Elsevier

The Lancet

Volume 368, Issue 9548, 11–17 November 2006, Pages 1660-1672
The Lancet

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Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study

https://doi.org/10.1016/S0140-6736(06)69571-8Get rights and content

Summary

Background

Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas.

Methods

1047 overweight or obese type 2 diabetes patients (body-mass index 27–40 kg/m2) with a haemoglobin A1c (HbA1c) concentration of 6·5–10·0% (mean 7·3% [SD 0·9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848.

Findings

692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: −1·4 kg [SD 3·6]; 5 mg/day: −2·3 kg [4·2], p=0·01 vs placebo; 20 mg/day: −5·3 kg [5·2], p<0·0001 vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness.

Interpretation

These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.

Introduction

Type 2 diabetes frequently co-exists with a cluster of other cardiovascular and metabolic risk factors including abdominal obesity, low HDL-cholesterol concentrations, high triglyceride concentrations, and raised blood pressure,1 and is considered to be a cardiovascular disease risk equivalent.2, 3 A recent population-based retrospective cohort study showed that diabetes confers an equivalent cardiovascular risk to ageing 15 years in people aged 40 years or older.4 The treatment of multiple cardiovascular and metabolic risk factors is central to the management of type 2 diabetes.5

Being overweight or obese—in particular, abdominally obese—increases the risk of type 2 diabetes and cardiovascular disease,6, 7 yet those with diabetes often have more difficulty in losing weight8 and experience weight gain associated with most antidiabetic medications.5

The endocannabinoid system, consisting of the cannabinoid type 1 (CB1) receptor and endogenous lipid-derived ligands,9 seems to modulate energy homoeostasis as well as glucose and lipid metabolism,10, 11, 12 both through central orexigenic effects and peripheral metabolic effects in adipose tissue, liver, and skeletal muscle.13, 14, 15 Patients with obesity or hyperglycaemia caused by type 2 diabetes exhibit higher concentrations of endocannabinoids in visceral fat or serum, respectively, than the corresponding controls.16

In non-diabetic overweight or obese patients, 20 mg daily of the selective CB1 receptor blocker rimonabant has been shown to produce substantial weight loss and waist circumference reduction (a key marker of intra-abdominal adiposity), and improvements in multiple cardiovascular and metabolic risk factors.17, 18 These data were further confirmed in overweight or obese patients with untreated dyslipidaemia.19 Part of these metabolic improvements could be attributed to a moderate, but significant, increase in plasma adiponectin levels.19

This multicentre randomised controlled trial was designed to assess the efficacy and safety of rimonabant in combination with a mild hypocaloric diet and advice for increased physical activity in overweight or obese patients with type 2 diabetes who were already on metformin or sulphonylurea monotherapy.

Section snippets

Patients

This randomised, double-blind, placebo-controlled study was done in 159 centres in 11 countries (in Europe, North America, and South America) between October, 2001, and May, 2004. Patients aged 18–70 years with type 2 diabetes who had been treated with metformin or sulphonylurea monotherapy for at least 6 months (stable dose for at least 3 months), but who remained inadequately controlled, were recruited. Inclusion criteria were body-mass index of 27–40 kg/m2, a haemoglobin A1c (HbA1c) level of

Results

513 men and 532 women were randomised to double-blind treatment. 692 patients (66·2%) completed the 1-year follow-up (figure 1). Two randomised patients were not exposed to treatment and 11 randomised patients were excluded from the analysis of weight (two for non-exposure and nine for missing post-baseline weight assessment). Baseline characteristics were much the same in the three groups (table 1), except smoking, which was slightly lower in the 20 mg/day rimonabant group (p=0·02), and

Discussion

The main finding of the RIO-Diabetes trial is that 20 mg/day rimonabant for 1 year significantly reduced weight, waist circumference, and HbA1c levels and improved a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylurea. These results extend previous findings in non-diabetic overweight or obese patients to those with type 2 diabetes.17, 18, 19 Patients with type 2 diabetes are

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