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Does rimonabant independently affect free fatty acid and glucose metabolism?
Jessica Triay1, Manpreet Mundi, Samuel Klein
1Endocrine Research Unit, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota 55905, USA.
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.
Insights
Rimonabant, a drug blocking the endocannabinoid receptor 1, did not improve insulin regulation of fatty acid and glucose metabolism beyond the effects of weight loss alone in obese individuals. Further research is needed to understand its metabolic effects.
Area of Science:
- Metabolic Syndrome Research
- Pharmacology
- Obesity Treatment
Background:
- Endocannabinoid receptor 1 (ECR1) blockade is investigated for potential benefits in managing obesity-related metabolic complications.
- Central and peripheral effects of ECR1 blockade are hypothesized to influence metabolic pathways.
Purpose of the Study:
- To evaluate the efficacy of rimonabant in improving insulin regulation of free fatty acid and glucose metabolism.
- To determine if rimonabant's effects exceed those attributable solely to weight loss.
Main Methods:
- A double-blind, placebo-controlled substudy involving 67 abdominally obese individuals with metabolic syndrome.
- Participants underwent a 12-month lifestyle weight management program with either rimonabant (20 mg/d) or placebo.
- Insulin sensitivity was assessed using hyperinsulinemic-euglycemic clamps, measuring IC50(palmitate), IC50(palmitate)f, IC50(HGO), and glucose disposal slope.
Main Results:
- Rimonabant treatment led to a greater decrease in body fat compared to placebo (4.5% vs 1.9%).
- No significant differences were observed in primary or secondary outcomes related to insulin regulation of free fatty acid and glucose metabolism between groups.
- Post hoc analysis indicated a correlation between BMI changes and IC50(palmitate) in the rimonabant group, but this was not significantly different from placebo when controlling for BMI loss.
Conclusions:
- The observed improvements in insulin regulation with rimonabant were not superior to those achieved through weight loss alone.
- Rimonabant's impact on metabolic regulation in humans appears to be primarily mediated by its weight-reducing effects.
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