טיפול במשך שנה ב-rimonabant 20 mg (תכשיר של חברת סנופי-אבנטיס הנמצא בשלבי פיתוח מתקדמים) בלווי דיאטה דלת קלוריות גרם להפחתה משמעותית במשקל, וכן גם ירידה במדדי סיכון קרדיווסקולרים. כך עולה ממחקר שפורסם השבוע ב-LANCET.

הרקע למחקר הוא העובדה שבמודל חיה, השימוש בחסם -(cannabinoid-1 receptor (CB1 גרם לפנוטייפ של הרזיה, במקרים של השמנת יתר שנוצרה מדיאטה מכוונת שגרמה גם להפרעת שומנים בדם. המטרה הייתה להעריך השפעת ה-rimonabant על משקל גוף וגורמי סיכון קרדיווסקולרים במטופלים הסובלים מעודף משקל או השמנת יתר.

השתתפו במחקר 1507 מטופלים עם BMI של מעל 30, או מעל 27 אשר סבלו מדיסליפידמיה מטופלת או לא מטופלת ו/או יתר לחץ דם. הם חולקו אקראית לקבוצות שקיבלו פלציבו, או rimonabant במינון של 5 מ”ג ליום או 20 מ”ג ליום, וזאת בתוספת לדיאטה דלת קלוריות (שהסתכמה ב”גירעון” של 600 קלוריות ליום).

נקודת הקצה העיקרית במחקר הייתה השינוי במשקל מתקופת הבסיס לאחר שנת טיפול, מתוך הקבוצה שהתמידה במחקר. (ITT ) .

נמצא שאיבוד המשקל היה גדול יותר באופן מובהק סטטיסטי בקבוצות  שטופלו ב-rimonabant במינון 5 מ”ג (ירידה של 3.4 ק”ג בממוצע) ו-20 מ”ג (ירידה של 6.6 ק”ג) בהשוואה לקבוצת הפלציבו שירדה ב-1.8 ק”ג בלבד.

שיעור גבוה יותר של מטופלים שטופלו ב-rimonabant במינון 20 מ”ג השיג ירידה של לפחות 5% ו-10% ממשקל גופם, בהשוואה לפלציבו. כמו כן קבוצה זו השיגה שיפור מובהק גם בירידה בהיקף המתניים, עלייה ברמת ה-HDL-C , ירידה ברמת הטריגלצרידים, תנגודת אינסולין, ונוכחות של סינדרום מטבולי.

האפקטיביות של rimonabant במינון 5 מ”ג הייתה מתונה יותר או ללא מובהקות סטטיסטית. באופן כללי התרופה הייתה נסבלת היטב עם תופעות לואי קלות וחולפות בלבד.

החוקרים מסכמים איפוא שהטיפול ב-rimonabant במינון 20 מ”ג ליום, המשולב עם דיאטה דלת קלוריות למשך שנה, מוביל לירידה משמעותית במשקל הגוף, היקף המתניים ושיפור במדדי סיכון קרדיווסקולרים.

Lancet 2005; 365: 1389-97

להלן מידע נוסף, באנגלית, הנוגע למחקר זה, אשר הועבר אלינו באדיבות חברת סנופי-אוונטיס:

1st YEAR RESULTS OF RIO-EUROPE STUDY PUBLISHED IN THE LANCET

Published report of study concludes rimonabant holds therapeutic promise in improving several cardiovascular and metabolic risk factors

Antwerp, Belgium, April 15 2005

The first year results of the two year trial Rimonabant In Obesity – Europe (RIO-Europe), a Phase III clinical study comparing rimonabant, the first agent in a new therapeutic class known as selective cannabinoid type 1 (CB1) blockers, to placebo, were published today in The Lancet. The reported findings in overweight or obese patients taking rimonabant 20mg once daily show a significant reduction in body weight, waist circumference – a marker of intra-abdominal adiposity as well as  improvements in insulin resistance and lipid and glucose profiles. The improvement in lipids (HDL-cholesterol and triglycerides) was shown to be partially independent from weight loss, suggesting a direct effect of rimonabant on these important metabolic cardiovascular risk parameters. The trial findings also revealed a decrease in the number of patients with metabolic syndrome [i] in the rimonabant 20 mg/day group.

Despite advances in the management of cardiovascular disease (CVD) in recent decades, CVD nonetheless remains the leading cause of mortality worldwide. Obesity is a major public health burden and a key risk factor for the development of cardiovascular disease.[ii] Obesity is typically measured by body mass index (BMI); however, recent findings have shown that abdominal obesity is a much better predictor of heart attack than weight or BMI. ii Reducing abdominal fat is a recognized priority for reducing the risk of CVD.[iii] The one-year results of the RIO-Europe study confirm rimonabants potential to become an important tool in the reduction of multiple cardiovascular risk factors by lowering body weight and improving metabolic syndrome-associated parameters in overweight or obese subjects.

At one year, patients treated with rimonabant 20mg/day lost an average of 6.6 kg (p<0.001 vs placebo) compared to 3.4kg for patients on rimonabant 5mg/day (p=0.002 vs placebo) and 1.8 kg for those on placebo. Patients on rimonabant 20mg/day also had an average decrease in their waist circumference of 6.5 cm (p< 0.001) versus 3.9 cm for those on rimonabant 5mg (p=0.002 vs placebo) and 2.4 cm  for those on placebo.

Among patients completing the study, 67.4% of patients treated with rimonabant 20mg/day lost more than 5% of their initial body weight (p< 0.001 vs placebo), compared to 44.2% of patients in the rimonabant 5mg/day group (p=0.001 vs placebo) and 30.5% in the placebo group. Moreover, 39% (p<0.001 vs placebo) of patients on rimonabant 20mg/day lost more than 10% of their initial body weight compared to 15.3% of those on rimonabant 5mg/day and 12.4% of those on placebo.

The percentage of patients fulfilling the criteria for the metabolic syndrome was reduced by 54% after treatment with rimonabant 20mg compared to 21% treated with placebo (p<0.001).In addition to the reduction in weight and waist circumference, a statistically significant improvement in metabolic risk factors with rimonabant 20mg vs. placebo was also observed. In patients treated for one year with rimonabant 20 mg/day, HDL-cholesterol (good cholesterol) increased by 22.3% (p< 0.001 vs placebo), compared to 16.2% (p=0.005) in the rimonabant 5mg/day group and 13.4% in the placebo group. Triglycerides were reduced by 6.8% in patients treated with rimonabant 20 mg (p < 0.001 vs. placebo), compared to an increase of 5.7% and 8.3% in rimonabant 5mg and placebo groups respectively. Almost 50% of the rimonabant-induced changes in HDL-cholesterol and triglycerides were independent of the weight loss observed, suggesting a direct effect of the drug on lipid metabolism.

A significant reduction in fasting plasma glucose of 0.09 mmol/L was seen in patients treated with rimonabant 20mg (p=0.026 vs placebo) compared with an increase of 0.03 mmol/L in the placebo treated group. A similar pattern was observed for insulin levels which decreased by 1.0 µIU/mL in the rimonabant 20mg group (p<0.001 vs placebo) versus an increase of 1.8µIU/mL in the placebo-treated group Finally, a decrease of 0.3 % in HOMA-IR (a measure of insulin resistance) was seen in the rimonabant 20mg group (p=0.002 vs placebo) compared with an increase of 0.4% in the placebo-treated group.

“The RIO-Europe 1-year trial results indicate that patients treated with rimonabant 20mg/day experienced improvements across a broad range of cardiovascular risk factors.  Not only have we seen a reduction in body weight, but patients were also able to achieve significant reduction in waist circumference, a measure of dangerous intra-abdominal adiposity. Patients also experienced sizeable improvements in their lipid and glycemic profiles.” said Luc Van Gaal, M.D., Professor of Diabetology, Metabolism and Clinical Nutrition, University Hospital Antwerp, Belgium, Principal Investigator of the RIO-Europe trial “What is particularly noteworthy in the study findings is the effect rimonabant 20mg had on metabolic and cardiovascular risk factors, which is partly independent of weight loss,” he added.

The RIO-Europe findings also showed rimonabant was well tolerated. Side effects were mainly mild and transient and most frequently involved nausea (4.3 %, 5.1 % and 12.9 % for placebo, rimonabant 5mg and rimonabant 20mg respectively), diarrhea (3.0 %, 6.0 % and 7.2 % for placebo, rimonabant 5mg and rimonabant 20mg respectively) and dizziness (4.9 %, 7.0 %, 8.7 % for placebo, rimonabant 5mg and rimonabant 20mg respectively). Only in a very small number of cases did these side effects lead to discontinuation of drug use.

RIO Europe, an international, multicentre, randomized, double-blind, placebo-controlled, parallel-group study, compared rimonabant 20mg/day and 5mg/day to placebo in 1,507 overweight/obese patients (Body Mass Index (BMI) ≥ 30 kg/m² or BMI > 27 kg/m² with co-morbidities such as treated or untreated dyslipidemia and/or treated or untreated hypertension). 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 104 weeks of double‑blind treatment using a randomization ratio of 2:2:1.  At each visit patients received dietary counselling and were encouraged to increase physical activity. The study was conducted in 60 centres across Europe and the United States for a period of 2 years.

RIO-Europe is one of four phase III studies comprising the RIO program, to assess the efficacy and safety of rimonabant in weight reduction and metabolic risk factor improvement in over 6,600 overweight or obese patients.  The one-year results of the RIO-Europe study were first released at the European Society of Cardiology congress in Munich in September 2004. The two year data were reported recently at the 2005 annual scientific session of the American College of Cardiology in Orlando, Florida.

The improvements in metabolic and cardiovascular risk factors in patients receiving rimonabant 20mg/day are beyond those expected through weight reduction alone. The publication concludes that the 1 year study results show that rimonabant produced clinically meaningful weight loss, reduction in waist circumference and associated improvements in several metabolic and cardiovascular risk factors and holds therapeutic promise