Bronander and Bloch insulin levels, a 53% decrease in leptin levels, a statisti- cally signiﬁcant decrease in non-esteriﬁed fatty acids, and statistically signiﬁcant improvement in insulin sensitivity. When these experiments were repeated in CB-1 knockout mice rimonabant had no effect, indicating that the beneﬁcial effect of rimonabant is mediated entirely through the CB-1 receptor. Interestingly, CB-1 knockout mice also appear to have a greater tendency towards anxiety-like responses and anhedonic state (Martin et al 2002). In an obese rat model, Vickers et al showed that 4 weeks of treatment with rimonabant decreased food intake and weight. Discontinuation of rimonabant led to increased food intake and signiﬁcant weight regain (Vickers et al 2003). This ﬁnding suggests that the effects of rimonabant on weight are reversible upon cessation of treatment. Leptin is a beneﬁcial adipose tissue derived neuropep- tide that appears to be strongly associated with weight and metabolism (Kershaw and Flier 2004). Rats with genetically deﬁcient leptin signaling are obese and are used as a research model of obesity. It appears that leptin modulates appetite at least in part by reducing levels of endocannabinoids in the hypothalamus (Di Marzo et al 2001). As mentioned above, Bensaid et al demonstrated that blockade of CB-1 by rimonabant increased levels of adiponectin in wild type mice and in obese rats with defective leptin signaling (Bensaid et al 2003). Adiponectin is a protein product of white adipose tissue and is beneﬁcial in lipid and glucose metabolism. Some of the known effects of adiponectin include increasing skeletal muscle fatty acid transport and oxidation, improvement of hepatic insulin sensitivity, and decreasing vascular inﬂam- mation (Chandran et al 2003). Together these animal studies demonstrate that by block- ing CB-1, administration of rimonabant leads to sustained weight loss, decreased free fatty acid levels, and improvement in insulin sensitivity that is reversible upon discontinuation of the drug. These effects are likely mediated through multiple mechanisms including decreased energy intake and changes in metabolism related to increases in circulating levels of leptin and adiponectin. Efﬁcacy of rimonabant in clinical trials of overweight and type 2 diabetes mellitus In a 16-week phase IIb trial enrolling obese individuals, aver- age weight loss was 1.1, 3.5, 3.9, and 4.4 kg for once daily doses of placebo, 5 mg, 10 mg, and 20 mg of rimonabant respectively (Di Marzo and Matias 2005). In the phase III clinical trial program doses of 5 mg and 20 mg daily were compared with placebo. Since the 20 mg dose is likely to 184 be the most utilized in clinical practice, presentation of the results of these trials will focus on that dose. As part of this phase III program there have been four major completed, pla- cebo-controlled, double-blind, randomized controlled trials of rimonabant in humans: Rimonabant in Obesity – Europe (RIO-EU), Rimonabant in Obesity – Lipids (RIO-Lipids), Rimonabant in Obesity – North America (RIO-NA), and Rimonabant in Obesity – Diabetes (RIO-DM) (Van Gaal et al 2005; Després et al 2005; Pi-Sunyer et al 2006; Scheen et al 2006). Participants in all trials were overweight (body mass index [BMI] 27 kg/m2) or obese (BMI 30 kg/m2) and were randomized to one of three groups, rimonabant 5 mg daily, rimonabant 20 mg daily, or placebo and followed for at least 1 year. All patients were asked to follow a hypo-calorie diet aimed at reducing caloric intake by approximately 600 kcal/day. In each study, prospective subjects underwent a 4-week placebo run-in, during which a number of patients were excluded; these patients were not included in subsequent intention-to-treat (ITT) analysis. Exclusion criteria common to all four trials included clinically signiﬁcant cardiovascular, endocrine, pulmonary, neurological, dermatological, gastrointestinal, hepatic, hematological, renal, and psychiatric diseases (including severe depression). In all but the RIO-DM trial diabetic patients were excluded. Com- mon measured parameters included changes from baseline in weight, waist circumference, systolic blood pressure (SBP) and diastolic blood pressure (DBP), changes in levels of high den- sity lipoprotein cholesterol (HDL-C), serum triglycerides (TG), fasting glucose, fasting insulin, and total cholesterol to HDL-C ratio. In each study, change from baseline in each parameter was calculated using ITT, last observation carried forward (LOCF) analysis. Detailed differences in methodology and the results of each trial are described below. Rimonabant in obesity – Europe (RIO-EU) In RIO-EU 1507 obese patients (BMI 30 kg/m2) or over- weight patients (BMI 27 kg/m2) with either hypertension or dyslipidemia were randomized to placebo, 5 mg or 20 mg of rimonabant daily (Van Gaal et al 2005). Eighty per cent of participants were female, 94% were white, and the mean age at baseline was 45 years. At baseline, 41% had hypertension, 61% had dyslipidemia, and 41% met criteria for the metabolic syndrome. The mean baseline weight was 101 kg. Only 61% of participants completed the trial. In the intention to treat (ITT) analysis with the last observation carried forward (LOCF) the 5 mg group decreased body weight 3.4 kg (p = 0.002 vs placebo) and the 20 mg group decreased 6.6 kg (p < 0.001 vs placebo). The proportions of Vascular Health and Risk Management 2007:3(2)