Does rimonabant independently affect free fatty acid and glucose metabolism?

Context: Endocannabinoid receptor 1 blockade is proposed to improve metabolic complications of obesity via central and peripheral effects. Objective: Our objective was to test whether rimonabant improves insulin regulation of free fatty acid and glucose metabolism after controlling for fat loss. Design: This was a double-blind, placebo-controlled substudy of the visceral fat reduction assessed by computed tomography scan on rimonabant (VICTORIA) trial. Participants and Setting: Sixty-seven abdominally obese, metabolic syndrome volunteers age 35-70 yr participated at academic medical center general clinical research centers. Intervention: Intervention included a 12-month lifestyle weight management program plus rimonabant 20 mg/d or placebo. Main Outcome Measures: Body composition and two-step euglycemic, hyperinsulinemic clamp before and after intervention were performed. Insulin sensitivity was assessed as insulin concentration needed to suppress by 50% palmitate concentration [IC _{50(palmitate)}], flux [IC _50(palmitatef], and hepatic glucose output [IC _50(HGO)] and as insulin-stimulated glucose disposal (Δ glucose disappearance per Δ insulin concentration - glucose slope). Results: Body fat decreased by 4.5 ± 2.9% (SD) in the rimonabant and 1.9 ± 4.5% in the placebo group (P < 0.005). The primary [improvement in IC _{50(palmitate)} and IC _{50(palmitate)}f] and secondary [improvement in IC _50(HGO) and glucose slope] outcomes were not significantly different between the rimonabant and placebo groups. Post hoc analyses revealed that 1) changes in body mass index (BMI) and IC _{50(palmitate)} were correlated (P = 0.005) in the rimonabant group; this relationship was not significantly different from placebo when controlling for greater BMI loss (P = 0.5); 2) insulinregulated glucose disposal improved in both groups (P=0.002)andcorrelated with changes in BMI. Conclusions: Improvements observed in insulin regulation of free fatty acid and glucose metabolism with rimonabant treatment in humans was not greater than that predicted by weight loss alone.