Bronander and Bloch Table 2 Selected placebo subtracted results from rimonabant in obesity (RIO) trials after 1 year. Only shown are those results that are statistically signﬁcant Measure RIO-EU RIO-Lipids RIO-NA RIO-DM Weight (kg) –4.7 –5.4 –4.7 –3.9 Waist circumference (cm) –4.2 –4.7 –3.6 –3.3 SBP (mmHg) ns –1.8 ns –2.4 DBP (mmHg) ns –1.5 ns ns HDL-C (% change) 8.9 8.1 7.2 8.3 TG (%change) –15.1 –12.4 –13.2 –16.4 Total C:HDL-C ratio –0.29 –0.32 –0.28 –0.35 Fasting glucose (mmol/L) –0.06 ns ns –0.97 Fasting insulin (µU/mL) –2.8 –2.6 –2.8 ns Peak size LDL-C particle (Å) nr 1.2 nr nr Adiponectin (µg/ml) nr 1.5 nr nr Leptin (ng/ml) nr –3.8 nr –3.4 HOMA-IR (%) –0.7 nr –0.8 –1.1 CRP (mg/L) nr –0.5 nr –1.4 Data are from ITT-LOCF analysis. Data are placebo subtracted from the 20 mg rimonabant treatment group. Abbreviations: ns, not signiﬁcant (p > 0.05); nr, not reported; SBP, systolic blood pressure; DBP, diastolic blood pressure; C, cholesterol; HOMA-IR, insulin resistance mea- sured by homeostasis model assessment; CRP, C-reactive protein. the MetSyn decreased from a baseline of 34.8% to 21.2% in the 20 mg group. Investigators used analysis of covariance (ANCOVA) to demonstrate that the effects in HDL-C, TG, fasting insulin, and insulin resistance were twice that attribut- able to the weight loss alone, once again pointing to a weight- independent effect of CB-1 blockade. Neither treatment group showed signiﬁcant changes in fasting glucose, SBP, or DBP. Table 2 illustrates the placebo subtracted change from baseline in the major metabolic variables measured at the completion of the ﬁrst year of the study. During the second year of the study, subjects who contin- ued to receive 20 mg of rimonabant maintained the weight loss achieved during the ﬁrst year (placebo subtracted mean loss of 7.4 kg) and continued to show signiﬁcant beneﬁcial changes in HDL-C, triglycerides, total cholesterol to HDL-C ratio, waist circumference, fasting insulin, and insulin resis- tance. However, subjects who received rimonabant 20 mg the ﬁrst year followed by placebo the second year slowly regained most of their previously lost weight and waist circumference. After completion of year two, subjects who received 1 year of rimonabant followed by 1 year of placebo had similar weight and metabolic parameters to those who received placebo for the full two years. Based on these results, it appears that chronic administration of rimonabant, at least longer than 1 year, may be necessary in order to maintain the beneﬁcial clinical effect over the long term. Rimonabant in obesity – diabetes (RIO-DM) Although the results of RIO-DM have been presented at mul- tiple national meetings and have been widely disseminated, 186 the results were not published as a complete manuscript in a peer-reviewed journal until fall 2006 (Scheen et al 2006). In RIO-DM 1045 overweight or obese patients with T2DM were randomized to daily doses of placebo, 5 mg, or 20 mg of rimonabant for 1 year in a fashion similar to the above- mentioned trials. Additional inclusion criteria for RIO-DM included monotherapy oral hypoglycemic treatment with either metformin or a sulfonylurea for at least 6 months, fasting glucose of 5.55–15.04 mmol/L (100–271 mg/dL), and hemoglobin A1C (HbA1C) between 6.5% and 10%. Exclusion criteria included any clinically signiﬁcant micro- vascular or macravascular diseases related to T2DM, systolic BP 160 mmHg, or diastolic BP 95 mmHg, pregnancy, lactation, recent change in smoking status, or the use of anti- obesity drugs in the prior 3 months. In addition, subjects using concomitant medications known to affect weight, including antidepressants, were excluded. Patient demographics were roughly similar across the three treatment groups. Overall, 88.5% of participants were white and 50.1% were female. Average baseline weight was about 98 kg and mean base- line HgbA1C was 7.3%. The majority of patients were on metformin monotherapy at baseline. Sixty-six per cent of patients completed the 1-year follow-up. In the ITT-LOCF analysis, the placebo group lost 1.4 kg body weight compared with a 2.3 kg loss (p = 0.01 vs placebo) for the 5 mg treatment group and a 5.3 kg loss (p < 0.0001 vs placebo) for the 20 mg group. Waist circumference decreased 1.9 cm in the placebo group compared with a decreases of 2.9 cm (p = 0.02 vs placebo) and 5.2 cm (p < 0.0001 vs placebo) respectively in the 5 mg and 20 mg groups. Beneﬁcial effects Vascular Health and Risk Management 2007:3(2)