Four published clinical trials have assessed the efficacy and safety of rimonabant in the treatment of obesity and cardiometabolic risk factors. Other studies of the drug have been presented as posters at clinical meetings, but they are not reviewed in this article.
The iSmonabant In Obesity (RIO) Program consists of four published clinical trials comparing rimonabant 5 mg and 20 mg with placebo. RIO-Lipids and RIO-Diabetes were one-year trials; RIO-Europe and RIO-North America were two-year trials. Results of RIO- Lipids, RIO-Diabetes, and RIO-North America, as well as the first-year results of RIO-Europe, have been published.
Despres et al. and the RIO-Lipids Study
Despres et al. conducted a randomized, double-blind study for 12 months to evaluate the efficacy and safety of rimonabant in overweight or obese patients (BMI, 27-40 kg/m2) with untreated dys-lipidemia. Patients included in the study, called Rimonabant in Obesity-Lipids (RIO-Lipids), were required to have fasting plasma triglyceride levels of 1.7 to 1.79 mmol/L (150 to 700 mg/dl), a ratio of total cholesterol to high-density lipoprotein-cholesterol (HDL-C) above 5 for men and above 4.5 for women, or both.
Patients were excluded for the following reasons:
A total of 1,036 patients were randomly assigned to the following groups: placebo (n = 342), rimonabant 5 mg (n = 345) once daily, or rimonabant 20 mg (n = 346) once daily. In the intention-to-treat-population (ITT)/last-observation-carried-forward (LOCF) analyses, patients receiving rimonabant 20 mg lost 6.9 kg; with rimonabant 5 mg, they lost 3.1 kg; and with placebo, they lost 1.5 kg.
The net weight loss for patients receiving rimonabant 20 mg, when adjusted for placebo, was 5.4 kg. A significant decrease in weight loss was observed in the two rimonabant treatment groups, compared with the placebo group, at the end of the 12 months. The proportion of patients who lost 10% or more of their weight was 32.6% with rimonabant 20 mg; the proportion of those who lost the same amount of weight was 7.2% with placebo (P < 0.001).
Weight loss occurred during the first nine months of the study period, and a plateau was observed for the remaining three months without weight being regained. In waist circumference, a significant decrease of 7.1 cm was observed with rimonabant 20 mg; a reduction of 3.5 cm was seen with 5 mg; and a decrease of 2.4 cm occurred with placebo (P = 0.029).
A significant increase in HDL-C levels was noted for both rimonabant doses (19% with 20 mg, 14°% with 5 mg), compared with 11% for placebo (P = 0.025). Triglyceride levels remained stable with rimonabant 5 mg and placebo but decreased by 12% when the dose was 20 mg.
Although the result was not significant, LDL-C levels increased by approximately 7% in all three study groups.
Reductions in fasting glucose were not observed in any of the groups. The prevalence of the metabolic syndrome was significantly reduced by 41% in the patients receiving rimonabant 20 mg because of the reduction in waist circumference and the increase in HDL-C levels.
Adverse drug events (ADEs), reported in 5% or more of the rimonabant-treated patients, included nausea, dizziness, influenza, anxiety, diarrhea, and insomnia, and they occurred early in the study period. These ADEs were more common in patients receiving rimonabant 20 mg. More patients in the 20-mg group discontinued the study because of ADEs, compared with patients in the other two groups.
The most frequently occurring ADEs leading to discontinuation from the study were nausea (in 1.2% of patients receiving 20 mg, in 0.6% with 5 mg, and in 0% with placebo) and psychiatric disorders, including depression (in 2.9% of patients receiving 20 mg, in 1.7% given 5 mg, and in 0.6% given placebo) and anxiety (in 1.7% of patients receiving 20 mg, in 0.3% with 5 mg, and in 0.6% with placebo).
Van Gaal et al. and the RIO-Europe Study
A two-year, multicenter, randomized, double-blind, placebo-controlled study (RIO-Europe) was conducted to assess the efficacy and safety of rimonabant 5 and 20 mg in reducing body weight and improving cardiovascular risk factors in overweight or obese individuals. Obese patients over the age of 18 with a BMI of 30 kg/m2 or more and overweight patients with a BMI of 27 kg/m2 or more with treated or untreated hypertension or with treated or untreated dyslipidemia participated in the study. Patients were excluded from the study if they had diabetes mellitus; cardiovascular, pulmonary, hepatic, or renal disorders; and substantial neurological and psychological illness.
The primary endpoint of the study was the change in weight from baseline in the ITT/LOCF population after one year of treatment. A total of 1,507 patients received placebo (n = 305), rimonabant 5 mg (n = 603), or rimonabant 20 mg (n = 599) once daily with a hypocaloric diet of 600 kilocalories/day. Patients underwent a two-week screening period, followed by a four-week single-blind, placebo run-in period.
Nine hundred twenty patients (66%) completed the one-year follow-up phase: placebo, 178 patients (58.4%); rimonabant 5 mg, 379 patients (62.7%); and rimonabant 20 mg, 363 patients (60.6%).
In the ITT/LOCF population, a significantly greater mean weight loss from baseline was observed with rimonabant 5 mg (-3.4 kg, P = 0.002) and 20 mg (-6.6 kg, P < 0.001) than with placebo (-1.8 kg).
A significant decrease in waist circumference from baseline was also observed with 5 mg (-3.9 cm, P = 0.002) and 20 mg (-6.9 cm, P < 0.001), compared with placebo (-2.4 cm).
Significantly more patients in the two rimonabant groups who completed the study also achieved a weight loss of 5% or more from baseline, compared with the placebo group (67.4% with rimonabant 20 mg; 44.2% with rimonabant 5 mg; and 30.5% with placebo). However, the proportion of patients achieving a weight loss of 10% or more from baseline was greater with 20 mg (39%) than with placebo (12.4%, P < 0.001), but no difference was found between rimonabant 5 mg (15.3%) and placebo (12.4%).
Compared with patients receiving placebo, the 20-mg group showed significant improvements in levels of HDL-C, triglycerides, fasting plasma glucose, and insulin.
Most ADEs were reported with the 20-mg dose of rimonabant. Nausea was reported by 13% of patients receiving 20 mg, by 5% receiving 5 mg, and by 4% receiving placebo. The percentages of patients discontinuing the study because of ADEs were 14.5% (87 patients) receiving 20 mg, 8.3% (50 patients) receiving 5 mg, and 9.2% (28 patients) receiving placebo.
Of the 87 patients who discontinued rimonabant 20 mg during the trial, approximately 50% (42 patients, or 7% of all patients receiving that dose) did so because of psychiatric disorders, with depression being the most common (22 patients, or 3.7%).
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Pi-Sunyer et al. and the RIO-North America Study
In the two-year, randomized, double-blind, placebo-controlled RIO-North America trial, Pi-Sunyer et al. compared the safety and efficacy of rimonabant with placebo in obese adults with a BMI of 30 kg/m2 or more and in overweight adults with a BMI of 27 kg/m2 or more with treated or untreated hypertension or dyslipidemia. Patients with diabetes mellitus were excluded from this study.
At the end of one year, the investigators performed efficacy analyses using the ITT/LOCF population to determine weight loss and, at the end of two years, whether patients had avoided regaining weight. After a four-week run-in period, with a total of 3,045 patients, 607 received placebo, 1,216 received rimonabant 5 mg, and 1,222 received rimonabant 20 mg once daily in conjunction with a low-calorie diet and exercise.
After one year, 51% of the placebo and rimonabant 5-mg patients completed the study. The 20-mg group had a slightly higher completion rate of 55%.
Patients lost significantly more weight with rimonabant 5 mg and 20 mg than with placebo. The percentage of patients achieving a weight loss of 10% or more was 25.2% with rimonabant 20 mg and 8.5% with placebo (P < 0.001). Only 10.6% of the 5-mg patients lost 10% or more of their baseline body weight.
The rimonabant 20-mg group experienced a greater decrease in waist circumference (-6.1 cm vs. -2.5 cm with placebo; P < 0.001); a greater decrease in triglyceride levels (-5.3% vs. 7.9% with placebo; P < 0.001); and a greater increase in HDL-C levels (12.6°% vs. 5.4°% with placebo; P< 0.001).
At the end of one year, patients receiving rimonabant 20 mg were randomly reassigned to continue taking the 20-mg dose or to receive placebo for a one-year follow-up period; patients taking placebo continued with the same treatment.
In the two-year ITT-LOCF population, the patients who remained on rimonabant 20 mg maintained a mean weight loss of 7.4 kg from their baseline weight; the patients who were reassigned to receive placebo regained most of their weight previously lost. Seventeen percent of patients receiving rimonabant 20 mg achieved a weight loss of 10% or more, compared with 8% of placebo patients.
After two years, the mean decrease from baseline in waist circumference was also greater in those receiving rimonabant 20 mg (-5.0 cm) than in the placebo group (-2.2 cm) (P< 0.001).
In terms of cardiometabolic risk factors in the second year of the study, patients receiving placebo had decreased levels of HDL-C and increased levels of triglycerides. A continued increase in the level of HDL-C from baseline was observed in those who received placebo or rimonabant 20 mg for two years, but the increase was significantly greater for patients taking rimonabant (P < 0.001). Triglyceride levels and features of the metabolic syndrome declined more from baseline with rimonabant 20 mg than with placebo (P< 0.001).
The percentage of patients who withdrew from the study after the first year because of ADEs was greater in those taking rimonabant 20 mg (12.8%), compared with those taking rimonabant 5 mg (9.4%) and placebo (7.2%). ADEs leading to discontinuation from the study in all treatment groups consisted of psychiatric, nervous system, and gastrointestinal tract effects. It was interesting that 6.2% of the rimonabant 20-mg patients discontinued the study because of psychiatric disorders, compared with 2.3% of the placebo patients. The overall rates of ADEs, withdrawal rates, and ADEs leading to withdrawals from the study were lower in the second year than in the first year.
The trial authors concluded that the significant weight loss achieved with rimonabant at the end of one year was well maintained during the second year in patients receiving rimonabant treatment over two years, and a favorable effect on cardiometabolic risk factors was seen.
Scheen et al. and the RIO-Diabetes Study
A multicenter, randomized, double-blind, placebo-controlled study of one year’s duration evaluated the efficacy and safety of rimonabant in combination with diet and exercise in overweight or obese patients with type-2 diabetes who had been treated with metformin or sulfon-ylurea monotherapy for at least six months. To be eligible for the study, patients had to have a glycosylated hemoglobin (HbA1c) between 6.5% and 10% and a fasting glucose concentration between 100 and 271 mg/dl (5.5 and 15.04 mmol/ L). A total of 1,045 patients were assigned to receive rimonabant 5 mg once daily (358), rimonabant 20 mg once daily (339), or placebo (348).
After one year of treatment, ITT data showed that the weight change from baseline was significantly greater in patients receiving rimonabant 5 mg (-2.3 kg, P = 0.001 vs. placebo) and rimonabant 20 mg (-5.3 kg, P < 0.001 vs. placebo) compared with placebo (-1.4 kg). A net weight loss of 3.9 kg was achieved with the 20-mg dose.
A significant reduction in waist circumference was also observed with both rimonabant doses compared with placebo. The mean HbA1c change from baseline was -0.6% for the rimonabant 20-mg group, whereas patients receiving placebo experienced an increase of 0.1% (P < 0.0001). More of the rimonabant 20-mg patients achieved a HbA1c of below 7%, compared with patients receiving placebo (P < 0.0001). Significantly greater improvements in fasting glucose, HDL, triglycerides, and non-HDL levels were observed with rimonabant 20 mg than with placebo (P< 0.0001 for all).
As with the other studies, the most common ADEs occurring in 5% or more of patients were nausea, diarrhea, vomiting, dizziness, hypoglycemia, fatigue, and anxiety. These ADEs were mild to moderate and generally occurred during the early stages of treatment. Depressed mood disorders, nausea, and dizziness were the most common ADEs leading to discontinuation of treatment in patients receiving rimonabant 20 mg.
The authors concluded that the RIO-Diabetes trial demonstrated that rimon-abant at a dose of 20 mg/day, in combination with diet and exercise, could significantly reduce body weight and waist circumference and improve HbA1c levels as well as various cardiovascular and metabolic risk factors in overweight or obese patients with type-2 diabetes that has not been adequately controlled with metformin or sulfonylurea monotherapy.
The Study .Evaluating Rimonabant Efficacy in Drug-№4ive DiahEtic Patients (SERENADE) compared the effectiveness of rimonabant 20 mg once daily with placebo in improving blood glucose control, indicated by HbA1c. This study was presented at the International Diabetes Federation World Diabetes Congress in Cape Town, South Africa, in December 2006. Patients were enrolled in the study according to the following criteria:
Patients receiving rimonabant 20 mg once daily demonstrated a significant decrease in HbA1c levels (0.8%), from a baseline of 7.9%, compared with a 0.3% decrease in patients receiving placebo (P = 0.002). In patients with baseline HbA1C levels of 8.5% or above, a significantly greater reduction in HbA1c levels was observed with rimonabant 20 mg (1.9%) than with placebo (0.7%).
Patients in the rimonabant 20-mg group lost 6.7 kg; those in the placebo group lost 2.7 kg. Significant improvements in several cardiometabolic risk factors were observed with rimonabant 20 mg, compared with placebo, including a decrease in waist circumference, an increase in HDL-C levels, a decrease in triglycerides, a decrease in fasting plasma glucose, and an increase in adiponectin, a protein hormone that plays a role in the suppressing metabolic derangements that may result in type-2 diabetes.
The most common ADEs were dizziness (10.9% with rimonabant 20 mg vs. 2.1% with placebo), nausea (8.7% with 20 mg vs. 3.6% with placebo), upper respiratory tract infection (7.2% with 20 mg vs. 2.7% with placebo), anxiety (5.8% with 20 mg vs. 3.6% with placebo), and depressed mood (5.8% with 2 mg vs. 0.7% with placebo).
The most common ADEs leading to withdrawal from the study were nausea (2.2% with rimonabant 20 mg vs. 0% with placebo), depressed mood disorder (2.2% with 20 mg vs. 0% with placebo), and paraesthesia (2.2% with 20 mg vs. 0% with placebo).