sanofi-aventis announced that new data on rimonabant, its first-in-class cannabinoid type 1 (CB1) receptor blocker, showed that patients with type 2 diabetes not currently treated with anti-diabetic medications experienced significant improvements in blood sugar control and weight as well as other risk factors such as HDL-cholesterol (good cholesterol) and triglycerides when compared to placebo.
The study, called SERENADE, was presented at the International Diabetes Federation (IDF) World Diabetes Congress in Cape Town, South Africa. SERENADE is the second study demonstrating that rimonabant significantly improved blood sugar levels in people with type 2 diabetes.
In the SERENADE study, treatment-naïve type 2 diabetes patients receiving rimonabant 20mg per day for a duration of six months significantly lowered their HbA1c levels by 0.8 per cent from a baseline value of 7.9 as compared to a reduction of 0.3 per cent in the placebo group (p=0.002). In addition, patients with an HbA1c level greater than or equal to 8.5per cent at baseline, significantly reduced their HbA1c by 1.9 per cent with rimonabant as compared to 0.7 per cent with placebo (p<0.0009). Over 50 per cent of patients in the rimonabant arm of the trial achieved HbA1c levels below 7 per cent, the target for good glucose control as recommended by the American Diabetes Association (ADA).i Importantly, these improvements in blood glucose control were accompanied by significant and clinically meaningful reductions in body weight of 6.7 kg (14.8 lbs) in patients treated with rimonabant 20 mg, while those patients on placebo lost only 2.7 kg (5.95 lbs) (p<0.0001).
"The management of type 2 diabetes should not only focus on controlling blood sugar levels but also improve other risk factors such as weight, good and bad cholesterol, triglycerides and blood pressure," said Julio Rosenstock, M.D., Director of the Dallas Diabetes and Endocrine Centre at Medical City and also Clinical Professor of Medicine at the University of Texas Southwestern Medical School, Dallas, Texas who was an investigator in the SERENADE trial. "This study suggests that rimonabant can achieve improvement in blood glucose with the added benefit of significant weight loss and improvement in other risk factors."
Today, more than 194 million adults or 5 per cent of adults worldwide have been diagnosed with diabetes, with type 2 diabetes constituting 85-95 per cent of all diabetes in developed countries. Approximately 90 per cent of type 2 diabetes is attributed to people being overweight or obese.iii Diabetes and obesity are often associated with other risk factors for cardiovascular disease including high blood pressure and unhealthy cholesterol. Worldwide, diabetes is among the leading causes of blindness, renal failure and lower limb amputation, as well as death through its effects on cardiovascular disease (70-80 percent of people with diabetes die of cardiovascular disease).
Accompanying the improvements in HbA1c and weight seen in the rimonabant arm of the SERENADE trial were improvements in multiple cardiometabolic risk factors. Patients in the rimonabant arm decreased their waist circumference (a measure of abdominal obesity) by 6.1 cm (2.34 in) compared to a 2.4 cm (0.93 in) decrease for patients on placebo (p<0.0001). HDL-cholesterol or "good" cholesterol increased by 10.1 per cent compared to 3.2 per cent for patients on placebo (p<0.0001). Triglyceride levels (bad fats in the blood) decreased by 16.3 per cent compared to a 4.4 per cent increase for placebo (p=0.0031). There was a trend toward reduction in systolic blood pressure by 5 mmHg and diastolic blood pressure by 1.2 mmHg in the rimonabant 20 mg arm compared to a 2.2 mm Hg decrease in systolic blood pressure and an increase of 0.1 mm Hg in diastolic pressure in the placebo arm (p=NS).
Fasting Plasma Glucose decreased by 0.9 mmol/L (16.2 mg/dL) in the rimonabant 20 mg arm compared to a 0.1 mmol/L (1.8 mg/dL) increase in the placebo arm (p=0.0012). Adiponectin, a protein associated with reduced risk of diabetes and heart disease when present in high levels, increased by 1.6 µg/mL in the rimonabant 20 mg arm compared to a decrease of 0.2 µg/mL in the placebo arm (p=0.0001). Approximately 57 per cent of the improvements in HbA1C (p<0.001) were independent of the weight loss achieved, suggesting a direct effect of rimonabant on this parameter.
The overactivity of the Endocannabinoid System (ECS) in the fat tissue and muscle is found to promote fat accumulation and decrease glucose uptake, which can lead to an increased risk of developing insulin resistance and impaired glucose tolerance. By selectively blocking CB1 receptors of the ECS, which according to animal and human studies can be found in the brain, fat tissue, gastrointestinal tract, pancreas, liver and muscle, rimonabant results in a decrease in food intake, a loss of body weight, and direct improvements in blood sugars (HbA1c), HDLcholesterol and triglycerides.
"Some current medications for type 2 diabetes are often associated with weight gain," said Julio Rosenstock. "The fact that blood sugar levels were reduced along with weight loss and improvements in HDL-cholesterol ("good" cholesterol) and triglycerides may further support the novel mechanism of action of rimonabant, which is different from the mode of action of current oral anti-diabetic medications."
The most common side effects with placebo and rimonabant 20 mg reported in the SERENADE trial were dizziness (2.1% vs. 10.9%), nausea (3.6% vs. 8.7%), nasopharyngitis (7.9% vs. 7.2%), upper respiratory tract infection (2.7 % vs. 7.2%), anxiety (3.6% vs. 5.8%), depressed mood (0.7% vs. 5.8%), and headache (6.4% vs. 3.6%). The rate of serious adverse events was 3.6% for patients in the placebo arm versus 6.5 percent for patients in the rimonabant 20 mg. Overall, discontinuation rates due to adverse events in the trial were 2.1 per cent in placebo-treated patients versus 9.4 per cent for patients on rimonabant 20 mg. The most common adverse events leading to discontinuation for the placebo and rimonabant 20 mg patients, respectively, were nausea (0% vs. 2.2%), depressed mood disorder (0% vs. 2.2%) and paraesthesia (0% vs. 2.2%).
SERENADE (Study Evaluating Rimonabant Efficacy in Drug-NAive DiabEtic Patients) was a multi-centre, randomised, double-blind, placebo-controlled, parallel-group study comparing rimonabant 20 mg once daily to placebo in improving blood sugar control (as indicated by HbA1c) in treatment-naive type 2 diabetic patients not adequately controlled by diet alone for a period of six months.
The study was conducted on 278 patients at 56 study centres in the United States, Germany, Argentina, Chile, Hungary, Poland and the Netherlands. The primary endpoint of the trial was change from baseline of HbA1c levels. Secondary endpoints included weight and waist circumference, a key marker of intra-abdominal adiposity, fasting plasma glucose, lipid parameters and arterial blood pressure. To be included in the trial patients had to have a diagnosis of type 2 diabetes for at least two months but less than three years, HbA1c levels greater than 7 per cent and less than 10 per cent, and could not have been treated previously with an anti-diabetic medication within six months prior to screening.
SERENADE is part of an extensive worldwide phase IIIb clinical trial programme involving over 22,000 patients in eight studies, which will investigate the role of rimonabant in the treatment of type 2 diabetes and cardiovascular disease. About Rimonabant In Europe, rimonabant, known as ACOMPLIA® is approved as an adjunct to diet and exercise for the treatment of obese patients (BMI?30kg/m2), or overweight patients (BMI>27kg/m2) with associated risk factors, such as type 2 diabetes or dyslipidaemia. Rimonabant is currently commercialised in the United Kingdom, Germany, Denmark, Sweden, Finland, Norway, Ireland, Argentina and Austria.
At the end of October 2006, sanofi-aventis submitted a complete response to the US Food and Drug Administration (FDA) approvable letter received in February 2006. About sanofi-aventis sanofi-aventis 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.