Use of cannabinoid CB1 receptor antagonists for the treatment of metabolic disorders

Abdominal obesity is associated with numerous metabolic abnormalities, including insulin resistance, impaired glucose tolerance/type-2 diabetes, and atherogenic dyslipidaemia with low high-density lipoprotein (HDL) cholesterol, high triglycerides, and increased small dense low-density lipoprotein (LDL) cholesterol. A proportion of these metabolic disorders may be attributed to increased endocannabinoid activity. The selective cannabinoid 1 (CB1) receptor antagonist rimonabant has been shown to reduce body weight, waist Circumference, insulin resistance, triglycerides, dense LDL, C-reactive protein (ORP), and blood pressure, and to increase HDL and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. Besides ail improvement in glucose tolerance in non-diabetic Subjects, a reduction of 0.5-0.7% in haemoglobin A1C(HbA(1c)) levels was consistently observed in various groups of patients with type-2 diabetes. Almost half the metabolic changes Could not be explained by weight loss, Supporting direct peripheral effects of rimonabant. Ongoing studies Should demonstrate whether improved metabolic disorders with CB-l receptor antagonists (rimonabant, taranabant, etc.) Would translate into fewer cardiovascular complications among high-risk individuals. (C) 2008 Published by Elsevier Ltd.