Rimonabant Reduces Liver Fat Content in Abdominally Obese Patients

The FDA still fails to approve Rimonabant even with the results of the ADAGIO-Lipids trial which showed that Rimonabant significantly improves cardiovascular and metabolic risk markers, and reduces both intra-abdominal fat and liver fat content, in patients with abdominal obesity.

The study's objective was to evaluate the effects of Rimonabant on multiple cardiometabolic risk factors in 803 abdominally obese patients with low high-density (HDL) cholesterol and elevated triglyceride levels. Patients were randomized to Rimonabant 20 mg daily for 1 year or placebo.  In addition to plasma samples, a subgroup of 231 patients was assessed by computed tomography (CT) to determine the endocannabinoid's effect on visceral and liver fat content.

Dr. Jean-Pierre Despres of Hopital Laval Research Centre in Quebec, Canada, and colleagues point out that liver fat is a strong correlate of metabolic risk factors, independent of visceral fat.

Rimonabant treatment significantly increased HDL cholesterol 7.4% over baseline and reduced triglyceride levels by 18%. Active treatment also significantly reduced low-density lipoprotein (LDL) and HDL particle sizes, and lowered apolipoprotein A1 and B, and levels of HDL2, HDL3, C-reactive protein, and adiponectin.

Rimonabant decreased abdominal subcutaneous adipose tissue area by 5.1% compared with placebo. There was a 10.1% reduction in visceral fat compared with placebo. The ratio of visceral-to-subcutaneous adipose tissue and liver fat content were also significantly reduced with Rimonabant, as was the liver-to-spleen attenuation ratio.  Systolic blood pressure dropped 3.3 mm Hg and diastolic blood pressure dropped 2.4 mm Hg with active treatment compared with placebo.
Rimonabant had a favorable safety profile and was similar to that of other studies of the drug. However, the drug has hit roadblocks in gaining FDA approval.

Dr. Despres stated that, "The findings support what I have been saying for 20 years. Obesity is not the main problem. It's where the fat is located….  More important than losing weight is to lower risk of heart attack and death. Rimonabant can do this in targeted patients."

"The liver is loaded with endocannabinoid receptors. Rimonabant effectively blocks the receptors and reduces liver fat," Dr. Despres said.

"Rimonabant should not be perceived as an 'antiobesity blockbuster' medication," he stressed. "We need to target the drug for the right patient -- the patient with abdominal fat and liver fat."

In an accompanying editorial, Dr. Marja-Riitta Taskinen of Helsinki (Finland) University Hospital observes that, "The circumstances surrounding the decision to terminate the viable and extensive research program are not clear but will hamper the translation of the promises from the recent studies."

"Hopefully this is not the end of the line for cannabinoid type-1 receptor antagonists," Dr. Taskinen adds.

Arterioscler Thromb Vasc Biol 2009;29:339-340,416-423.