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University Hospital Antwerp

Improvement in Cardiovascular Risk Factors With Rimonabant Demonstrated in Two-Year Study

Antwerp, Belgium (ots/PRNewswire)

- Results from RIO-Europe trial demonstrated that first-year
improvements in cardiovascular risk factors are seen through two-year
study period
Luc Van Gaal, M.D.
     Principal Investigator
     RIO-Europe
     On behalf of the RIO Steering Committee
The results of a two-year phase III study in 1,507 patients
treated with rimonabant, the first in a new class of therapeutic
agents called selective CB1 Blockers, demonstrated that the
improvements in cardiovascular risk factors achieved with rimonabant
20 mg/day at the end of the first year of treatment were maintained
in the second year. The study also demonstrated the safety and
tolerability profile of rimonabant versus placebo.
The two-year results of the RIO-Europe trial were presented today
at the Scientific Sessions of the American College of Cardiology in
Orlando, Florida by Luc Van Gaal, M.D., Professor of Diabetology,
Metabolism and Clinical Nutrition, University Hospital of Antwerp,
Belgium and principal investigator of the study. The first-year
results of the RIO-Europe study had been presented at the European
Society of Cardiology meeting in August 2004.
The two-year findings of the RIO-Europe trial are consistent with
those of the other two-year trial in the rimonabant phase III
program, RIO-North America, results of which were announced at the
scientific sessions of the American Heart Association in November
2004. "The RIO-Europe findings demonstrated that in addition to
maintaining body weight loss, two-year treatment with rimonabant 20
mg/day compared with placebo reduced waist circumference improved
metabolic profile and reduced the number of patients meeting the NCEP
(National Cholesterol Education Program) criteria for metabolic
syndrome, thus diminishing cardiovascular risk factors in patients
studied," said Professor Van Gaal.
RIO-Europe objectives and design
The RIO-Europe trial is one of four phase III studies comprising
the RIO program, which assesses the efficacy and safety of rimonabant
in weight reduction and metabolic risk factor improvement in over
6,600 overweight and obese patients studied world-wide.
RIO-Europe is a phase III, multinational multicenter, randomized,
double-blind, and placebo-controlled trial comparing two fixed-dose
regimens of rimonabant (5 mg and 20 mg once daily) to placebo for a
period of two years. The study was conducted on 1,507 patients at 40
centers in Europe and 20 centers in the US. The objectives of the
trial were to assess the effects of rimonabant on weight loss for a
period of one year and to determine rimonabant's potential to
maintain weight loss during a second year of treatment. The study
also assessed improvement in waist circumference and in metabolic
risk factors (eg, dyslipidemia, glucose metabolism, and metabolic
syndrome) and evaluated the safety and tolerability profile of
rimonabant over the two-year period.
After a screening period of two weeks, patients were prescribed a
hypocaloric diet (designed to reduce daily caloric intake by 600 kcal
from the patients' energy requirements) and entered a four-week
single-blind placebo run-in period. Afterward, 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.
RIO-Europe findings
The findings presented today demonstrated the two-year benefits of
rimonabant 20 mg/day treatment vs placebo in the study population.
Among patients completing the study, waist circumference, was reduced
by 7.5 cm (2.9 inches) in patients treated with rimonabant 20 mg/day
for the full two year period vs. 3.4 cm (1.3 inches) for patients in
the placebo group (P<.001). Among all patients who entered the study,
waist circumference was reduced by 5.7 cm (2.24 inches) and 1.8 cm
(0.71 inches) in patients treated with rimonabant 20 mg/day and the
placebo group (P<.001), respectively. Among patients completing the
study, 59.7% of patients treated with rimonabant 20 mg/day lost more
than 5% of their initial body weight vs 23.4%of those in the placebo
group (P<.001). Among all patients who entered the study, 44.4% of
patients treated with rimonabant 20 mg/day lost more than 5% of their
initial body weight vs 15.6% of those in the placebo group (P<.001).
Among patients completing the study, 32.1% of patients treated with
rimonabant 20 mg/day lost more than 10% of their initial body weight,
vs 10.9% of those in the placebo group (P<.001). Among all patients
who entered the study, 22.0% of patients treated with rimonabant 20
mg/day lost more than 10% of their initial body weight vs 6.3% of
those in the placebo group (P<.001).
Metabolic parameters, such as HDL-cholesterol and triglyercides,
were significantly improved in patients treated with rimonabant 20
mg/day throughout the two-year period. Among patients completing the
study, HDL-cholesterol increased by 28.2% in the rimonabant 20 mg/day
group vs 16.8% in the placebo group (rimonabant 20 mg/day vs placebo
(P<.001). Among all patients who entered the study, HDL-cholesterol
increased by 22.6% in the rimonabant 20 mg/day group vs 12.6% in the
placebo group (rimonabant 20 mg/day vs placebo (P<.001)). Among
patients completing the study, triglycerides were reduced by 8.8% in
patients treated with rimonabant 20 mg/day throughout the two-year
period vs an increase of 6.3% in the placebo group (rimonabant 20
mg/day vs placebo (P<.001)). Among all patients who entered the
study, triglycerides were reduced by 4.1% in patients treated with
rimonabant 20 mg/day vs an increase of 10% in the placebo group
(rimonabant 20 mg/day vs placebo (P<.001)). A statistical analysis of
the data suggested that approximately half of the improvements in HDL
cholesterol and triglyceride profiles observed in patients treated
with rimonabant 20 mg/day were independent of the weight loss
achieved in this group.
Although people with diabetes were not included in the study,
patients on rimonabant 20 mg/day showed improved insulin sensitivity
as measured by HOMA (Homeostasis Model Assessment) compared with
those on placebo (P<.001). Of particular note is that the number of
patients completing the study who met the diagnostic criteria for
metabolic syndrome was reduced by approximately 50% in patients
treated with rimonabant 20 mg/day vs a decrease of approximately
20.0% in the placebo group (P<0.001). Metabolic syndrome includes a
series of health risks or conditions that increase a person's chances
to develop heart disease, stroke and diabetes. (1)
Safety & tolerability
The safety and tolerability of rimonabant 20 mg vs placebo were
assessed in this two-year study. Side effects were mainly mild and
transient and appeared mainly in the first year. The most common side
effects included nausea (13.7% for 20 mg/day, 6.0% for 5 mg/day, 5.2%
for placebo), dizziness (9.3% for 20 mg/day, 8.1% for 5 mg/day, 5.2%
for placebo), diarrhea (8.2% for 20 mg/day, 7.3% for 5 mg/day, 4.6%
for placebo) and vomiting (5.2% for 20 mg/day, 2.5% for 5 mg/day,
1.6% for placebo). Overall discontinuation rates due to adverse
events in the two years of the study were 13.1%, 10.9% and 18.9% in
the placebo, rimonabant 5 mg/day and rimonabant 20 mg/day groups,
respectively. In the RIO-Europe trial and in two preceding studies
(RIO-Lipids 1-year and RIO-North America 2-year), rimonabant
demonstrated a safe cardiovascular profile with no significant EKG,
blood pressure or heart rate changes on average. (2)
Intra-abdominal adiposity
Obesity is a major public health burden and a key risk factor for
the development of cardiovascular disease, the leading cause of
mortality worldwide. (3) 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. (3) Abdominal obesity can be simply measured by waist
circumference (4), and is an indicator of intra-abdominal adiposity,
the hidden fat present deep within the abdomen (5). It is this
intra-abdominal adiposity (inside the abdomen) which is one of the
most significant contributors to the development of cardiovascular
risk factors such as dyslipidemia, insulin resistance, or metabolic
syndrome and which may lead to diabetes, heart attack, stroke or
other cardiovascular disease. (5) Approximately 46% of adult
Americans have a waist circumference that exceeds the at-risk level
(40 inches for men and 35 inches for women). (6) The prevalence of
abdominal obesity in the US has tripled in the last 40 years. (7)
Rimonabant and the Endocannabinoid (EC) System
The EC System is a physiological system in the body that is
believed to play a key role in the central and peripheral regulation
of energy balance, fat accumulation as well as in glucose and lipid
metabolism. (8) CB1 receptors are found in the brain as well as in
peripheral tissues of the body such as adipocytes (or "fat cells"),
which are involved in lipid and glucose metabolism. (9) This system
represents a promising target for intervention(s) aimed at reducing
cardiovascular risk. (9) Rimonabant is the first in a new class of
drugs called CB1 blockers. By selectively blocking both centrally and
peripherally the CB1 receptors, rimonabant regulates the overactive
EC System. (9) Results from clinical trials show that rimonabant
reduces cardiovascular risk factors by reducing intra-abdominal
adiposity and improving metabolic parameters beyond the level
expected through weight reduction alone.
References
    (1) Grundy SM, et al. Definition of the Metabolic Syndrome: Report of
        the National Heart, Lung and Blood Institute / American Heart
        Association Conference on Scientific Issues Related to Definition.
        Circulation. 2004, 433-436.
    (2) Rimonabant in Obesity, North American Data. Rimonabant in the
        Reduction of Major Cardiovascular Risk Factors Data, presented at
        AHA, 2004; Rimonabant in Obesity, Lipids Data. Rimonabant in the
        Reduction of Major Cardiovascular Risk Factors Data, presented at
        ACC, 2004.
    (3) Yusuf et al, Effect of potentially modifiable risk factors associated
        with myocardial infarction in 52 countries (the INTERHEART study):
        case-control study. The Lancet, Volume 364 Number 9438, September 11-
        17, 2004.
    (4) Despres JP. Treatment of obesity: need to focus on high risk
        abdominally obese patients. BMJ. 2001;322;716-720.
    (5) Sharma AM, Adipose tissue: a mediator of cardiovascular risk.
        International Journal of Obesity, Volume 26, Suppl.24, S5-S7.
    (6) Ford ES, Mokdad AH, Giles WH Trends in waist circumference among U.S.
        adults. Obes Res. 2003; 11:1223-1231.
    (7) Okosun IS, Chandra KM, Boev A, et al. Abdominal adiposity in U.S.
        adults: prevalence and trends, 1960-2000. Prev Med. 2004;39:197-206.
    (8) Pagotto U. The endocannabinoid system: a new player in reinforcement
        and energy control functions. Poster presented at the Metabolic
        Syndrome, Type 2 Diabetes and Atherosclerosis Conference, Marrakech,
        19 - 23 May 2004.
    (9) Horvath TL. Endocannabinoids and the regulation of body fat: the
        smoke is clearing. J Clin Invest. 2003;112:323-326.

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