Does rimonabant independently affect free fatty acid and glucose metabolism?

Abstract

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 [IC50(palmitate)], flux [IC50(palmitate)f], 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.

Fig. 1.

Schematic of euglycemic-hyperinsulinemic clamp study. Isotopes administered were 1) [6-²H₂]glucose (constant infusion), 2) [U-¹³C]palmitate (infused over the last 60 min of each study interval), and 3) 20% dextrose labeled with [6-²H₂]glucose (to maintain euglycemia at 5 mmol/liter). Blood sampling for glucose enrichment and concentration (GEC) and palmitate enrichment and concentration (PEC) was performed over the last 30 min of each time period.

Fig. 2.

Correlations between changes in BMI and insulin sensitivity of glucose and fatty acid metabolism are shown. In the rimonabant group, there were significant correlations between changes in BMI and changes in insulin sensitivities of palmitate concentration (r = 0.61; P = 0.004) (A), hepatic glucose production (HGO) (r = 0.61; P = 0.003) (B), and glucose disposal (r = 0.45; P = 0.05) (C). Although the trends were not significant in the placebo group, the slopes of association were not different.