Bronander and Bloch Development Involving Administration of Rimonabant: the Intravascular Ultrasound Study (STRADIVARIUS) may be the most clinically meaningful. This long-term international effort will examine the effect of rimonabant therapy on an important surrogate endpoint, the progression of coronary ath- eroma as measured by intravascular ultrasound, using similar methodology to what has been done with other proven risk reduction strategies. Most of these trials are several years away from completion but will answer some important questions about the effects of rimonabant in managing cardiometabolic risk. These trials should also add important data on safety and tolerability in persons with important comorbid conditions. Hopefully, future studies will also seek a more diverse patient population since the published trials to date have in- cluded predominantly white patients. It will also be important to study the effects of rimonabant in patients with a history of mild depression and other psychiatric conditions and in persons on pharmacological treatment for depression. The currently published trials speciﬁcally excluded these conditions yet many obese patients either have a diagnosis of or risk factors for depression (Herva et al 2006). It will also be important to study the effects of rimonabant with concomitant use of other weight loss medications such as orlistat and sibutramine as well as other lipid-lowering and hypoglycemic agents. Since rimonabant works through a unique mechanism, combination therapy may offer a cumulative effect on weight loss and other cardiometabolic endpoints. In addition to effects on cardiometabolic risk, the central nervous system effects of rimonabant may be useful in other conditions such as tobacco or alcohol dependence. At least one large prospective randomized clinical trial investigating the use of rimonabant for smoking cessation has been completed. The Studies with Rimonabant and Tobacco Use—United States (STRATUS-US) was a 10-week trial where chronic tobacco users desiring to quit were randomized to either placebo, 5 mg rimonabant, or 20 mg rimonabant once daily (Anthenelli and Dale 2004). Patients in the 20 mg group were more successful at quitting smoking (36%) than the placebo group (21%). Nevertheless the US Food and Drug Administration (FDA) issued a letter to the manufacturer stating that rimonabant will not be considered for smoking cessation at this time (Sanoﬁ Aventis 2006). Future studies should continue to look into this indication as well as useful- ness in other addictive disorders such as alcoholism. Perspective and conclusion Rimonabant has recently received approval for marketing as a weight management drug in Europe with the precaution 188 that it should not be used in patients with serious uncon- trolled psychiatric illnesses like major depression or who are receiving anti-depressant medication. In the US, the FDA issued an “approvable” letter for rimonabant as a weight loss agent, but at the time this manuscript was written it has not yet received ﬁnal approval for marketing in the US (Sanoﬁ Aventis 2006). Assuming that rimonabant will soon be available to prac- titioners and their patients worldwide, it will be interesting to see how this unique therapeutic agent is used clinically. Although the absolute magnitude of the effect on weight loss is similar to other available pharmacological agents, the overall effect on weight is relatively modest, especially compared with the effect that can be attained with bariatric surgery or medically supervised very low calorie diets in motivated individuals. The placebo-corrected reduction in weight of about 5 kg seen with rimonabant 20 mg daily in the RIO trials, while certainly clinically meaningful, represents only a small fraction of the excess weight many overweight and obese individuals need to lose in order to signiﬁcantly improve their health and quality of life. Although regulatory agencies have so far offered indica- tions for rimonabant as a weight management drug only, the true potential beneﬁt of this novel pharmacological approach lies in its ability to positively affect multiple cardiometabolic risk factors simultaneously. Since statistical analysis sug- gests that only approximately 50% of the affect on HDL-C, triglycerides, and HgbA1C (in subjects with DM) can be at- tributed to weight loss alone, presumably rimonabant should offer additional beneﬁt in reducing cardiometabolic risk over and above other similarly effective weight loss strategies. It should be noted that in keeping with the design of the RIO studies all the results cited in this review use ITT-LOCF analysis. Given the high rate of non-completers in these clini- cal trials, these results underestimate the beneﬁts of those who completed 1 year of therapy. At least in RIO-EU, subjects who remained on rimonabant for the full year demonstrated signiﬁcantly more favorable results than those who did not complete the study. Nonetheless, it should be noted that the changes in lipid parameters seen in RIO-Lipids and other studies are relatively modest compared with other available therapies such as nicotinic acid, ﬁbrates, and even high dose omega 3s, and importantly there is no apparent effect on LDL-C, the primary target of intervention for patients with dyslip- idemia according to the US National Cholesterol Education Program. As patients on previous lipid lowering agents were excluded from RIO-Lipids, it is also unclear whether Vascular Health and Risk Management 2007:3(2)