Evidence of the Month

Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.

O. Ziegler Service de Diabétologie, Maladies Métaboliques, Maladies de la Nutrition CHU de Nancy Hôpital Jeanne d'Arc Toul, France	Click here to download PowerPoint slides of this commentary.
	Click here for the programme evaluation and post-test.

Background
Rimonabant, the first selective cannabinoid type 1 (CB₁) receptor blocker of the endocannabinoid system, has been shown to reduce body weight and waist circumference and to improve cardiovascular and metabolic risk factors in non-diabetic overweight or obese individuals. Almost half of the metabolic effects observed with rimonabant occur independently of weight loss, suggesting the direct peripheral effects of the drug. The Rimonabant In Obesity and related disorders (RIO)-Diabetes trial studied the safety and efficacy of rimonabant in overweight and obese individuals with Type 2 diabetes who were being treated with metformin or sulfonylureas.

Methods and Key Results
RIO-Diabetes was conducted at 159 centres in 11 countries (in Europe and North and South America; ClinicalTrials.gov number: NCT00029848). A total of 1047 individuals with Type 2 diabetes who were already on metformin or sulfonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity and randomly assigned to double-blind therapy with placebo (n=348), rimonabant 5 mg/day (n=360), or rimonabant 20 mg/day (n=339) for 12 months. Overall baseline values included a body-mass index of 27 to 40 kg/m², a mean weight of 96.3 ± 14.7 kg, and HbA_1c concentrations of 6.5 % to 10.0 % (mean, 7.3 ± 0.9 %). The mean prevalence of the metabolic syndrome was 79% at baseline. The primary endpoint was weight change from baseline after 1 year of treatment, in the intention-to-treat population.

Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: −1.4 ± 3.6 kg; 5 mg/day: −2.3 ± 4.2 kg, P=0.01 vs placebo; 20 mg/day: −5.3 ± 5.2 kg, P<0.0001 vs placebo). The placebo-corrected weight loss after 1 year of treatment with rimonabant 20 mg/day was 3.9 ± 0.3 kg for the whole population, but 4.3 ± 0.4 kg in individuals treated with metformin and 3.1 ± 0.5 kg in those treated with sulfonylurea (P<0.0001 for both). The percent of individuals achieving weight loss of 5% or more at the last follow-up visit was 49.4% in the rimonabant 20-mg group as compared with 14.5% in the placebo group (P<0.0001). The percent of individuals achieving weight loss of 10% or more was also significantly greater for individuals receiving 20-mg rimonabant than for those in the placebo group (16.4% vs 2.0%, P<0.0001). Waist circumference was significantly decreased in the rimonabant 5-mg and 20-mg groups by 2.9 cm (P=0.02) and 5.2 cm (P<0.0001), respectively, compared with 1.9 cm in the placebo group.

HbA_1c reductions of 0.1 % and 0.6 % were significant in the rimonabant 5-mg (P=0.03) and 20-mg (P<0.0001) groups, respectively, compared with placebo.

Compared with placebo, rimonabant 20 mg also demonstrated significant improvements in the prevalence of the metabolic syndrome and improvement in its constituents, including fasting insulinaemia, HOMA (homeostasis model assessment) insulin resistance, systolic blood pressure, C-reactive protein levels, high-density lipoprotein (HDL) cholesterol levels, and triglyceride levels.

The rate of completion of the study was 66.2%, without differences between groups. Rimonabant was generally well tolerated. The most common adverse events leading to study discontinuation in the rimonabant 20-mg group were depressed mood disorders, nausea, and dizziness. The other common adverse events, occurring in 5% or more of rimonabant-treated individuals, were diarrhoea, vomiting, hypoglycaemia, fatigue, and anxiety. These events were generally mild or moderate, transient, and seen early in the treatment period.

Clinical Implications
The results of RIO-Diabetes show the therapeutic value of rimonabant 20 mg/day in individuals with Type 2 diabetes. Rimonabant 5 mg/day was clinically less effective. One year of treatment with rimonabant 20 mg resulted in moderate weight loss associated with favourable effects on HbA_1c level and on several cardiometabolic risk factors, including triglyceride level, HDL cholesterol level, and systolic blood pressure. Weight management complicates the treatment of Type 2 diabetes because a majority of these individuals are not only overweight or obese but also resistant to weight loss. Moreover, many traditional oral agents (sulfonylureas, thiazolidinediones) that provide significant treatment benefits for individuals with Type 2 diabetes are also associated with weight gain; the same is true for insulin therapy. Rimonabant could offer the potential for significant improvements in glycaemic control without weight gain, although long-term durability of glycaemic control (>52 weeks) with rimonabant has not been established.

The placebo-corrected reduction in HbA_1c levels of 0.7 % observed with 20 mg/day of rimonabant is clinically important, for it has been shown that every 1 % reduction in HbA_1c is associated with a reduction in risk of about 20% for any endpoint related to diabetes. The favourable effect of rimonabant on glycaemic control has been recently confirmed in SERENADE (Study Evaluating Rimonabant Efficacy in Drug-NAive DiabEtic Patients).

About 50% of the improvements in HDL-cholesterol concentrations and HbA_1c levels could not be attributed to observed weight loss, as already seen in other RIO trials. This is consistent with the direct peripheral metabolic effects of the drug (via CB₁ receptors in the liver or in adipose tissue). For example, the blockade of CB₁ receptors has been shown to inhibit hepatic fatty acid synthesis and hepatic lipid accumulation and also to increase the secretion of adiponectin by adipocytes, an adipokine that plays a key role as far as insulin resistance is concerned.

Individuals with severe psychiatric disorders or on antidepressants were excluded, so the safety of rimonabant in such individuals has yet to be determined. At the moment, individuals with self-reported depression or severe anxiety have to be excluded from the prescription.

To summarise, rimonabant 20 mg/day, in combination with diet and exercise, significantly reduces body weight and waist circumference and improves blood glucose control, dyslipidaemia, and the metabolic syndrome in overweight or obese individuals with Type 2 diabetes inadequately controlled by metformin or sulfonylureas. Its multifactorial mechanisms warrant further investigation and may provide insights into other pathologies. Long-term studies are needed to demonstrate that this new approach to improve glucose control and reduce a number of cardiovascular and metabolic risk factors is able to decrease cardiovascular events.

Rimonabant is indicated in Europe and in Argentina, Brazil, and Mexico as an adjunct to diet and exercise for the treatment of obese individuals or overweight individuals with associated risk factors, such as Type 2 diabetes or dyslipidaemia.

This Website Feature is funded by an unrestricted educational grant from Pfizer Inc.