Sanofi US News

Sanofi-aventis announced that the results of the RIO-Lipids trial were published today in The New England Journal of Medicine. The trial evaluated rimonabant in overweight or obese patients with abnormal blood lipids (high triglycerides and/or high total cholesterol/HDL-cholesterol ratios) and the findings showed that patients on rimonabant 20mg once daily experienced a significant improvement in a range of cardiometabolic risk factors that may contribute to type 2 diabetes and heart disease. These improvements included a reduction in triglyceride levels and increases in HDL-cholesterol (good cholesterol). There were also reductions in waist circumference and body weight, improved glucose tolerance, and decreased blood pressure. Significant improvements were also seen in emerging risk markers, including an increase in adiponectin, a protein associated with reduced risk of diabetes and heart disease and a reduction in C-Reactive Protein (CRP), which is a marker of inflammation associated with cardiovascular risk(1,2).
 
Importantly, a statistical analysis suggested that the increases in adiponectin observed in the trial were beyond the anticipated improvements, which could be attributed to weight loss alone, raising the potential of a direct effect of rimonabant on this risk marker.
“One of the more noteworthy findings of the RIO-Lipids trial is the evidence that rimonabant , the first selective CB 1 Blocker, through its effects in peripheral tissues significantly increases adiponectin levels (produced by fat cells) beyond what could be expected from weight loss alone. This provides evidence for the potential of rimonabant to improve multiple cardiometabolic risk factors in patients with excess abdominal adiposity and other comorbidities such as diabetes or dyslipidemia.,” said Jean-Pierre Després, Ph.D., Director of Research, Québec Heart Institute, Laval Hospital Research Center, Sainte-Foy, Quebec, and Principal Investigator of the RIO-Lipids trial.
 
At one year, patients treated with rimonabant 20mg/day achieved a 12.6% reduction in triglyceride levels compared to a 0.2% reduction for patients on placebo (p<0.001 vs. placebo). This was accompanied by a 19.1% increase in HDL-cholesterol for patients on rimonabant 20mg/day compared to 11.0% for those on placebo (p<0.001 vs. placebo). This change was correlated with the increases in adiponectin seen in the study and suggests a key role of the latter in explaining the weight loss independent effects of rimonabant. Relative to
placebo, total cholesterol and LDL cholesterol levels remained unchanged although, LDL particle size shifted towards a healthier, less atherogenic profile.
 
Patients on rimonabant 20mg/day had an average decrease in their waist circumference of 7.1 cm (2.7in) versus 2.4 cm (0.94in) for those on placebo (p<0.001 vs. placebo). High waist circumference is a practical indicator of abdominal adiposity (excess fat in the abdomen), which is acknowledged as a risk factor for cardiovascular disease and type 2 diabetes(3). Therefore, the reduction in waist circumference seen with rimonabant is an important indicator of a reduced cardiometabolic risk profile. Consistent with the findings of other RIO trials, patients on rimonabant 20mg/day lost an average of 6.9 kg (15.2lbs) compared to 1.5 kg (3.3lbs) for those on placebo (p<0.001 vs. placebo). Further, 58.4% of patients treated with rimonabant 20mg/day lost more than 5% of their body weight, compared to 19.5 % of patients in the placebo group (p<0.001 vs. placebo). Moreover, 32.6% of patients on rimonabant 20mg/day lost more than 10% of their body weight compared to 7.2% of those patients on placebo (p<0.001 vs. placebo).
 
Even in this non-diabetic population, treatment with rimonabant 20mg/day led to decreased insulin levels and improvements in glucose tolerance, both important predictors for the development of type 2 diabetes.
 
Decreases in both systolic and diastolic blood pressure were seen in the rimonabant 20mg/day arm. Patients treated with rimonabant 20mg/day showed a 2.1 mmHg decrease in systolic blood pressure compared to 0.3 mm Hg decrease for patients in the placebo arm (p=0.048 vs. placebo). Diastolic blood pressure in turn decreased by 1.7 mm Hg in patients in the rimonabant 20mg/day arm compared to a 0.2 mm Hg decrease in patients in the placebo arm (p=0.011 vs. placebo).
These cardiometabolic risk factors – abdominal obesity, high triglycerides, low HDL-cholesterol, elevated blood glucose and raised blood pressure – often cluster together(4). In this study, 52.9% of patients treated with rimonabant 20mg/day and 51.9% of patients on placebo met the criteria for diagnosis of the metabolic syndrome (patients with a least 3 of the 5 above cardiometabolic risk factors)(5). By the end of the study, the prevalence of the syndrome fell to 25.8% in patients on rimonabant 20mg/day whereas 41% of patients on placebo still met the criteria (p<0.001).
In addition to the improvements seen in traditional cardiometabolic risk factors, significant improvements were also seen in emerging risk markers adiponectin and CRP. Adiponectin levels increased significantly in patients receiving rimonabant 20mg/day (p< 0.001 vs. placebo). It was reported that 57% of this increase could not be attributed to weight loss alone, implying a possible direct effect of rimonabant on the improvement of this risk marker. This confirms previous laboratory findings that rimonabant stimulates adipocytes to increase adiponectin production. CRP also decreased significantly in patients receiving rimonabant 20mg/day (p=0.020).
 
“The RIO-Lipids trial results indicated that patients with atherogenic dyslipidemia treated with rimonabant 20mg/day not only improved their lipid profiles but also experienced significant improvements across a broad range of cardiometabolic risk factors. It is the first time that with one agent we have seen such a wide array of cardiometabolic improvements, such as triglyceride levels, HDL-cholesterol levels, shift in LDL particle size, glucose tolerance, systolic and diastolic blood pressure, adiponectin and CRP as well as weight and waist circumference,” said Professor Després. “The RIO-Lipids findings also confirmed the consistency of rimonabant in improving multiple cardiometabolic risk factors which has been seen in other RIO trials, he added.
 
Safety and tolerability were consistent with other reported RIO studies. Side effects were generally transient and self-limiting and most commonly included nausea, dizziness, influenza, anxiety, diarrhea and insomnia. The most frequent side effects leading to discontinuation in placebo, rimonabant 5 mg and 20mg groups included depression (0.6% vs.1.7% and 2.9%), anxiety (0.6% vs. 0.3% and 1.7%) and nausea (0% vs. 0.6% and 1.2%).
 
The RIO Lipids publication concludes that rimonabant may constitute a novel therapeutic approach to improving the cardiometabolic risk profile seen in overweight / obese patients with dyslipidemia.

RIO-Lipids is an international, multi-centre, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose 1 year study, comparing rimonabant 20mg/day and 5mg/day to placebo in 1,036 overweight/obese patients (Body Mass Index (BMI) 27-40 kg/m²) with untreated dyslipidemia (plasma triglycerides 1.69-7.90 mmol/L and/or total cholesterol/HDL ratio >5 (men) or >4.5 (women). After a screening period of two weeks, patients were prescribed a mild hypocaloric diet (designed to reduce daily caloric intake by 600 kcal from the patients’ energy requirements) and entered a four-week placebo run-in period. Afterwards, patients were randomly assigned to one of the three treatment groups: rimonabant 20 mg or 5 mg or placebo for 52 weeks of double-blind treatment using a randomization ratio of 1:1:1. At each visit patients received dietary counselling and were encouraged to increase physical activity. The study was conducted in 67 centres across Canada, the United States and Europe for a period of 1 year.
 
RIO-Lipids is one of four phase III trials comprising the RIO program examining the effects of rimonabant on cardiometabolic risk factors in over 6,600 overweight or obese patients. The results of the RIO-Lipids study were first released at the American College of Cardiology congress in March 2004.

The sanofi-aventis Group is the world’s third largest pharmaceutical company, ranking number one in Europe. Backed by a world-class R&D organization, sanofi-aventis is developing leading positions in seven major therapeutic areas: cardiovascular, thrombosis, oncology, metabolic diseases, central nervous system, internal medicine, and vaccines. The sanofi-aventis Group is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY).
 
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Sanofi-aventis Group subsidiaries in the United States include Sanofi-Synthelabo Inc., Aventis Pharmaceuticals Inc. and Sanofi Pasteur Inc.

Julissa Viana 908-243-1232 julissa.viana@sanofi-aventis.com

Nazira Amra 33 - (0) 630 32 63 15 nazira.amra@sanofi-aventis.com

1. Matsuzawa Y et al. Adiponectin And Metabolic Syndrome. Arterioscler Thromb Vasc Biol 2004;24:29-33.
    
2. Patel VB et al. C-Reactive Protein: A ‘Golden Marker’ For Inflammation And Coronary Artery Disease. Cleveland Clinic Journal of Medicine 2001;68(6):521-534.
    
3. Sharma AM. Adipose Tissue: A Mediator of Cardiovascular Risk. International Journal of Obesity 2002;26(4)S5-S7.
    
4. U.S. Department of Health & Human Services. Prevalence of Selected Cardiovascular Disease Risk Factors Among American Indians and Alaska Natives – United States, 1997. Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report June 2000;49(21).
    
5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.