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 [IC50(palmitate)], flux [IC50(palmitatef], and hepatic glucose output [IC50(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 IC50(palmitate) and IC50(palmitate)f] and secondary [improvement in IC50(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 IC50(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) insulin-regulated glucose disposal improved in both groups (P = 0.002) and correlated 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.