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J Am Coll Cardiol, 2006; 47:1919-1926, doi:10.1016/j.jacc.2005.12.067 (Published online 21 April 2006).
© 2006 by the American College of Cardiology Foundation
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STATE-OF-THE-ART PAPER

Rimonabant: A Cannabinoid Receptor Type 1 Blocker for Management of Multiple Cardiometabolic Risk Factors

Eli V. Gelfand, MD* and Christopher P. Cannon, MD{dagger},*

* Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center
{dagger} TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Manuscript received November 29, 2005; accepted December 14, 2005.

* Reprint requests and correspondence: Dr. Christopher P. Cannon, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115 (Email: cpcannon{at}partners.org).


   Abstract
Top
 Abstract
Obesity, Metabolic Syndrome, and...
 The Endocannabinoid System
 Physiology of the Cannabinoid...
 Rimonabant
 References
 
Rimonabant is a first selective blocker of the cannabinoid receptor type 1 (CB1) being developed for the treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking. In four large trials, after one year of treatment, rimonabant 20 mg led to greater weight loss and reduction in waist circumference compared with placebo. Therapy with rimonabant is also associated with favorable changes in serum lipid levels and an improvement in glycemic control in prediabetes patients and in type 2 diabetic patients. At the same dose, rimonabant significantly increased cigarette smoking quit rates as compared with placebo. Rimonabant seems to be well tolerated, with a primary side effect of mild nausea. As an agent with a novel mechanism of action, rimonabant has a potential to be a useful adjunct to lifestyle and behavior modification in treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking.

Abbreviations and Acronyms
  BMI = body mass index
  CB1 = cannabinoid receptor type 1
  HDL = high-density lipoprotein
  LDL = low-density lipoprotein
  RIO = Rimonabant in Obesity
  STRATUS = Studies with Rimonabant and Tobacco Use
  THC = tetrahydrocannabinol


   Obesity, Metabolic Syndrome, and Smoking: the Scope of the Problem
Top
 Abstract
 Obesity, Metabolic Syndrome, and...
The Endocannabinoid System
 Physiology of the Cannabinoid...
 Rimonabant
 References
 
Cardiovascular disease remains by far the leading cause of morbidity and mortality in the developed world, accounting for almost one million deaths annually in the U.S. alone. Tobacco smoking remains the primary preventable cause of death, contributing to nearly 20% of all deaths worldwide. Recent startling reports project a decline in life expectancy in the U.S. during the 21st century (1). These reports warn of a catastrophic impact of the global obesity epidemic on rates of diabetes mellitus and cardiovascular disease in the upcoming years. Currently in the U.S., 28% of men and 34% of women are obese, and the largest increases in obesity rates have affected children and minorities (2). In this country, obesity is estimated to be associated with over 100,000 excess deaths every year (3).

The old view of adipose tissue as an inert storage depot was supplanted more recently by its depiction as a dynamic endocrine organ. Adipose tissue secretes a variety of factors, or adipokines, that contribute to insulin resistance, vascular endothelial dysfunction, and atherogenesis (4,5). It is therefore not surprising that abdominal obesity is not an isolated pathophysiological entity, but often coexists with hypertension, glucose intolerance, and dyslipidemia. Recognizing this, the 2001 National Cholesterol Education Program (Adult Treatment Panel III) put forward specific guidelines that define a population with metabolic syndrome (Table 1) (6), and describe individuals with a markedly elevated risk of developing diabetes and clinically significant atherosclerosis. Indeed, the presence of metabolic syndrome may be associated with a significant excess burden of myocardial infarction, stroke, and overall cardiovascular mortality (7).


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  		Table 1. Components of Metabolic Syndrome, as Defined by the Adult Treatment Panel III
 
Modification of cardiometabolic risk factors, including smoking and abdominal obesity, has a well-documented favorable effect on clinical outcomes. Smoking cessation is associated with a rapid decrease in the risk of developing adverse cardiovascular events, including myocardial infarction, stroke, and sudden death (8,9). A decrease in body weight and reduction in waist circumference is associated with favorable changes in the lipid profile and C-reactive protein and a decrease in mortality (10,11). However, success with behavior modification and currently available medications in achieving reliable abstinence from tobacco and with sustained weight loss is quite limited. Surgical procedures, such as gastric banding or gastric bypass, are effective for sustained weight loss, but are clearly invasive and are associated with nontrivial morbidity and mortality (12). Therefore, these are generally used as a last resort for patients with morbid obesity (body mass index [BMI] >40 kg/m2) and those with multiple obesity-related complications (13). With regard to smoking cessation, behavioral therapy, nicotine replacement therapy, and pharmacologic approaches (buproprion) have generally yielded only modest quit rates (14), and many individuals resume smoking within one year. Additionally, many who successfully quit smoking gain a considerable amount of weight, which serves as a barrier for those who are considering tobacco cessation.

Despite disappointing results for treatment of obesity and for smoking cessation, both are mandated as part of the overall cardiometabolic risk factor reduction for primary and secondary prevention of heart disease (Table 2) (15,16). An intriguing new combined approach to treating the obesity and glucose intolerance features of metabolic syndrome, as well as aiding smoking cessation, involves manipulation of the endogenous cannabinoid system, specifically with the cannabinoid receptor type 1 (CB1) antagonist rimonabant.


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  		Table 2. ACC/AHA Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction Guidelines: Risk Factor Modification
 

   The Endocannabinoid System
Top
 Abstract
 Obesity, Metabolic Syndrome, and...
 The Endocannabinoid System
Physiology of the Cannabinoid...
 Rimonabant
 References
 
Cannabis.   Hemp (Cannabis sativa) has been cultivated in many parts of the world for over 4,500 years. The plant is used for its fiber and oil, and abused as a recreational drug (marijuana, hashish). The main psychoactive alkaloid in cannabis is {Delta}-9-tetrahydrocannabinol (THC), but the plant contains more than 60 other cannabinoids, some of which modulate the actions of THC. Synthetic THC (dronabinol) is used to treat post-chemotherapy nausea and emesis, as well as anorexia associated with human immunodeficiency virus infection.

Cannabinoid receptors and their ligands.   The cannabinoids exert their pharmacologic action through the interaction with the specific receptors CB1 and CB2, which were described in the late 1980s and later were cloned (17,18) (Table 3). The CB1 receptors are primarily distributed to the brain (19) and adipose tissue (20), but are also found in the myocardium (21), vascular endothelium (22), and sympathetic nerve terminals (23). The CB2 receptors are primarily located in the lymphoid tissue and peripheral macrophages (24). Both receptors function as transmembrane G-proteins. Existence of CB3 receptors has been postulated (25), but the receptor itself has not yet been cloned.


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  		Table 3. History of Endocannabinoid System Research and Rimonabant Trials
 
Cannabinoid receptors have affinity for at least two endogenous ligands: small lipid molecules arachidonylethanolamide (anandamide), and 2-arachidonoylglycerol (2-AG). Under normal conditions, the endocannabinoid system is not tonically active, rather endocannabinoids are produced on demand, act locally, and are rapidly inactivated via cellular uptake and enzymatic hydrolysis (26).

More recently, cannabinoid antagonists were developed, of which rimonabant has been the most extensively studied. It has a high affinity for the central CB1 receptors (27), and its potential clinical uses will be discussed later in this review.


   Physiology of the Cannabinoid System
Top
 Abstract
 Obesity, Metabolic Syndrome, and...
 The Endocannabinoid System
 Physiology of the Cannabinoid...
Rimonabant
 References
 
Cardiovascular effects.   Cannabinoids have long been known to have potent psychotropic actions, but their wide-ranging effects on the cardiovascular system are just beginning to be unraveled.

In anesthetized rat models, intravenously administered anandamide produces a triphasic hemodynamic response (28): a brief period of vagally mediated bradycardia and hypotension, followed by a transitory pressor reaction, and a relatively prolonged vasodepressor response. The latter is the dominant effect of anandamide in animal models, and it results from CB1-mediated inhibition of norepinephrine release from presynaptic nerve terminals (29). In humans, acute administration of the cannabinoids produces vasodilation and tachycardia with a variable net effect on systemic blood pressure (30), but long-term use of THC results in CB1-mediated hypotension and bradycardia (31,32).

Although CB1 receptors are mostly expressed on the neuronal terminals, there is evidence showing that other cell types express these receptors and participate in cannabinoid physiology. Endocannabinoids induce vasodilation by acting directly on the CB1 receptors in the arterial smooth muscle in the brain (33). These compounds also induce vasodilation in a variety of vascular beds through an endothelium-dependent increase in nitric oxide synthesis (34), but at least some of the vasodilation is probably independent of the CB1 receptor system.

Endocannabinoid systems seem to be involved in regulation of vascular tone in hepatic disease, hypertension, and other disorders. In advanced cirrhosis, endocannabinoids mediate the vasodilatory state through their interaction with the CB1 receptors. In spontaneously hypertensive rats, the cardiac and vascular endothelial CB1 system becomes tonically active, and such animals show a more pronounced vasodepressor/hypotensive response to anandamide than do wild types (35). Rimonabant blocks the vasodepressor effect of anandamide in hypertensive animals, but not in normal animals, indicating that the CB1 system is largely inactive under normal hemodynamic conditions.

Recent work shows that the endocannabinoid system also plays a role in hemodynamics of shock states. Indeed, under conditions of experimental hemorrhage (36), myocardial infarction (37), or endotoxemia (38,39), macrophages and circulating platelets elaborate anandamide, which contributes to the onset of hypotension and shock. Blockade of CB1 receptors with rimonabant attenuates these effects.

Metabolic effects.   There is increasing evidence showing that the endocannabinoid system plays a central role in regulating metabolism and body composition by enhancing the central orexigenic drive and increasing peripheral lipogenesis (Table 4) (40).


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  		Table 4. The Effects of CB1 Blockade on Food Intake and Cardiometabolic Risk Factors
 
Control of food intake and body composition is the result of a series of complex interactions between the adipocytes, the mesolimbic system, the hypothalamus, and the gastrointestinal tract. A sense of hunger is mediated in part by the gut hormone ghrelin, which is produced in higher concentrations during diet-induced weight loss (41). Leptin, an endogenous hormone, can reduce the food intake. Serum concentration of leptin is directly proportional to the degree of adiposity, but obese individuals have lower sensitivity to leptin (42). An adipose tissue-specific protein, adiponectin, stimulates fatty acid oxidation and a decrease in body weight. Its levels are reduced in obesity (43).

Both cannabinoid receptors and their endocannabinoid ligands are present in all of the tissues that play an important role in regulation of food intake. Levels of endocannabinoids in the hypothalamus are decreased after administration of leptin (44). The CB1 agonists are potent, dose-dependent inducers of hyperphagia in rodents (45–47), and antagonism of CB1 receptors prevents hyperphagia in a starvation model (44). Knockout mice lacking CB1 receptors show a lean phenotype, primarily as a result of spontaneously reduced caloric intake (40). Indeed, when such animals are fed a high-fat, obesity-promoting diet, they remain lean, and compared with wild-type animals, show lower plasma insulin levels and a higher sensitivity to leptin (48). In the liver, endocannabinoids, acting via CB1 receptors, act to induce lipogenic gene expression and stimulate de novo synthesis of fatty acids (49).

Endocannabinoids and addiction.   Regions of the brain thought to be involved in drug relapse behavior contain high levels of CB1 receptors (19), and compelling evidence suggests a role for the endocannabinoid system in formulation and propagation of addiction to psychoactive substances. Specifically, endocannabinoids seem to modulate cue reactivity and conditioned reinforcement after prolonged abstinence of drug and natural reinforcers (50). These effects have been shown for a wide range of addictive substances, including cocaine (51), heroin (52), amphetamines (53), and alcohol (54). Studies have shown an important role for the endocannabinoid system in the modulation of nicotine addiction. Indeed, the rewarding effects of nicotine were abolished in knockout mice lacking CB1 receptors (55), and as described further below, administration of the selective CB1 antagonist rimonabant decreases nicotine-seeking behaviors (56). Interestingly, endocannabinoid involvement in nicotine dependence seems to be limited to its psychological aspects, as the physical aspects of nicotine withdrawal are not attenuated in CB1-deficient mice (57).


   Rimonabant
Top
 Abstract
 Obesity, Metabolic Syndrome, and...
 The Endocannabinoid System
 Physiology of the Cannabinoid...
 Rimonabant
References
 
Rimonabant was first described in 1994 by Rinaldi-Carmona et al. (27). At lower concentrations, it blocks the CB1 receptors. At very high concentrations, rimonabant behaves as a CB2 receptor antagonist (27), blocks calcium and potassium channels (58), and may directly affect cellular gap junctions (59).

Rimonabant for treatment of obesity and cardiometabolic risk factors: animal data.   The impact of rimonabant therapy on metabolism, food intake, and body composition was first investigated by several groups in standard rodent models. In an important study, Di Marzo et al. (44) showed that treatment with rimonabant was associated with a reduction in food intake and a 4% loss of body weight in wild-type mice, but not in CB1 receptor-deficient mice. Decrease in adiposity accounted for most of the rimonabant-induced weight loss, because muscle mass remained unchanged (60). Ravinet-Trillou et al. (61) showed that in mice with diet-induced obesity, rimonabant therapy was associated with only a transient reduction in food intake, but a marked and sustained weight reduction (20%) and a depletion of fat stores (~50%). In that study, rimonabant-treated animals showed lower plasma glucose and insulin levels, as well as improved insulin resistance. Notable recent findings by the same group suggest that decreased food intake alone cannot account for the sustained weight loss during rimonabant treatment. In fact, after the first week of treatment, a mild increase in food intake ensues, yet steady weight loss continues (60). Explanation may lie with the evidence that rimonabant induces changes in the adipose tissue both at the cellular and at the molecular levels. Grossly, adipocytes in rimonabant-treated animals are smaller and reflect a marked decrease in fat stores rather than adipocyte apoptosis (60). Using deoxyribonucleic acid chip technology, Jbilo et al. (60) showed that gene modulations induced by rimonabant treatment were opposite to those effected by a high-fat diet, and were very similar to those in CB1 knockout mice. Rimonabant was also shown to increase adiponectin levels by stimulating adiponectin messenger ribonucleic acid expression in the adipocytes (20). These findings lend strong support to the CB1-mediated mechanism of the anti-obesity action of rimonabant. In addition, treatment with rimonabant was associated with an induction of several glycolytic enzymes, which could explain the glucose-lowering effect of rimonabant. Finally, there was a reduction in the expression of multiple pro-inflammatory proteins, known to be upregulated in obesity (60).

Rimonabant for treatment of obesity: trials in humans..   Based on the animal data, the Rimonabant in Obesity (RIO) phase 3 program of four randomized double-blind placebo-controlled clinical trials in humans was initiated (Table 5).


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  		Table 5. Clinical Trials of Rimonabant (as of December 2005)
 
The RIO-Lipids trial
The RIO-Lipids trial enrolled 1,036 patients with mild or moderate obesity (mean BMI, 34 kg/m2) and untreated hyperlipidemia (62). Patients were randomized in a parallel fashion to receive rimonabant 20 mg/day, rimonabant 5 mg/day, or matching placebo for one year, and weight loss was assessed at the end of treatment. At the end of one year, treatment with rimonabant was associated with significantly greater weight loss compared with placebo (Fig. 1). Indeed, 58.4% of subjects in the high-dose rimonabant group had sustained a loss of ≥5% body weight, compared with 30.0% in the low-dose rimonabant group and 19.5% in the placebo group (p < 0.001 for high-dose rimonabant vs. placebo). A more substantial ≥10% weight loss was sustained by 32.6% of subjects in the high-dose rimonabant group, compared with 10.6% in the low-dose group and 7.2% in the placebo group (p < 0.001 for high-dose rimonabant vs. placebo) (Fig. 2). Among patients who completed a full one-year course of treatment, 72.9% of patients in the high-dose group lost ≥5% body weight, compared with 27.6% for placebo (p < 0.001). With regard to the lipid parameters, at the end of treatment the subjects in the high-dose rimonabant group had a 23% increase in high-density lipoprotein (HDL) levels and a 15% decrease in triglyceride levels. Both were different from placebo (p < 0.001 for both). The C-reactive protein levels were lower in the high-dose rimonabant group (27% reduction vs. 11% for placebo, p = 0.007), and the low-density lipoprotein (LDL) levels were not significantly affected by treatment. Rimonabant 20 mg also increased adiponectin levels by 57.7% (p < 0.001), a change that was partly independent of weight loss alone. An important final finding was that at the end of treatment, the proportion of patients satisfying the National Cholesterol Education Program-Adult Treatment Panel III criteria for metabolic syndrome was significantly lower in the high-dose rimonabant-treated group compared with placebo (25.8% vs. 41.0%, p < 0.001) (62).


Figure 1
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  		Figure 1 Change in body weight among subjects in the Rimonabant in Obesity (RIO)-Lipids study. Reprinted, with permission, from Despres et al. (62).

 

Figure 2
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  		Figure 2 Percentage of subjects achieving ≥10% weight loss at one year with rimonabant (solid bars) 20 mg/day versus placebo (open bars) in the first two Rimonabant in Obesity (RIO) trials among those completing the study.

 
The RIO-Europe trial
Results of RIO-Lipids were confirmed in a similar-sized RIO-Europe trial (63,64) that enrolled obese subjects with BMI ≥30 kg/m2, or >27 kg/m2 with a comorbidity, defined as hypertension or dyslipidemia. In this trial, 1,507 subjects were enrolled and assigned randomly to receive rimonabant 20 mg/day, rimonabant 5 mg/day, or placebo. Subjects were also given instructions for moderate physical exercise and a mild hypocaloric diet. Among patients completing one full year of treatment (61%), loss of ≥5% body weight was achieved significantly more frequently in both rimonabant groups compared with placebo (67.4% for 20 mg, 44.2% for 5 mg vs. 30.5% for placebo, p < 0.01 for both placebo comparisons). Treatment with either dose of rimonabant was also associated with significantly greater waist circumference reduction than placebo (6.5 cm for 20 mg, 3.9 cm for 5 mg, 2.4 cm for placebo, p < 0.01 for both comparisons). Triglyceride levels decreased and HDL levels increased in both rimonabant groups, and the investigators suggested that elevated levels of adiponectin were contributing to these effects. Finally, treatment with high-dose rimonabant was associated with a significantly greater reduction in the percentage of subjects with metabolic syndrome than placebo: from 42.2% at baseline to 19.6% at one year (63) and 21.5% at two years (p < 0.001 compared with placebo) (64).

The RIO-NA trial
Obese patients in North America (NA) were enrolled into the RIO-NA trial (65). In addition to evaluating the efficacy of rimonabant for primary weight loss, this 3,045-subject trial had evaluated whether weight loss achieved with rimonabant could be maintained after withdrawal of the drug. As in prior RIO trials, subjects were initially randomized to rimonabant 20 mg/day, rimonabant 5 mg/day, or placebo for one year. However, after the completion of one year of treatment, subjects in the two rimonabant groups underwent a second randomization, either to continue receiving their previously assigned dose of rimonabant or to be switched to a matching placebo. The first-year outcomes were similar to those of the other RIO trials: weight loss was significantly greater in the rimonabant treatment groups (–6.3 kg for 20 mg/day, –4.4 kg for 5 mg/day vs. –1.6 kg for placebo, p < 0.01 for both comparisons). After two years, subjects re-randomized to placebo after the end of one year have regained much of their weight (overall loss of 3.2 kg vs. 2.3 kg for patients on placebo for two years), whereas those who were treated with rimonabant 20 mg/day for the full two years lost an average of 7.4 kg (p < 0.01 for placebo comparison). Rates of metabolic syndrome were improved with rimonabant, with which a significant reduction was seen in the 20-mg dose group (34.8% to 21.1%) compared with placebo (31.7% to 29.2%). An increase in HDL of 24.5% was seen in the rimonabant 20 mg/day group, compared with 13.8% in the placebo group.

The RIO-Diabetes trial
The most recent study reported from the RIO phase 3 program was the RIO-Diabetes trial (66), which enrolled 1,047 patients with type 2 diabetes mellitus and a BMI 27 to 40 kg/m2. Again, subjects were randomized to receive rimonabant 20 mg/day, rimonabant 5 mg/day, or placebo for one year. All patients were also treated with an oral hypoglycemic drug, as prescribed by their treatment physician, with the majority receiving metformin. At the end of one year, therapy with rimonabant 20 mg was associated with an average weight loss of 5.3 kg, compared with 1.4 kg in the placebo group (p < 0.001). Average levels of glycosylated hemoglobin were decreased by 0.6% in the rimonabant 20 mg group from a baseline level of 7.3%, but were increased in the placebo group by 0.1% (p < 0.001). Effects of the rimonabant 5 mg/day were less significant. Importantly, 43% of all subjects treated with rimonabant achieved an optimal glycosylated hemoglobin level of <6.5%, compared with just 21% of those receiving placebo (p < 0.001).

In summary, the RIO trials showed that in patients with obesity, including those with cardiovascular comorbidities, continued therapy with rimonabant as compared with placebo is associated with a significant reduction in body weight and waist circumference. Such therapy is also associated with other favorable changes in the cardiometabolic risk profile, including an improvement in glycemic control in type 2 diabetics, an improvement in the lipid profile, and an overall decrease in the prevalence of metabolic syndrome.

The Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—the Intravascular Ultrasound Study (STRADIVARIUS).
The ongoing STRADIVARIUS trial (67) will test whether the improvement in the cardiometabolic risk profile effected by rimonabant translates into changes within the coronary circulation. The STRADIVARIUS trial is enrolling obese subjects who either are smokers or have at least two additional features that fit the standard definition of metabolic syndrome, and in whom a clinically indicated coronary angiography reveals a 20% to 50% stenosis. The volume of atheroma will be assessed by intravascular ultrasound. Subjects will then be randomized to rimonabant 20 mg/day, rimonabant 5 mg/day, or placebo, and the end point will be change in the volume of target atheroma at the time of a mandatory repeat angiography at 18 months. There are also plans for a large clinical outcomes trial to begin in the coming year.

Rimonabant for smoking cessation: the Studies with Rimonabant and Tobacco Use (STRATUS) trials.   Enrolling concurrently with the RIO program, the STRATUS trials are examining the potential role of rimonabant as an adjunct in smoking cessation (Table 5).

In a randomized, double-blind, placebo-controlled STRATUS-United States (US) trial (68), 787 subjects were enrolled who smoked ≥10 cigarettes/day (average, 23 cigarettes/day) for at least two months and who were motivated to quit. Subjects were randomly assigned to receive rimonabant 20 mg/day, rimonabant 5 mg/day, or placebo for 10 weeks, and were asked to quit smoking on day 15 of the study. End points included smoking abstinence rate as well as a change in body weight in those who were abstinent from cigarettes at one year. At the end of the study, the rate of abstinence was significantly higher in the high-dose rimonabant group compared with placebo (36.2% vs. 20.6%, p < 0.001), but not in the low-dose rimonabant group (20.2%). Among subjects with prolonged abstinence, those in the placebo group gained an average of 3.7 kg of body weight, compared with 0.6 kg in the high-dose rimonabant group (p < 0.001), representing an impressive 84% reduction in weight gain for rimonabant over placebo. Subgroup analysis showed that among subjects who were initially overweight, those who were abstinent from tobacco while receiving rimonabant 20 mg/day had not gained any weight by one year (weight change –0.1 kg vs. +1.7 kg for placebo, p < 0.001). As with the RIO trials, no differences were noted in the rate of dropout among the treatment groups.

The STRATUS-Europe (EU) has a protocol identical to STRATUS-US, and is following up 789 subjects in Europe; STRATUS-Worldwide (WW) is a large one-year maintenance study with a treatment-free one-year follow-up that was conducted among 5,055 subjects across 54 sites worldwide. Results from both of these trials are expected within one year.

Potential uses of rimonabant in other disorders.   Involvement of the endocannabinoid system in a wide variety of neuropsychiatric, cardiac, vascular, and metabolic pathophysiological processes, and a wealth of animal data on both endogenous ligands and rimonabant, offer multiple intriguing possibilities for clinical use in humans. A phase 2 clinical trial of rimonabant to reduce alcohol consumption is being sponsored by the National Institutes of Health (69). Animal experiments showing that blockade of CB1 receptors with rimonabant attenuates shock caused by extreme hemorrhage (36), endotoxemia (38), or myocardial infarction (37) will likely prompt human clinical trials in the near future. Rimonabant may also find use in the treatment of vasodilatory state and chronic hypotension in patients with advanced liver disease (70).

Adverse effects in clinical trials of rimonabant.   Initial experience with rimonabant shows that it is generally well tolerated. In the RIO phase 3 program, the one-year dropout rates were high (36% to 49%), but were typical of obesity trials and did not differ from placebo. The most common adverse effect was mild nausea. Given its pharmacology, there is concern regarding the neuropsychiatric effects of rimonabant, such as higher incidence of anxiety and depressed mood disorders. Use of the Hospital Anxiety and Depression scale in RIO-Europe showed no difference between the treatment groups in the average subscale scores for either major depression or anxiety (63). During one year of treatment, six subjects (1.0%) in the rimonabant 20 mg/day group and one subject (0.3%) in the placebo group discontinued their study drug because of depression. For depressed mood disorders, the rates were 3.7% and 3.0% for rimonabant 20 mg/day and placebo, respectively. Similarly, in RIO-Lipids, the Hospital Anxiety and Depression scale scores were similar for anxiety and depression between the two treatment groups and placebo (62). Therefore, it seems that the percentage of patients experiencing neuropsychiatric side effects is small. Monitoring for on-treatment anxiety and depression in the future will nonetheless be necessary to ensure safe use of this important new therapy.


   Footnotes
 
Dr. Cannon serves on advisory boards and consult for Sanofi-Aventis and has spoken at medical symposia sponsored by this company. The authors also recently completed a trial (CLARITY-TIMI 28) sponsored by Sanofi-Aventis, but do not currently have ongoing research grants. Dr. Cannon serves as an unpaid member of the STRADIVARIUS trial Steering Committee, led by Dr. Steven E. Nissen.


   References
Top
 Abstract
 Obesity, Metabolic Syndrome, and...
 The Endocannabinoid System
 Physiology of the Cannabinoid...
 Rimonabant
 References
 

  1. Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century N Engl J Med 2005;352:1138-1145.[Abstract/Free Full Text]
  2. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002 JAMA 2004;291:2847-2850.[Abstract/Free Full Text]
  3. Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight, overweight, and obesity JAMA 2005;293:1861-1867.[Abstract/Free Full Text]
  4. Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis Endocrinology 2003;144:2195-2200.[Abstract/Free Full Text]
  5. Eckel RH. Obesity Circulation 2005;111:e257-e259.[Free Full Text]
  6. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA 2001;285:2486-2497.[Free Full Text]
  7. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome Diabetes Care 2001;24:683-689.[Abstract/Free Full Text]
  8. Iso H, Date C, Yamamoto A, et al. Smoking cessation and mortality from cardiovascular disease among Japanese men and women: the JACC Study Am J Epidemiol 2005;161:170-179.[Abstract/Free Full Text]
  9. Goldenberg I, Jonas M, Tenenbaum A, et al. Current smoking, smoking cessation, and the risk of sudden cardiac death in patients with coronary artery disease Arch Intern Med 2003;163:2301-2305.[Abstract/Free Full Text]
  10. Eriksson KF, Lindgarde F. No excess 12-year mortality in men with impaired glucose tolerance who participated in the Malmo Preventive Trial with diet and exercise Diabetologia 1998;41:1010-1016.[CrossRef][ISI][Medline]
  11. Wadden TA, Anderson DA, Foster GD. Two-year changes in lipids and lipoproteins associated with the maintenance of a 5% to 10% reduction in initial weight: some findings and some questions Obes Res 1999;7:170-178.[ISI][Medline]
  12. Flum DR, Salem L, Elrod JA, Dellinger EP, Cheadle A, Chan L. Early mortality among Medicare beneficiaries undergoing bariatric surgical procedures JAMA 2005;294:1903-1908.[Abstract/Free Full Text]
  13. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis JAMA 2004;292:1724-1737.[Abstract/Free Full Text]
  14. Karnath B. Smoking cessation Am J Med 2002;112:399-405.[CrossRef][ISI][Medline]
  15. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle N Engl J Med 2000;343:16-22.[Abstract/Free Full Text]
  16. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina) J Am Coll Cardiol 2002;40:1366-1374.[Free Full Text]
  17. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA Nature 1990;346:561-564.[CrossRef][Medline]
  18. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids Nature 1993;365:61-65.[CrossRef][Medline]
  19. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain Proc Natl Acad Sci U S A 1990;87:1932-1936.[Abstract/Free Full Text]
  20. Bensaid M, Gary-Bobo M, Esclangon A, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells Mol Pharmacol 2003;63:908-914.[Abstract/Free Full Text]
  21. Bonz A, Laser M, Kullmer S, et al. Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle J Cardiovasc Pharmacol 2003;41:657-664.[CrossRef][ISI][Medline]
  22. Liu J, Gao B, Mirshahi F, et al. Functional CB1 cannabinoid receptors in human vascular endothelial cells Biochem J 2000;346:835-840.[CrossRef][ISI][Medline]
  23. Ishac EJ, Jiang L, Lake KD, Varga K, Abood ME, Kunos G. Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves Br J Pharmacol 1996;118:2023-2028.[ISI][Medline]
  24. Hanus L, Breuer A, Tchilibon S, et al. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor Proc Natl Acad Sci U S A 1999;96:14228-14233.[Abstract/Free Full Text]
  25. Fride E, Foox A, Rosenberg E, et al. Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a "CB3" receptor Eur J Pharmacol 2003;461:27-34.[CrossRef][ISI][Medline]
  26. Giuffrida A, Beltramo M, Piomelli D. Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology J Pharmacol Exp Ther 2001;298:7-14.[Abstract/Free Full Text]
  27. Rinaldi-Carmona M, Barth F, Heaulme M, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor FEBS Lett 1994;350:240-244.[CrossRef][ISI][Medline]
  28. Varga K, Lake K, Martin BR, Kunos G. Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide Eur J Pharmacol 1995;278:279-283.[CrossRef][ISI][Medline]
  29. Niederhoffer N, Schmid K, Szabo B. The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression Naunyn Schmiedebergs Arch Pharmacol 2003;367:434-443.[CrossRef][ISI][Medline]
  30. Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ. Characterization of the absorption phase of marijuana smoking Clin Pharmacol Ther 1992;52:31-41.[ISI][Medline]
  31. Benowitz NL, Jones RT. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion Clin Pharmacol Ther 1975;18:287-297.[ISI][Medline]
  32. Lake KD, Compton DR, Varga K, Martin BR, Kunos G. Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors J Pharmacol Exp Ther 1997;281:1030-1037.[Abstract/Free Full Text]
  33. Gebremedhin D, Lange AR, Campbell WB, Hillard CJ, Harder DR. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current Am J Physiol 1999;276:H2085-H2093.[ISI][Medline]
  34. Deutsch DG, Goligorsky MS, Schmid PC, et al. Production and physiological actions of anandamide in the vasculature of the rat kidney J Clin Invest 1997;100:1538-1546.[ISI][Medline]
  35. Batkai S, Pacher P, Osei-Hyiaman D, et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension Circulation 2004;110:1996-2002.[Abstract/Free Full Text]
  36. Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock Nature 1997;390:518-521.[CrossRef][Medline]
  37. Wagner JA, Hu K, Bauersachs J, et al. Endogenous cannabinoids mediate hypotension after experimental myocardial infarction J Am Coll Cardiol 2001;38:2048-2054.[Abstract/Free Full Text]
  38. Varga K, Wagner JA, Bridgen DT, Kunos G. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension FASEB J 1998;12:1035-1044.[Abstract/Free Full Text]
  39. Godlewski G, Malinowska B, Schlicker E. Presynaptic cannabinoid CB(1) receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats Br J Pharmacol 2004;142:701-708.[CrossRef][ISI][Medline]
  40. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis J Clin Invest 2003;112:423-431.[CrossRef][ISI][Medline]
  41. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery N Engl J Med 2002;346:1623-1630.[Abstract/Free Full Text]
  42. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans N Engl J Med 1996;334:292-295.[Abstract/Free Full Text]
  43. Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice Proc Natl Acad Sci U S A 2001;98:2005-2010.[Abstract/Free Full Text]
  44. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake Nature 2001;410:822-825.[CrossRef][Medline]
  45. Williams CM, Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors Psychopharmacology (Berl) 1999;143:315-317.[CrossRef][Medline]
  46. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats Br J Pharmacol 2001;134:1151-1154.[CrossRef][ISI][Medline]
  47. Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol Br J Pharmacol 2002;136:550-557.[CrossRef][ISI][Medline]
  48. Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity Int J Obes Relat Metab Disord 2004;28:640-648.[CrossRef][ISI][Medline]
  49. Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity J Clin Invest 2005;115:1298-1305.[CrossRef][ISI][Medline]
  50. De Vries TJ, de Vries W, Janssen MC, Schoffelmeer AN. Suppression of conditioned nicotine and sucrose seeking by the cannabinoid-1 receptor antagonist SR141716A Behav Brain Res 2005;161:164-168.[CrossRef][ISI][Medline]
  51. De Vries TJ, Shaham Y, Homberg JR, et al. A cannabinoid mechanism in relapse to cocaine seeking Nat Med 2001;7:1151-1154.[CrossRef][ISI][Medline]
  52. Fattore L, Spano MS, Cossu G, Deiana S, Fratta W. Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats Eur J Neurosci 2003;17:1723-1726.[CrossRef][ISI][Medline]
  53. Anggadiredja K, Nakamichi M, Hiranita T, et al. Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade Neuropsychopharmacology 2004;29:1470-1478.[CrossRef][ISI][Medline]
  54. Gallate JE, Saharov T, Mallet PE, McGregor IS. Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist Eur J Pharmacol 1999;370:233-240.[CrossRef][ISI][Medline]
  55. Castane A, Valjent E, Ledent C, Parmentier M, Maldonado R, Valverde O. Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence Neuropharmacology 2002;43:857-867.[CrossRef][ISI][Medline]
  56. LeFoll B, Goldberg SR. Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences Neuroreport 2004;15:2139-2143.[CrossRef][ISI][Medline]
  57. Balerio GN, Aso E, Berrendero F, Murtra P, Maldonado R. Delta9-tetrahydrocannabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice Eur J Neurosci 2004;20:2737-2748.[CrossRef][ISI][Medline]
  58. White R, Hiley CR. The actions of the cannabinoid receptor antagonist, SR 141716A, in the rat isolated mesenteric artery Br J Pharmacol 1998;125:689-696.[CrossRef][ISI][Medline]
  59. Chaytor AT, Martin PE, Evans WH, Randall MD, Griffith TM. The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication J Physiol 1999;520:539-550.[Abstract/Free Full Text]
  60. Jbilo O, Ravinet-Trillou C, Arnone M, et al. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance FASEB J 2005;19:1567-1569.[Abstract/Free Full Text]
  61. Ravinet-Trillou C, Arnone M, Delgorge C, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice Am J Physiol Regul Integr Comp Physiol 2003;284:R345-R353.[Abstract/Free Full Text]
  62. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia N Engl J Med 2005;353:2121-2134.[Abstract/Free Full Text]
  63. VanGaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study Lancet 2005;365:1389-1397.[CrossRef][ISI][Medline]
  64. VanGaal LF. 2-year data from the RIO-Europe study: metabolic effects of rimonabant in overweight/obese patients. Presented at: American College of Cardiology Scientific Sessions; Orlando, FL: 2005..
  65. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 2006;295:761–75..
  66. Scheen AJ. Effects of rimonabant in patients with type 2 diabetes mellitus. Results of the RIO-DIABETES trial. Presented at: American Diabetes Association Scientific Sessions; San Diego, CA: 2005..
  67. STRADIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—the Intravascular Ultrasound Study)http://www.clinicaltrials.gov/ct/gui/show/NCT00124332?order=2 2005Accessed September 26, 2005.
  68. Anthenelli RM. Effects of rimonabant in the reduction of major cardiovascular risk factors. Results from the STRATUS-US trial (Smoking Cessation in Smokers Motivated to Quit). Presented at: American College of Cardiology Scientific Sessions; New Orleans, LA: 2004..
  69. Rimonabant to Reduce Alcohol Consumption—A Phase II Clinical Trialhttp://www.clinicaltrials.gov/ct/gui/show/NCT00075205?order=1 2005Accessed September 26, 2005.
  70. Batkai S, Jarai Z, Wagner JA, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis Nat Med 2001;7:827-832.[CrossRef][ISI][Medline]



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