Rimonabant In Obesity ( RIO ) Trials

Four large randomized double-blind placebo-controlled multicentric trial collectively termed as RIO (Rimonabant In Obesity) trials investigated efficacy of Rimonabant 5 or 20mg once daily in over weight and obese patients.

The RIO trials included the 1-year RIO-lipids (n=1036) and RIO Diabetes (n=1047) trials and 2-year RIO-Europe (RIO-EU; n=1508) and RIO-North America (RIO-NA; n=3045) trials. In year 2 of the RIO-NA trial, patients taking Rimonabant were randomized to receive either placebo or the same Rimonabant dosage (patients receiving placebo continued to receive placebo).

Patient were put on a mildly hypocaloric diet and randomization was preceded by a 4-week, single blind, placebo run-in period.

Inclusion criteria included a baseline BMI of 28-40 kg/m2 or either 30 or 27 kg/m2 plus treated or untreated dyslipidemia and/or hypertention.

In the RIO-Lipids trial, patients had untreated dyslipidaemia (fasting TG levels of 1.69-7.90 mmol/L and a ratio of total cholesterol to HDL-C of > 4.5 for women and >5.0 for men). In the RIO Diabetes trial, patients had treated type 2 diabetes (HbA1c 6.5-10%, fasting glucose 5.6-15.0 mmlo/L and monotherapy with either metformin or a sulfonylurea for 6 months, with a stable dosage for 3 months)

The primary end point for all the trials were weight change at 1 year. Other end points included changes from base line in weight at 2 years, waist circumference, lipid profile, glycaemic control and/or metabolic syndrome prevalence.

Weight loss and Maintenance therapy with Rimonabant

In over weight or obese patient, rimonabant reduced weight to a significantly greater extent than placebo. At one year mean weight loss was significantly greater with rimonabant 20mg once daily than with placebo in the RIO-EU, RIO-NA, RIO-Lipids and RIO-Diabetes trials. Rimonabant recipients without type-2 diabetes lost 6.3 -6.9kg, where as placebo recipients lost1.5 -1.8 kg, patients with type-2 diabetes lost 5.3 and 1.4 kg after I year of treatment with rimonabant or placebo.

Maintenance of weight loss occurred when rimonabant 20mg once daily was continued for 2 years. In the RIO-NA study, patients receiving rimonabant during year 1 who were randomized to a second year of rimonabant maintained a 3.6 kg placebo adjusted loss from baseline at the end of the 2-year study period, where as those re-randomized to placebo regained most of the weight lost (p<0.001). In the 2-year completer population of the RIO-EU study, total weight loss was greater with rimonabant than with placebo (7.2 vs 2.5kg;p<0.001)

The proportion of obese of overweight patients achieving a weight loss of 5% or 10% of their baseline weight after1 year was significantly (p<0.001) greater with rimonabant than with placebo in all four trials.

Weight loss of >5% or >10% of baseline continued to be significantly (p<0.001) greater with rimonabant than with placebo after 2years ( 5%: 40% Vs 19%), 10% 17% Vs 8% and 32% vs. 11%.

Decrease in Waist circumference with Rimonabant

Mean decrease from baseline in waist circumference were significantly greater with rimonabant 20 mg once daily than with placebo at 1 year in the RIO -EU (6.5 vs2.4 cm), RIO-NA (6.1 vs2.5 cm), RIO-Lipid (7.1 vs2.4 cm) and RIO-Diabetes (5.2 vs1.9 cm) trials.

The overall reduction in waist circumference remained significantly (p<0.001) greater in rimonabant compared with placebo recipients after 2 years of treatment. (5.0 vs2.2cm and 7.5 vs3.4 cm)

Placebo-subtracted analysis showed that rimonabant 20 mg was associated with significant (all p_0001) weight loss (mean -47 kg [SE 04] for ITT and -51kg [06] for completers) and reduction in waist circumference (-42 cm [05] and -40 cm [06]; In the ITT population, a significantly greater proportion of patients in the rimonabant groups achieved weight loss of 5% or greater from baseline compared with the placebo group. The proportion of completers who had 10% or more weight loss was also greater in the rimonabant 20 mg group than in the placebo group, but not different between the 5 mg group and placebo. A similar pattern of results was seen in completers

In morbidly obese patients (BMI _40 kg/m2), a similar effect on weight loss was recorded compared with the whole study population. Results showed no interaction between sex and weight loss: no significant difference in changes was detected between men and women.

Changes in metabolic and cardiovascular risk factors with Rimonabant:

Rimonabant generally improved the cardiometabolic profile (i.e., glycemic control, lipid levelsand metabolic syndromeprevalence) in obese or overweight patients to a significantly greater degree than placebo.

Changes in metabolic and cardiovascular risk factors are shown in table below.

Changes in metabolic and cardiovascular risk factors

Changes in Lipid profile with Rimonabant:

Improvement in HDL-C levels from baseline were significantly greater in rimonabant that placebo recipients in RIO-EU, RIO-Lipids and RIO-Diabetes after 1 year of treatment.

Treatment with rimonabant 5 mg and 20 mg increased HDL-cholesterol by 162% (SE 08; p=0048 compared with placebo) and 223% (09; p_0001), respectively, compared with 134% (11) in the placebo group (figure below).

Mean percentage change from baseline in HDL-cholesterol (A) and triglycerides (B) Data are mean (SE) values for patients completing each scheduled visit, and LOCF (values for the full ITT population with the last observations carried forward). *p_0001 vs placebo. p=0002 vs placebo.

Triglyceride levels were similarly improved with 1 year of rimonabant treatment in all four trials. Triglyceride concentrations were reduced by 68% (SE 15; p_00001 vs placebo) in the rimonabant 20 mg group, compared with an increase of 57% (19) in the 5 mg group and 83% (26) in the placebo group. Results in completers are presented in the figure below.

Effect of Rimonabant for 52 Weeks on Body Weight, Waist Circumference, Plasma Triglyceride Levels, and High-Density Lipoprotein (HDL) Cholesterol Levels.

Body weight and waist circumference were measured at randomization (week 0) and every four weeks thereafter until week 52, and plasma HDL cholesterol and triglyceride levels were measured at randomization (week 0) and every three months thereafter until week 52. Values are shown as means SE for all patients for whom measurements were taken at each visit and results are shown in the figure below.

Effect of Placebo or Rimonabant for 52 Weeks on Body Weight, Waist Circumference, Plasma Triglyceride Levels, and High-Density Lipoprotein (HDL) Cholesterol Levels

The effect on lipid was shown to be independent of weight loss

Improvement in glycemic control and Insulin resistance with Rimonabant:

Rimonabant significantly improved glycemic control compared to placebo in obese or overweight patients64. In the RIO-Diabetes study, statistically significant improvements from baseline were seen in HBA1c values in Rimonabant compared with placebo recipient. The effect of rimonabant on HBA1c levels was not entirely attributable to weight loss alone;~57% of changes was determined to be independent of the effect of weight loss.

1-year treatment with rimonabant 20 mg resulted in a significant reduction in fasting plasma glucose, compared with the placebo group. A similar pattern was observed for insulin concentration. A decrease from baseline in HOMA-IR (homeostasis model assessment-insulin resistance) was seen in the rimonabant 20 mg, whereas this index increased in the placebo group. No significant differences in fasting plasma glucose, fasting insulin, or HOMA-IR, were noted between the rimonabant 5 mg group and placebo. Results for completers are presented in the table below. Rimonabant 20 mg was associated with a significant reduction in 2-h insulin (-110 _U/mL [SD 401] from baseline vs -23_U/mL [385] with placebo; p=0019), a marker of insulin resistance.

A significantly greater percentage of patients receiving rimonabant in RIO-Diabetes study achieved clinically significant end point of HbA1c<6.5% than those receiving placebo (42.9% vs 20.8%) p<0.001), 67.9% of rimonabant recipients achieved a HbA1c level <7.0%, compared with 47.6% of placebo recipients.

Patients without type-2 diabetes also had improved glycemic control parameters after rimonabant treatment. Compared to placebo, rimonabant 20 mg once daily for 1 year significantly improved fasting insulin levels and/or insulin resistance. Fasting glucose level improved from baseline in rimonabant recipient in the RIO-EU, RIO-NA and RIO-Lipids trials.

Effect of Rimonabant for 52 Weeks on the Plasma Glucose and Insulin Responses to Oral Glucose Challenge and the Plasma Adiponectin Level

Values for plasma glucose and insulin were measured before the 75-g oral glucose challenge and 30, 60, and 120 minutes afterward, and values are shown for patients for whom measurements were available for each time point. Levels fasting plasma insulin, the one-hour and two hour plasma glucose and insulin levels, and the insulin and glucose AUCs during the 75-g oral glucose-tolerance test decreased significantly in the group receiving 20 mg of rimonabant ( P=0.011 to <0.001).

Plasma adiponectin levels increased with rimonabant treatment (at a dose of 20 mg) by 57.7 percent - an increase significantly greater than that observed in the placebo group.

The increase correlated with weight loss in each group (r=-0.27, r=-0.30, and r=-0.26 in the placebo group, the 5-mg rimonabant group, and the 20-mg rimonabant group, respectively; P<0.001).

However, 57 percent of the increase in adiponectin levels observed in the group receiving 20 mg of rimonabant could not be attributed to weight loss. Changes in adiponectin levels produced by rimonabant at a dose of 20 mg also positively correlated with changes in levels of HDL cholesterol (r=0.27, P<0.001) and apolipoprotein A-I (r=0.38, P<0.001). Plasma leptin levels decreased significantly in the groups receiving 5 mg of rimonabant (P=0.002) and 20 mg of rimonabant (P<0.001) in a dose dependent fashion Plasma C-reactive protein levels decreased by 0.9 mg per liter in the group receiving 20 mg of rimonabant (P=0.020)

The results are depicted in the figure below. The integrated areas under the curves (AUCs) are shown in the insets with the P values obtained with the use of the repeated-measures analysis. Panel C shows the effect on plasma adiponectin levels, and Panel D shows the changes in adiponectin levels according to changes in body weight. P values correspond to the mean differences between the rimonabant groups and the placebo group. The asterisk denotes P<0.001, and the dagger P=0.049.

Effect of Placebo or 20 mg of Rimonabant for 52 Weeks on the Plasma Glucose and Insulin Responses to Oral Glucose Challenge (Panels A and B), and the Plasma Adiponectin Level (Panels C and D)

Significant decrease from baseline in systolic BP in rimonabant compared with placebo recipient were seen in RIO-Lipids (-2.1 vs-0.3mmHg;) and RIO-Diabetes (-0.8 vs+1.6mmhg0 after 1 year of treatment. Diastolic BP was also significantly improved in rimonabant recipients in RIO-Lipids (-1.7vs-0.2mmHg).

Rimonabant: Effect on Metabolic Syndrome

Rimonabant treatment decreased the prevalence of the metabolic syndrome in obese or overweight patients.

At 1 year, the proportion of patients fulfilling the NCEP ATPIII criteria for the metabolic syndrome in all four RIO trials was significantly lower in rimonabant than placebo recipients After 2 years of rimonabant treatment, the prevalence of the metabolic syndrome in rimonabant recipients remained significantly lower than with corresponding percentage in the placebo group.

Reductions in cardiovascular risk factors in the Rimonabant in Obesity trial programme

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