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Imaging results from the Adagio-Lipids reveal that effects of Rimonabant on cardiometabolic risk profile include loss of visceral fat and mobilization of liver fat

Québec, Canada - April 29, 2008 • At a late breaking presentation made on April 29th during the Annual meeting of the European Atherosclerosis Society held in Istanbul, the investigators of ADAGIO-Lipids presented the key findings of a one year trial aiming at further studying the effects of rimonabant on several features of HDL and on a comprehensive set of cardiometabolic markers. Furthermore, an imaging substudy using computed tomography was conducted to test, for the first time, the hypothesis that rimonabant could induce a loss of visceral fat and liver fat. “We know that the most prevalent form of the metabolic syndrome is associated with abdominal obesity, particularly with an excess of visceral fat as well as with accumulation of fat at undesired sites such as the liver, the heart, the muscle and the pancreas, a phenomenon referred to as ectopic fat deposition” mentioned Dr Jean-Pierre Després from the Hôpital Laval Research Center, Université Laval, Québec, CANADA, who is the principal investigator of ADAGIO-Lipids. “Although we had evidence from the phase III studies conducted with rimonabant that antagonism of the endocannabinoid system could induce a reduction in waist circumference (a crude marker of abdominal fat) and improve several features of the metabolic syndrome, no study had ever quantified the effect of this drug on visceral adiposity and liver fat” he added. ADAGIO-Lipids was a study conducted in 799 patients with abdominal obesity and with the high triglyceride – low HDL-cholesterol dyslipidemia. Patients were randomized to moderate caloric restriction (600 kcal/day) with either a placebo or rimonabant (20mg/day). First, results confirmed the consistent effects of rimonabant on several markers of cardiometabolic risk. For instance, HDL-cholesterol was increased by 7.4% with rimonabant compared to placebo (p<0.0001) whereas triglyceride levels were reduced by 18% with rimonabant compared to placebo (p<0.0001). Whereas rimonabant had no effect on LDL-cholesterol levels, the drug induced a major shift in the distribution of the size of LDL particles with a substantial reduction in the proportion of small, atherogenic LDL (decrease of 6.5% vs placebo, p<0.0001) and a concomitant increase in the concentration of large LDL particles (increase of 4.8% vs placebo). Several markers of HDL concentration and quality were also improved with rimonabant compared to placebo including an increase in apo A-I (+3.2% vs placebo, p=0.02), HDL particle size (+0.9% vs placebo, p<0.001) and an increase in levels of both HDL2 (+52.6% vs placebo, p<0.03) and HDL3 (+4.3% vs placebo, p<0.01) subfractions. Apo B was also significantly reduced (-4.4% vs placebo, p<0.01) leading to a decrease in the apo B/apo A-I ratio (p<0.0001). Inflammation was also improved as revealed by a 17% reduction in CRP levels compared to placebo (p<0.01) whereas there was a very significant increase in the blood concentration of an important adipose tissue-derived cytokine, adiponectin, which increased by 18.9% compared to placebo (p<0.0001). “Results of ADAGIO-Lipids are pretty much “textbook” regarding what we knew from endocannabinoid physiology and their effect on lipid metabolism” mentioned Dr Després. “All markers of cardiometabolic risk improved in the right direction with rimonabant therapy, including a significant reduction of -3.3 mmHg for systolic and of -2.4 mmHg for diastolic blood pressure (p<0.0001). The next important question was, how does rimonabant work?” “Results of the CT imaging study are pretty straightforward. We found that rimonabant therapy for one year induced a preferential mobilization of visceral adipose tissue compared to placebo (reduction of 10.1% vs placebo, p<0.0005), which was greater that the loss of subcutaneous fat (decrease of 5.1% vs placebo, p<0.005)” stated Dr Robert Ross, the co-principal investigator of ADAGIO-Lipids. “Another relevant finding is that we report for the first time that rimonabant induced a significant mobilization of liver fat (decrease in the fatty liver index, p<0.005) which was associated with a significant improvement in ALT levels (p<0.001), a commonly used marker of liver function also associated with the features of the metabolic syndrome” he added. As CB1 receptors are located in organs other than the brain, such as the adipose tissue and the liver, results of ADAGIO-Lipids are consistent with the hypothesis that antagonism of these peripheral CB1 receptors could slow lipogenesis in both adipose tissue and the liver, leading to loss of both visceral and liver fat. Regarding safety, as patients previously treated for symptoms of depression were excluded from the ADAGIO-Lipids trial, the incidence of side effects leading to discontinuation was essentially similar to the previously published phase III studies. “These results provide further evidence of the acceptable safety profile of rimonabant provided that the drug is used as currently recommended in clinical practice. Patients with a history of depression or on anti-depressants should not be treated with rimonabant.” emphasized Dr Després. “As we now have evidence that patients with visceral obesity represent the subgroup of overweight/obese patients with an activated endocannabinoid system, results of ADAGIO-Lipids provide support to the notion that patients with visceral obesity who are often either dyslipidemic or with type 2 diabetes (or both) represent a relevant subpopulation of overweight/obese patients who would particularly benefit from rimonabant therapy” jointly concluded Dr Després and Ross. Jean-Pierre Després, Ph. D. Hôpital Laval, institut universitaire de cardiologie et de pneumologie Phone : (418) 656-4863 Fax : (418) 656-4610 E-mail : jean-pierre.despres@crhl.ulaval.ca Web Site : www.HopitalLaval.qc.ca



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