were also seen in fasting glucose, insulin resistance, HDL- C, total cholesterol to HDL-C ratio, triglycerides, and systolic BP. However, after adjusting for weight loss, the residual effects on triglycerides and systolic BP were not signiﬁcant. Like in RIO-Lipids, all three randomized groups showed an increase in LDL-C of approximately 7%. Table 2 illustrates the placebo subtracted change from baseline in the major metabolic variables measured at the completion of the study. Unlike the other studies, RIO-DM also examined change in placebo subtracted HbA1C. After one year of therapy, in the 20 mg group there was an absolute decrease in HbA1C of –0.6% compared with a change of only +0.1% with placebo (p < 0.0001). Additionally, 42.9% of the patients receiving 20 mg of rimonabant achieved a HbA1C of <6.5% compared with only 20.8% in the placebo group. According to the statistical analysis used by the investigators, the effects of rimonabant 20 mg on HbA1C were twice that attributable to weight loss alone. A similar side-effect proﬁle was seen in this trial compared with the other RIO trials and is discussed in the following section. Safety and tolerability of rimonabant in the RIO clinical trials As noted above, in each RIO study a large number of patients (34%–47%) did not complete the full year of study drug. While concerning, this high drop-out rate is similar to that seen in other trials of obesity treatment and there was no statistically signiﬁcant difference in overall discontinuation rates between treatment groups. Although overall discontinu- ation rates were similar, discontinuations speciﬁcally due to adverse effects were greater in the rimonabant-treated groups. The most common reasons for discontinuation in treatment groups included the psychiatric disorders of depression, anxi- ety, and irritability, followed by nausea. Discontinuation rates due to psychiatric complaints and disorders for each of the RIO trials are shown in Table 3. Overall, nausea is the most common adverse event reported with rimonabant in these clinical trials. The incidence of adverse effects diminished Rimonabant and cardiometabolic risk over time suggesting either a degree of tolerance or that the majority of side-effects occurred fairly quickly after initiation of treatment. All of the RIO trials screened for depression and anxiety throughout the studies with the Hospital Anxiety and Depres- sion Scale (HADS) (Zigmond and Snaith 1983). This scale contains 7 items assessing depression and 7 items assessing anxiety with each item scored from zero to three. Scores 11 usually require additional assessment. There were no reported differences in groups on this scale; however, exclusion crite- ria for each study speciﬁcally excluded patients with a known history of severe depression. Additionally, in three of the trials (RIO-Europe, RIO-NA, and RIO-DM) subjects taking either antidepressants or medications known to alter weight (including anti-depressants) were also excluded. Importantly, the number of patients in each group who scored 11 on the HADS and the number removed after subsequent psychiatric consultation have not been included in the published manu- scripts (Gadde and Allison 2006). Safety was also assessed by examining the effect of treat- ment on multiple other parameters including QTc intervals on electrocardiogram, hematological parameters, liver function, kidney function, and blood pressure. No signiﬁcant incidence of adverse effects was seen in any of these parameters in any trials. In RIO-DM there was a higher incidence of hypogly- cemia in the rimonabant 20 mg group compared with placebo (5% vs 2%) and this occurred more frequently in patients on concomitant sulfonylurea (but not on metformin) therapy. Future directions for research with rimonabant The beneﬁcial cardiometabolic effects of rimonabant have led to interest in further research in multiple areas. Ongoing trials include those examining the effects of rimonabant on cardiovascular events endpoints (myocardial infarction, stroke, or cardiovascular death), progression of atheroma, visceral fat accumulation, and prevention of diabetes in individuals with impaired glucose tolerance. Of these planned clinical trials, perhaps the Strategy to Reduce Atherosclerosis Table 3 Discontinuations during RIO trials due to any adverse event and due to psychiatric disorders Any adverse event Psychiatric disorders Placebo Rimonabant 20 mg Placebo RIO-EU 9.2% 14.5% 5.2% RIO-Lipid 7.0% 15.0% 2.4% RIO-NA 7.2% 12.8% 2.3% RIO-DM 5.5% 15.0% 0.9% Vascular Health and Risk Management 2007:3(2) Rimonabant 20 mg 7.0% 7.6% 6.2% 3.6% 187