine Cardiovascular OUTcome study is underway.[65] The tolerability of sibutramine is 70% in obesity trials with the majority of discontinuations being caused by poor compliance or adrenergic side effects (headache, dry mouth, tachycardia and tachypnoea). It has no additive effect when combined with orlistat and seems to act as a general appetite suppressant to reduce snacks in particular but anecdotally not to affect meal habits or portion sizes.

The clinical trial data for rimonabant shows superior weight loss (5.4 kg) compared with orlistat (2.85 kg) and sibutramine (4.85 kg) in clinical trials allied with a wider degree of benefit on cardiovascular risk factors. Compliance in all the obesity trials is about 70% and side effects are generally seen in 10-30%. The side effect profile of rimonabant is better than that of orlistat where gastrointestinal side effects occur in 20-30% and similar to sibutramine where compliance and side effect rates are similar but the drug is contraindicated in significant groups of patients (secondary prevention and hypertension). No data exists as yet for rimonabant in combination with other obesity medications. Given the profoundly different mechanism of action of rimonabant it is a good alternative where other anti-obesity medications have not been tolerated or are contraindicated. As it has beneficial action on lipid profiles that are not seen with orlistat, it may be superior to this agent in patients with notable dyslipidaemia as well as obesity and insulin resistance and also has beneficial effects in helping increase rates of cessation of smoking. The long-term benefits of rimonabant will be confirmed in studies looking directly at its effects on the progression of atherosclerosis by intravascular ultrasound and in a cardiovascular end-point trial (the Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints and Outcomes[66] trial) where rate of progression to diabetes is a secondary end-point.  Printer- Friendly Email This

Int J Clin Pract.  2006;60(12):1697-1706.  ©2006 Blackwell Publishing
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