Rimonabant as an adjunct therapy in overweight/obese patients with type 2 diabetes

We read with interest the extensive guidelines on diabetes, pre-diabetes, and cardiovascular diseases.1 However, we were surprised by the very low emphasis put on weight management and abdominal obesity and its association with increased risk of type 2 diabetes and cardiovascular disease.2,3 According to the Task Force, ‘increasing weight with a central distribution’ plays a crucial role in the complex pathophysiology of type 2 diabetes. Furthermore, ‘the recognition of the underlying insulin resistance with increased visceral adiposity is a key factor for an appropriate therapy, not only of hyperglycaemia but also of hypertension and dyslipidaemia’. However, if non-pharmacological lifestyle therapy was considered to improve metabolic control (class I, level A), drugs aiming to promote weight reduction and reduce abdominal adiposity were not considered. In the recent RIO-Diabetes trial evaluating rimonabant, a selective CB1 receptor blocker,4 1047 overweight/obese type 2 diabetes patients on monotherapy with metformin or sulfonylurea and with a mean baseline HbA1c of 7.3%, was given a mild hypocaloric diet and randomized to placebo or rimonabant 5 or 20 mg for 1 year. Weight loss was significantly greater with rimonabant 20 mg (−5.3 vs. −1.4 kg for placebo; P < 0.0001). Rimonabant 20 mg improved HbA1c levels in the overall population (−0.6 vs. +0.1% for placebo; P < 0·0001) and in the subgroup with baseline HbA1c ≥8% (−1.1 vs. −0.3%; P = 0.001). Other cardiometabolic risk factors, i.e. waist circumference, HDL cholesterol, triglycerides, insulin resistance, systolic blood pressure, and C-reactive protein levels, also improved significantly with rimonabant 20 mg. The 6-month SERENADE trial confirmed in drug-naive patients with recently diagnosed type 2 diabetes a significant HbA1c reduction (primary endpoint: −0.8% with rimonabant 20 mg vs. −0.3% with placebo; P = 0.0002), especially in the subgroup with baseline HbA1c ≥8.5% (−1.9% vs. −0.7; P = 0.0009).5 In addition, rimonabant was associated with significant reductions in weight, waist, insulin resistance, and triglycerides and increases in HDL cholesterol and adiponectin levels. New trials are currently evaluating the potential of rimonabant in the prevention of diabetes in overweight/obese patients with impaired glucose tolerance (prediabetes) (‘RAPSODI’) or in the management of insulin-treated patients with type 2 diabetes (‘ARPEGGIO’). Finally, the ongoing ‘CRESCENDO’ (Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints and Outcomes) study will assess whether rimonabant 20 mg can reduce the risk of major cardiovascular events in 17 000 abdominally obese patients with clustering risk factors (at least half with type 2 diabetes) followed for 5 years. Rimonabant 20 mg is recognized in Europe ‘as an adjunct to diet and exercise for the treatment of obese patients (BMI ≥ 30 kg/m2) or overweight patients (BMI > 27 kg/m2) with associated risk factor(s), such as type 2 diabetes or dyslipidaemia’. Furthermore, half of the observed improvements on HbA1c, as well as HDL cholesterol and triglycerides, was recognized to occur beyond weight loss, in agreement with direct peripheral metabolic effects.4 Even if we agree that lifestyle intervention is essential, the potential role of rimonabant, a drug targeting multiple cardiometabolic risk factors, in overweight/obese patients with type 2 diabetes and high-risk cardiovascular disease deserves consideration.