Background Rimonabant, a selective cannabinoid-1 receptor (CB1)blocker, has been shown to reduce body weight and improve cardiovascularrisk factors in obese patients. The Rimonabant in Obesity–Lipids(RIO-Lipids) study examined the effects of rimonabant on metabolicrisk factors, including adiponectin levels, in high-risk patientswho are overweight or obese and have dyslipidemia.
Methods We randomly assigned 1036 overweight or obese patients(body-mass index [the weight in kilograms divided by the squareof the height in meters], 27 to 40) with untreated dyslipidemia(triglyceride levels >1.69 to 7.90 mmol per liter, or a ratioof cholesterol to high-density lipoprotein [HDL] cholesterolof >4.5 among women and >5 among men) to double-blindedtherapy with either placebo or rimonabant at a dose of 5 mgor 20 mg daily for 12 months in addition to a hypocaloric diet.
Results The rates of completion of the study were 62.6 percent,60.3 percent, and 63.9 percent in the placebo group, the groupreceiving 5 mg of rimonabant, and the group receiving 20 mgof rimonabant, respectively. The most frequent adverse eventsresulting in discontinuation of the drug were depression, anxiety,and nausea. As compared with placebo, rimonabant at a dose of20 mg was associated with a significant (P<0.001) mean weightloss (repeated-measures method, –6.7±0.5 kg, andlast-observation-carried-forward analyses, –5.4±0.4kg), reduction in waist circumference (repeated-measures method,–5.8±0.5 cm, and last-observation-carried-forwardanalyses, –4.7±0.5 cm), increase in HDL cholesterol(repeated-measures method, +10.0±1.6 percent, and last-observation-carried-forwardanalyses, +8.1±1.5 percent), and reduction in triglycerides(repeated-measures method, –13.0±3.5 percent, andlast-observation-carried-forward analyses, –12.4±3.2percent). Rimonabant at a dose of 20 mg also resulted in anincrease in plasma adiponectin levels (repeated-measures method,57.7 percent, and last-observation-carried-forward analyses,46.2 percent; P<0.001), for a change that was partly independentof weight loss alone.
Conclusions Selective CB1-receptor blockade with rimonabantsignificantly reduces body weight and waist circumference andimproves the profile of several metabolic risk factors in high-riskpatients who are overweight or obese and have an atherogenicdyslipidemia.
The epidemic of obesity in developed countries illustrates theinability of homeostatic mechanisms to offset a sedentary lifestyle1and almost unlimited access to processed, energy-dense foodsof poor nutritional value. Although modification of nutritionaland physical-activity habits is the cornerstone of therapy forobesity, pharmacotherapy focusing on improvement of the metabolicrisk profile in abdominally obese patients who are at high riskof diabetes and cardiovascular disease may be required. Thenewly discovered endocannabinoid (EC) system and cannabinoidCB1 receptor,2 with their reported roles in the regulation ofenergy balance and body composition, offer a new target to induceweight loss and improve the metabolism of carbohydrates andlipids.2,3,4
The EC system consists of a family of locally produced, short-lived,endogenous, phospholipid-derived agonists (endocannabinoids)5,6and the GI/O-protein–coupled CB1 receptor7 that they activate.CB1 receptors are expressed predominantly in several areas ofthe brain and in peripheral organs, including the autonomicnervous system, liver, muscle, gastrointestinal tract, and adiposetissue.2 Administration of the first endocannabinoid discovered,anandamide, in the hypothalamus or of 2-arachidonoyl-glycerolin the nucleus accumbens can provoke food intake in satiatedrodents.8,9 As compared with wild-type animals, CB1-knockoutmice have leaner body composition, but this lean phenotype isnot fully explained by changes in food intake.3
Stimulation of the CB1 receptors in fat cells promotes lipogenesisand inhibits the production of adiponectin,3,10 a cytokine derivedfrom adipose tissue that has potentially important antidiabeticand antiatherosclerotic properties.11 Rimonabant, the firstspecific CB1-receptor blocker to enter clinical development,has been shown to reduce food intake and body weight in treatedanimals and to alter metabolic activity in adipose tissue12while inducing the expression of the adiponectin gene.13 Theresults of a phase 3 study involving obese patients (Rimonabantin Obesity–Europe [RIO-Europe] study) showed that rimonabantinduces significant weight loss and improves metabolic riskfactors for diabetes and cardiovascular disease.14 However,the patients enrolled in the study were selected only on thebasis of excess weight. Therefore, we examined the effects ofrimonabant in persons at higher risk of cardiovascular disease,such as patients with dyslipidemia who were overweight or obese.Also, since only traditional risk factors for cardiovasculardisease were measured in the RIO-Europe study, we explored theeffect of rimonabant on other key metabolic risk markers forcardiovascular disease such as the size of particles of low-densitylipoprotein (LDL) and the plasma levels of C-reactive proteinand adiponectin.
Methods
Study Design
The primary objective of the study was to assess the effectof 12 months of randomized, double-blind treatment with rimonabantat a dose of 5 mg or 20 mg, as compared with placebo, in additionto a hypocaloric diet (a deficit of 600 kcal per day in relationto the calculated daily intake to maintain body weight), onthe loss of body weight in patients who are overweight or obese(body-mass index [BMI], 27 to 40, with BMI defined as the weightin kilograms divided by the square of the height in meters),have untreated dyslipidemia, and do not have diabetes. Secondarymeasures included changes from baseline (randomization) in levelsof high-density lipoprotein (HDL) cholesterol, triglycerides,glucose, and insulin during an oral glucose-tolerance test andthe prevalence of the metabolic syndrome (according to the criteriaof the third report of the National Cholesterol Education ProgramAdult Treatment Panel [NCEP-ATPIII]).15 Additional efficacymeasures included waist circumference, leptin and adiponectinlevels, and relevant biochemical cardiovascular risk markers.The safety assessment included standard adverse-event reporting,vital signs, the QT interval corrected for heart rate (QTc),and anxiety and depression according to the hospital anxietyand depression scales.14,16 The range of scores for each scaleis 0 to 21, with higher scores indicating a worse condition.Data were gathered by the sponsor (Sanofi Aventis) and wereanalyzed jointly by the authors and the sponsor. The data analysisand the final analyses were reviewed and validated by the authors,who then wrote the manuscript.
The study was conducted between September 2001 and November2003 and was in compliance with the Helsinki Declaration. Itwas conducted at 67 sites in eight countries, with an independent,unblinded data safety monitoring board comprising five permanentmembers. At each meeting of the data safety monitoring board,it was mandatory to have at least three permanent independentmembers, including a clinician, a safety expert, and a statistician.All patients gave written informed consent for participationin the study.
Inclusion criteria were age of 18 to 70 years; BMI of 27 to40; fasting plasma triglyceride levels of 1.7 to 7.9 mmol perliter (150 to 700 mg per deciliter), a ratio of total cholesterolto HDL cholesterol higher than 5 (among men) and higher than4.5 (among women), or both; and variation in body weight withinthe previous three months of less than 5 kg. Exclusion criteriawere a history of pharmacologic treatment for dyslipidemia withinsix weeks before screening, pharmacologic treatment for weightloss within three months before screening, or treatment witha very-low-calorie diet within six months before screening;diabetes mellitus (type 1 or 2); clinically significant findingsindicating cardiovascular, endocrine, pulmonary, neurologic,psychiatric, gastrointestinal, hepatic, hematologic, renal,or dermatologic disease; a positive result on a test for hepatitisB surface antigen, hepatitis C antibody, or both; an abnormalthyrotropin level (greater than the upper limit of the normalrange or less than the lower limit of the normal range); oneor more of the following: levels of alanine aminotransferaseor aspartate aminotransferase greater than 2.5 times the upperlimit of the normal range; hemoglobin levels less than 11 gper deciliter, neutrophil levels less than 1500 per cubic millimeter,platelet levels of less than 100,000 per cubic millimeter, anda creatinine level greater than 150 µmol per liter (1.7mg per deciliter); a history of marijuana or hashish use; severedepression (depression requiring hospitalization or indicatedby a suicide attempt); and treatment for epilepsy, an eatingdisorder, or a malignant disease except basal-cell skin cancers(within five years). Other grounds for exclusion included systolicor diastolic blood pressure at screening that was higher than165 or 105 mm Hg, respectively; pregnancy or lactation; or lessthan 80 percent compliance with a hypocaloric diet and placeboduring the post-screening four-week, single-blind run-in period.14
After enrollment, patients were stratified according to baselinetriglyceride levels (>4.5 vs. 4.5 mmol per liter [400 mgper deciliter]) and weight loss during the run-in period (>2vs. 2 kg) and assigned to double-blind therapy, receiving placeboor rimonabant at a dose of 5 mg or 20 mg in a ratio of 1:1:1.Follow-up visits with a consulting dietitian occurred every2 weeks for the first two visits and monthly thereafter for12 months; standardized assessments of body weight, blood pressure,waist circumference, smoking status, and concomitant medicationswere performed at each visit. Patients were not eligible ifthey had recently (within the past six months) quit smokingor were considering quitting. Patients who had undergone randomizationwere not allowed to change smoking status during the study,and smokers who quit during the study period were ruled outbecause of the known effects of smoking cessation on body weight.
Assays
Standard laboratory tests were performed by ICON Laboratories(at sites in Farmingdale, New York, and Dublin). The peak sizeof LDL particles and the proportion of small (<255 Å)LDL particles were determined by means of nondenaturing 2 to16 percent polyacrylamide-gradient–gel electrophoresis.17Apolipoprotein B and apolipoprotein A-I were quantified by nephelometry.Serum C-reactive protein levels were measured by immunoturbidimetricassay, glucose with the use of the hexokinase method, insulinby immunometric assay, leptin by radioimmunoassay,18 and adiponectinby an enzyme-linked immunosorbent assay (B-Bridge International).A 75-g oral glucose-tolerance test was performed in the morningafter an overnight fast, and glucose and insulin areas underthe curve (AUCs) were calculated with the use of the trapezoidmethod.
Statistical Analysis
All statistical tests were two-sided, with an alpha level of0.05. The prespecified analysis of the primary end point (changein weight from baseline at the last observation carried forward)was conducted with the use of analysis of variance with themodified Bonferroni procedure (Hochberg) for adjustment formultiple comparisons. The analysis of variance included termsfor treatment and randomization subgroup. Because this analysisruled out scheduled measurements collected during the study,a post-hoc repeated-measures approach was performed for changesin weight from baseline, which provided a better estimate ofthe true effect of the study drug. The repeated-measures modelincluded the fixed effects (randomization subgroup, treatment,day [number of days after randomization], and treatment-by-dayinteraction) and a random effect (the patient). Similar methodswere used for the analysis of other efficacy end points.
Patients were classified as having a response of a 5 percentweight loss if they had a reduction in body weight from baselineat the last observation carried forward of at least 5 percent;the identification of those with a response of a 10 percentweight loss at the last observation carried forward was performedin a similar manner. The incidences of patients who had a weightloss of 5 percent and 10 percent and of those with the metabolicsyndrome at the last observation carried forward were analyzedwith the use of logistic-regression models. The models for patientswho had weight losses of 5 percent and 10 percent included termsfor treatment and randomization subgroup, and the model forthe metabolic syndrome included terms for treatment and thestatus of the metabolic syndrome at baseline. Because C-reactiveprotein values were not normally distributed, nonparametricanalyses were substituted for parametric analyses for this specificmarker. The effect of rimonabant independent of weight losswas tested with the use of analysis of covariance with weightloss as a covariate. The values in the tables are presentedas means ±SD and presented in the figures as means ±SEfor the intention-to-treat population.
Results
About 40 percent of the patients in each of the three treatmentgroups dropped out during the 12-month study, with a higherdropout rate due to adverse events in the group receiving 20mg of rimonabant and due to patients' requests in the placebogroup and the group receiving 5 mg of rimonabant (Table 1).The characteristics of the patients in the three groups weresimilar both at screening and at baseline, and there were similarimprovements during the four-week placebo run-in period in thethree groups with regard to all efficacy measures except HDLcholesterol levels, which declined in all three groups (Table 1).
Table 1. Patients' Assignments, Values at Screening, and Baseline Efficacy and Safety Values.
After a weight loss of approximately 2 kg in each group duringthe run-in period (Table 1), the placebo group had a furtherdecline of 2.3 kg over the next 12 months, as compared witha weight loss of 4.2 kg and 8.6 kg in the group receiving 5mg of rimonabant and the group receiving 20 mg of rimonabant,respectively (Table 2) (P<0.001 for both doses). Weight losswas generally greater among patients who completed the 12-monthstudy. In the overall population, the proportion of patientswho had a weight loss equal to or greater than 5 percent was19.5 percent in the placebo group and 58.4 percent in the groupreceiving 20 mg of rimonabant (P<0.001), whereas the proportionof those who had a weight loss equal to or greater than 10 percentwas 7.2 percent in the placebo group and 32.6 percent in thegroup receiving 20 mg of rimonabant (P<0.001). Weight lossoccurred during the first 9 months of the study period, afterwhich body weight stabilized until the end of the 12th monthwithout evidence of regain (Figure 1A). Changes in waist circumferenceshowed a similar dose response (Table 2) and temporal pattern(Figure 1B).
Table 2. Changes from Baseline for the Efficacy and Safety End Points in the Intention-to-Treat Population, According to the Repeated-Measures (RM) Method and Last-Observation-Carried-Forward (LOCF) Analyses.
Figure 1. Effect of Placebo or Rimonabant for 52 Weeks on Body Weight, Waist Circumference, Plasma Triglyceride Levels, and High-Density Lipoprotein (HDL) Cholesterol Levels.
Body weight and waist circumference were measured at randomization (week 0) and every four weeks thereafter until week 52, and plasma HDL cholesterol and triglyceride levels were measured at randomization (week 0) and every three months thereafter until week 52. Values are shown as means ±SE for all patients for whom measurements were taken at each visit (lines); P values were obtained after the repeated-measures analysis. P values correspond to the mean difference between the rimonabant groups and the placebo group.
The caloric restriction during the four-week run-in period producedreductions of 5.3±37.9 percent in triglycerides, 4.9±17.2percent in LDL cholesterol, and 3.6±11.9 percent in HDLcholesterol, which resulted in a 0.11±0.76 decrease inthe total cholesterol:HDL cholesterol ratio (Table 1). Duringtreatment, triglycerides remained stable in both the placebogroup and the group receiving 5 mg of rimonabant but fell anadditional 15.8±38.0 percent in the group receiving 20mg of rimonabant (P<0.001) (Table 2 and Figure 1C).
HDL cholesterol increased in a dose-dependent fashion, achievingan increase of 15.6±15.3 percent from baseline in thegroup receiving 5 mg of rimonabant (P=0.017) and of 23.4±21.8percent in the group receiving 20 mg of rimonabant (P<0.001)(Table 2 and Figure 1D). Although there was no change in levelsof LDL cholesterol, the distribution of LDL particles shiftedtoward larger size in the group receiving 20 mg of rimonabant,as compared with placebo, with a difference of 1.1 Å inthe peak size of LDL particles (P=0.008) and a 4.6 percent lowerproportion of small LDL particles (P=0.007) (Table 2). Changesin levels of HDL cholesterol translated into a dose-dependentreduction in the total cholesterol:HDL cholesterol ratio of–15.2 percent with 20 mg of rimonabant, which was greaterthan with placebo (P<0.001) (Table 2). Levels of fastingplasma insulin, the one-hour and two-hour plasma glucose andinsulin levels, and the insulin and glucose AUCs during the75-g oral glucose-tolerance test decreased significantly inthe group receiving 20 mg of rimonabant (Figure 2A and Figure 2B;P=0.011 to <0.001).
Figure 2. Effect of Placebo or 20 mg of Rimonabant for 52 Weeks on the Plasma Glucose and Insulin Responses to Oral Glucose Challenge (Panels A and B), and the Plasma Adiponectin Level (Panels C and D).
Values for plasma glucose and insulin were measured before the 75-g oral glucose challenge and 30, 60, and 120 minutes afterward, and values are shown for patients for whom measurements were available for each time point (Panels A and B). The integrated areas under the curves (AUCs) are shown in the insets with the P values obtained with the use of the repeated-measures analysis. Panel C shows the effect on plasma adiponectin levels, and Panel D shows the changes in adiponectin levels according to changes in body weight. P values correspond to the mean differences between the rimonabant groups and the placebo group. The asterisk denotes P<0.001, and the dagger P=0.049. To convert values for glucose to milligrams per deciliter, divide by 0.05551; to convert values for insulin to picomoles per liter, multiply by 6.
At baseline, 54 percent of the patients who underwent randomizationmet the NCEP-ATPIII criteria for the metabolic syndrome (Table 1).The prevalence of the metabolic syndrome fell to 25.8 percent,40.0 percent, and 41.0 percent in the groups receiving 20 mgof rimonabant, 5 mg of rimonabant, and placebo, respectively;the reduction in the group receiving 20 mg of rimonabant wassignificantly greater (P<0.001) than in the placebo groupand was attributed mainly to the reduction in waist circumferenceand the increase in HDL cholesterol levels.
Plasma adiponectin levels increased with rimonabant treatment(at a dose of 20 mg) by 57.7 percent — an increase significantlygreater than that observed in the placebo group (Figure 2C).The increase correlated with weight loss in each group (r=–0.27,r=–0.30, and r=–0.26 in the placebo group, the 5-mgrimonabant group, and the 20-mg rimonabant group, respectively;P<0.001). However, 57 percent of the increase in adiponectinlevels observed in the group receiving 20 mg of rimonabant couldnot be attributed to weight loss (Figure 2D). Changes in adiponectinlevels produced by rimonabant at a dose of 20 mg also positivelycorrelated with changes in levels of HDL cholesterol (r=0.27,P<0.001) and apolipoprotein A-I (r=0.38, P<0.001).
Plasma leptin levels decreased significantly in the groups receiving5 mg of rimonabant (P=0.002) and 20 mg of rimonabant (P<0.001)in a dose-dependent fashion (Table 2). Plasma C-reactive proteinlevels decreased by 0.9 mg per liter in the group receiving20 mg of rimonabant (P=0.020) (Table 2).
The proportions of patients who had treatment-related adverseevents or serious adverse events were slightly higher in thegroup receiving 5 mg of rimonabant and the group receiving 20mg of rimonabant than in the placebo group (treatment-relatedadverse events: 82.3 percent, 86.7 percent, and 81.6 percent,respectively; and serious adverse events: 5.2 percent, 4.0 percent,and 2.3 percent, respectively). There were no deaths in anyof the three groups. The treatment-related adverse events reportedin 5 percent or more of the patients in either rimonabant groupbut more commonly among those receiving 20 mg of rimonabantwere (in order of decreasing frequency) nausea, dizziness, influenza,anxiety, diarrhea, and insomnia; these occurred early in thetreatment period (Table 3). Overall discontinuation rates weresimilar in the three groups, but more patients discontinuedtreatment because of adverse effects in the group receiving20 mg of rimonabant (Table 1) than in the other groups. Themost frequent adverse events resulting in discontinuation inthe groups receiving rimonabant at 5 mg and 20 mg, as comparedwith placebo, included depression (1.7 percent and 2.9 percent,respectively, vs. 0.6 percent); anxiety (0.3 percent and 1.7percent vs. 0.6 percent); and nausea (0.6 percent and 1.2 percentvs. 0 percent).
Values for laboratory safety measures linked to obesity (i.e.,levels of alanine aminotransferase, aspartate aminotransferase,-glutamyltransferase, and uric acid) decreased with rimonabantat a dose of 20 mg (data not shown). Other values for safetymeasures included heart rate, systolic and diastolic blood pressure,QTc, and scores for anxiety and depression according to thehospital anxiety and depression scales (Table 1), and all exceptfor blood pressure were similar in the three groups during thestudy period. Decreases in systolic and diastolic blood pressurewith 20 mg of rimonabant were statistically significant (Table 2)and were greater among patients with hypertension at baseline(blood pressure, 140/90 mm Hg). For the 20-mg rimonabant versusplacebo groups, the respective decreases in patients with hypertensionwere as follows: systolic pressure, 13.1±11.5 vs. 7.2±10.7mm Hg, P=0.038; and diastolic pressure, 6.3±6.0 vs. 2.4±9.7mm Hg, P=0.022. Finally, there were no interactions betweentreatment assignment and sex (data not shown).
Discussion
The NCEP-ATPIII report and the recently published National Heart,Lung, and Blood Institute and American Heart Association consensusreport highlighted abdominal obesity as assessed by waist circumferenceas an important cardiovascular risk marker and the primary targetfor the treatment of the metabolic syndrome.15,19 Few toolsexist to treat collectively the underlying pathophysiology inhigh-risk, abdominally obese patients, and most published obesitystudies primarily enrolled patients who were at relatively lowcardiovascular risk (i.e., obese women not selected for thepresence of cardiovascular risk factors).20 In the recent RIO-Europestudy in obese patients, CB1-receptor blockade with rimonabantwas found to reduce body weight and waist circumference, improveplasma glucose–insulin homeostasis, and produce a substantialincrease in plasma HDL cholesterol levels — a change thatwas greater than what could be expected from weight loss alone.14These findings suggested a weight-loss–independent effectof rimonabant on metabolic risk that may be mediated by theeffect of rimonabant on adiponectin secretion by fat cells,as reported in studies in animals.13
Our study explored further the effect of rimonabant in a high-riskpopulation of patients with dyslipidemia who are overweightor obese, with a focus on metabolic risk markers such as thesize of LDL particles and levels of C-reactive protein and adiponectin.As compared with placebo, rimonabant at a dose of 20 mg perday induced significant weight loss and reduction in waist circumference,suggesting a substantial mobilization of abdominal fat, which,by itself, would predict an improved cardiovascular risk profile.21Additional effects of rimonabant at this dose, as compared withplacebo, included significant improvements in plasma triglycerides,plasma HDL cholesterol, and the total cholesterol:HDL cholesterolratio, as well as changes in LDL particle size, adiponectinlevels, glucose tolerance, fasting and post-challenge insulinlevels (markers for the risk of diabetes), and plasma C-reactiveprotein levels and in the proportion of patients meeting theNCEP-ATPIII criteria for the metabolic syndrome.
Rimonabant had no effect on LDL cholesterol levels. Patientswith abdominal obesity and the metabolic syndrome generallydo not have elevated levels of LDL cholesterol22 but, rather,express the high triglyceride–low HDL cholesterol–small,dense LDL dyslipidemia associated with insulin resistance phenotype.23Although the LDL cholesterol level itself powerfully predictscardiovascular risk,24 the metabolic risk profile of abdominalobesity23,25 further increases the risk of coronary heart diseasefor any level of LDL cholesterol.26 In the RIO-Lipids study,the proportions of small and large LDL particles were alteredwith rimonabant, as compared with placebo, in the absence ofany change in LDL cholesterol levels.
Although patients who meet the NCEP-ATPIII criteria for themetabolic syndrome have a distinct cardiovascular disease risk-factorprofile, the clinical relevance of making the metabolic syndromea treatable target beyond classic risk factors has been debated.27Therefore, the clinical relevance of reducing the proportionof patients meeting those NCEP-ATPIII criteria for the metabolicsyndrome by the use of rimonabant can be questioned if it isnot accompanied by favorable changes in markers for insulinresistance and abdominal obesity such as glucose tolerance andlevels of insulin, adiponectin, and C-reactive protein, allof which, when abnormal, are linked to visceral obesity andthe metabolic syndrome.28,29 The results of the RIO-Lipids studywith regard to C-reactive protein are thus consistent with thereported beneficial effect of weight loss on inflammation.30,31Whether the reduction in C-reactive protein levels will be additiveto or synergistic with the reduction in C-reactive protein levelsand the cardiovascular protection ascribed to statins and fibricacids32,33 remains to be explored. Although regarded as theleast prominent component of the metabolic syndrome,34 hypertensionis more prevalent among abdominally obese patients with insulinresistance, and the condition usually responds to weight loss.35Rimonabant at a dose of 20 mg reduced blood pressure overall,especially among patients with hypertension.
Finally, the results of the RIO-Lipids study provide evidencefor a weight-loss–independent effect of rimonabant onadiponectin levels. This finding may be of clinical importance,since a high adiponectin level has been reported to be predictiveof a reduced risk of diabetes and cardiovascular events.36,37Abdominal obesity is accompanied by reduced adiponectin levels,and such hypoadiponectinemia is partly responsible for the lowHDL cholesterol levels in abdominal obesity.38 Since the changesin adiponectin levels observed in the present study correlatedwith changes in HDL cholesterol and apolipoprotein A-I, thestimulation of adiponectin production with CB1-receptor blockadecould explain the consistent and weight-loss-independent effectof rimonabant on HDL cholesterol levels in the RIO-Europe andRIO-Lipids studies.
In conclusion, although pharmacotherapy alone will not eradicatethe epidemic of obesity, this study provides evidence that CB1-receptorblockade may constitute a new, clinically relevant pharmacologicapproach to improve the unfavorable cardiovascular risk profilein high-risk patients with dyslipidemia who are overweight orobese. The adverse-event profile of rimonabant observed in theRIO-Lipids study was found to be concordant with the resultsof the RIO-Europe study. Finally, the weight-loss–independenteffect of rimonabant on plasma adiponectin levels is consistentwith the reported in vitro effect of this CB1-receptor blockeron adiponectin production by adipose cells.
Supported by Sanofi Aventis.
Dr. Després reports having received consulting or lecturefees from Abbott Laboratories, AstraZeneca, Fournier Pharma,GlaxoSmithKline, Merck, Pfizer, Pharmacia, and Sanofi Aventisand grant support from Fournier Pharma, GlaxoSmithKline, Merck,Pfizer, and Sanofi Aventis. Dr. Golay reports having receivedconsulting or lecture fees from Hoffmann–La Roche, AbbottLaboratories, Merck, Pfizer, Servier, and Sanofi Aventis. Dr.Sjöström reports having received consulting or lecturefees from Biovitrum, GlaxoSmithKline, Johnson & Johnson,Merck, Roche, and Sanofi Aventis.
We are indebted to the members of the data safety monitoringboard: Drs. Michael Weintraub, Jean-Louis Imbs, Alain Leizorovicz,Elliot Danforth, and David P.L. Sachs; and to the staff of the67 clinical sites in eight countries (Australia, Canada, Finland,Italy, Spain, Sweden, Switzerland, and the United States) fortheir dedicated contribution to the study.
* The investigators and coinvestigators participating in the Rimonabantin Obesity–Lipids (RIO-Lipids) Study Group are listedin the Appendix.
Source Information
From the Quebec Heart Institute, Laval Hospital Research Center, and the Division of Kinesiology, Department of Social and Preventive Medicine, Laval University, Ste.-Foy, Que., Canada (J.-P.D.); the Service of Therapeutic Education for Chronic Diseases, University Hospital Geneva, Geneva (A.G.); and the Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden (L.S.).
Address reprint requests to Dr. Després at the Quebec Heart Institute, Laval Hospital Research Center, Pavilion Marguerite-D'Youville, 4th Fl., 2725 Chemin Ste.-Foy, Ste.-Foy, QC G1V 4G5, Canada, or at jean-pierre.despres{at}crhl.ulaval.ca.
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Appendix
The following investigators and coinvestigators participatedin the study: D. Carey, N. Wood, G. Wittert, D. Jesudason, P.Phillips, M.T. Kuruvila, A. Sverdlov, H. Sia, J. Proietto, K.Bate, P. Colman, L. Rando, M. Hooper, C. Ting, N. Kormas, T.Markovic, K. Steinbeck, I. Kormas, N. Caterson, S. Li, J. Hui,V. Wong, J.-P. Després, A. Tremblay, N. Alméras,P. Poirier, R. Aronson, M.E. Alexander, L.G. Goluboff, Y. Twum-Barima,P. Whitsitt, R. Verdonk, C. Li, J.-P. Ouellet, P. Marchand,M. Bezeau, R. Girard, F. Ross, R. Goldenberg, R. Schlosser,R. Aronson, M.-C. Audet, D. Bélanger, M. Boutin, A. Martel,R. Boucher, P.-P. Côté, G. Tellier, F. Cousineau,Y. Pesant, P. Chevalier, G. Laurin, G. Girard, A. Crépeau,L. Frenette, R. Bouchard, C. St.-Pierre, F. Turcotte, M. Loyer,M. Drapeau, P. Pelletier, A. Dugas, A. Rissanen, J. Puhakka,K. Pietilainen, P. Broas, S. Keinanen-Kiukaanniemi, M. Laakso,R. Pasquali, B. Ambrosi, L. Frittitta, C.M. Rotella, R. Vettor,X. Formiguera, A. Almenara, R. Gomis, M.J. Coves, J. Vidal,B. Moreno, J. Rivera, A. Jimenez, A. Zugasti, M.D. Rodriguez,J. Salas, M.J. Jimenez, L. Sjöström, A.M. Langkilde,K. Vikman-Adolfsson, C. Ehrnborg, U. Adamson, L. Adamson, A.von Dobeln, T. Kjellstrom, P. Katzman, R. Rosin, I. Lager, L.Eden, A. Pagnamenta, G. Noseda, C. Fragiacomo, J. Zerega, M.Ghielmetti, T. Reynaldos, A. Golay, V. Makoundou, C. Ries, G.Gastaldi, V. Giusti, M.A. Adamczyk, M.R. Modiano, C.L. Hannah,R.B. Salazar, R. Armbruster, F.E. Dunlap, D. Brune, E. Rufus,A.J. Heritch, J. Cavanaugh, A. Delpilar, M.A. Ziboh, S. Chipkin,B.L. Haag, M.P. Roy, R.J. Cooper, E. Cohen, S. Klugh, O.M. Quijano,V. Reddy, L. Metchick, B. Egan, W.H. Bestermann, K. Nashar,A. Jesri, D. Fiske, J.M. Houri, T. Evans, D.B. George, S.M.George, S. Polyhronopoulos, B.F. Scott, R.V. Steeves, J.L. Kantlehner,P.A. Warner, T.C. Harris, W.K. Kleinsteuber, G.T. Gerhard, S.J.Redmond, T. Passmore, E. Glover, C.R. Sullivan, P.N. Glover,C.L. Cerullo, J.H. Berry, S.C. Yerneni, R.M. Griffin, P.D. Nicholas,M.A. Borofsky, J.S. Weisberg, W. Santoro, C.H. Schmidley, J.T.Van Den Bosch, J.T. Lumley, D.F. Steffy, P.J. Baney, C.A. Wagner,E. Krishnan, L. Gringeri, A.F. Marchesani, C.W. Clark, D. Torelli,G.K. Phillips, L. Denton, S.M. Kneiss, L.G. Kelner, R. Rosenberg,S.B. Jones, D.B. Vine, A. Kivitz, S.P. Kafka, F.T. Murphy, V.M.Sommer, L.A. Krug, D.L. Rentz, S.K. Ritchey, M.J. Zumer, M.Dubeck, A. Maldonado, C. Cunningham, M.J. Koren, S. Greco, J.A.Jacqmein, D. Robinson, J.C. Hackenberg, D.M. Bartilluci, M.N.Lunde, M.J. Zarama-Medina, M.G. Somermeyer, E.A. Holum, S.L.McElroy, P.E. Keck, E. Nelson, R. Kotwal, S. Malhotra, L. Arnold,B. Martens, R. Kowatch, W.J. Mroczek, B.L. Berliner, J. Klein,A.R. George, W.P. Jennings, R. Nett, C.F. Serna, T.R. Weiss,M. Nides, D. Medway, H. Eisenbach, E. Marshall, S.E. Prohaska,R.E. Pruitt, D. Jacobus, R.W. Herring, J.B. Rosen, I.G. Carrasquilla,H.M. Silberman, C.K. Mitch-Gomez, S. Yahia, C.F. Yanes, S. Duncan-Garcia,S. Rosenblatt, J.M. Wilson, E.R. Lee, M.A. Flanagan, L. Rudolph,E.M. Lewiecki, E.W. Best, J. Chavez, I. Garcia, M. Gurule, L.Ierides, R.L. Romanik, G. Shockey, A.M. Germaine, K.L. Valderhaug,J.A. Brown, M. Smith, R. Laufer, L.D. Smith, R. Chan, C.R. Ellsworth,K.R. Becker, R.L. Goldman, W.B. Smith, A.B. Alper, G.M. Johnson,R.L. Gibson, R.K. Mautner, S.G. Swanson, J.J. Maly, P. Gillapsie,M.M. Snow, P. Railsback, J. Oden, R. Tanous, T.P. Hutchens,R.J. Bury, S.S. Bradley, J. Akhter, S.J. Scherr, K.R. Happel,M.J. Tonkon, E.R. Ross, N.C. Morcos, D.M. See, P. Rand, P.D.Toth, D.C. Weiser, J. Zavoral, J.M. Beard, C.J. Baumgartner,F.J. Zieve, J.R. Levy, S.K. Frederickson, D.I. Panebianco, K.A.Tidsel, B. Lindgren, and H. Zacur.
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4.5 mmol per liter [400 mg per deciliter]) and weight loss during the run-in period (>2 vs. 
-glutamyltransferase, and uric acid) decreased with rimonabant at a dose of 20 mg (data not shown). Other values for safety measures included heart rate, systolic and diastolic blood pressure, QTc, and scores for anxiety and depression according to the hospital anxiety and depression scales (Table 1), and all except for blood pressure were similar in the three groups during the study period. Decreases in systolic and diastolic blood pressure with 20 mg of rimonabant were statistically significant (Table 2) and were greater among patients with hypertension at baseline (blood pressure, 
140/90 mm Hg). For the 20-mg rimonabant versus placebo groups, the respective decreases in patients with hypertension were as follows: systolic pressure, 13.1±11.5 vs. 7.2±10.7 mm Hg, P=0.038; and diastolic pressure, 6.3±6.0 vs. 2.4±9.7 mm Hg, P=0.022. Finally, there were no interactions between treatment assignment and sex (data not shown). 
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