Effect of Rimonabant, a Cannabinoid-1 Receptor Blocker, on Weight and Cardiometabolic Risk Factors in Overweight or Obese Patients

Pi‐Sunyer, F. Xavier; Aronne, Louis J.; Heshmati, H. M.; Devin, Jeanne; Rosenstock, Julio

doi:10.1001/jama.295.7.761

Cited by 1,156 publications

(964 citation statements)

References 29 publications

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“…In four placebo-controlled, multinational, double-blind, clinical RIO (Rimonabant In Obesity) studies, rimonabant has been shown not only to reduce body weight, but additionally to improve cardiometabolic risk factors, such as waist circumference, HbA1c, high-density lipoprotein and triglyceride in overweight/obese patients. [12][13][14][15] The antiobese effect of rimonabant is ascribed to its CB1 receptor antagonism in the hypothalamus 16,17 and nucleus accumbens, [18][19][20] resulting in reduced food intake predominantly of palatable food. In addition to the central effects on food intake and body weight, the improvement in the cardiometabolic risk factors, which have been shown to be beyond that what would be expected by body weight reduction alone, is hypothesized to involve also peripheral CB1 receptor antagonism.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the central effects on food intake and body weight, the improvement in the cardiometabolic risk factors, which have been shown to be beyond that what would be expected by body weight reduction alone, is hypothesized to involve also peripheral CB1 receptor antagonism. [12][13][14][15] There are convincing results reported on the sustained body weight reduction in spite of the transient effects on food reduction in diet-induced obese mice, as well as in genetic rat models of obesity, such as the fa/fa Zucker rat. [21][22][23][24][25] The transience of reduced food intake in the presence of persistent reduction of body weight caused by rimonabant in rodent models has recently been elucidated to be caused by increased energy expenditure based on increased fat oxidation measured by indirect calorimetry, which contributed more to the sustained body weight reducing effect of rimonabant than reduced food intake.…”

Section: Introductionmentioning

confidence: 99%

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Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant

et al. 2008

Int J Obes

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Objective: The severity of obesity is often more determined by the distribution of fat depots rather than by body weight itself. Therefore, the effect of rimonabant on fat distribution pattern was investigated in female candy-fed Wistar rats. Design: Female Wistar rats were fed a high fat, high carbohydrate (candy-) diet for 12 weeks. During the last 6 weeks rats were treated with rimonabant. Food intake and body weight development were investigated, as well as effects on total body fat, especially visceral fat and ectopic lipid accumulation in skeletal muscle and liver, determined by in vivo magnetic resonance imaging/magnetic resonance spectroscopy. Results: Candy-diet increased body weight, which was predominantly due to the increased total fat mass with predominance of visceral fat accumulation. Treatment with rimonabant fully reversed the weight gain and fat deposition in the visceral cavity and skeletal muscle, in contrast to pair feeding. In spite of an only transient reduction of food intake, body weight reduction, as well as normalized body fat, reduced visceral fat and intramyocellular lipids were maintained over the treatment period. Conclusions: We conclude that additional factors other than reduced caloric intake must be responsible for the improvements in these lipid parameters. The complete cluster of results is consistent with increased lipid oxidation caused by rimonabant.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant

et al. 2008

Int J Obes

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“…In this context, it is also worthwhile to note that the most frequently encountered side effects during the recently conducted phase-III trials of the CB1 receptor antagonist rimonabant (SR141716) as an anti-obesity treatment included anxiety and mood disturbances. [29][30][31] Studies on the function of endocannabinoids in classic animal models of depression or antidepressant-like behavior, however, have so far been sparse and revealed contradictory results in rats and mice. The forced swim test (FST) represents one of the most widely used tests to detect antidepressant-like activities of drugs as well as depressionlike behavior in genetically engineered mice.…”

Section: Introductionmentioning

confidence: 99%

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

et al. 2007

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Dysregulation of the endocannabinoid system is known to interfere with emotional processing of stressful events. Here, we studied the role of cannabinoid receptor type 1 (CB1) signaling in stress-coping behaviors using the forced swim test (FST) with repeated exposures. We compared effects of genetic inactivation with pharmacological blockade of CB1 receptors both in male and female mice. In addition, we investigated potential interactions of the endocannabinoid system with monoaminergic and neurotrophin systems of the brain. Naive CB1 receptor-deficient mice (CB1 À/À ) showed increased passive stress-coping behaviors as compared to wild-type littermates (CB1 þ / þ ) in the FST, independent of sex. These findings were partially reproduced in C57BL/6N animals and fully reproduced in female CB1 þ / þ mice by pharmacological blockade of CB1 receptors with the CB1 receptor antagonist SR141716. The specificity of SR141716 was confirmed in female CB1 À/À mice, where it failed to affect behavioral performance. Sensitivity to the antidepressants desipramine and paroxetine was preserved, but slightly altered in female CB1 À/À mice. There were no genotype differences between CB1 þ / þ and CB1 À/À mice in monoamine oxidase A and B activities under basal conditions, nor in monoamine content of hippocampal tissue after FST exposure. mRNA expression of vesicular glutamate transporter type 1 was unaffected in CB1 À/À mice, but mRNA expression of brain-derived neurotrophic factor (BDNF) was reduced in the hippocampus. Our results suggest that impaired CB1 receptor function promotes passive stress-coping behavior, which, at least in part, might relate to alterations in BDNF function.

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“…This retention programme was implemented proactively and was successful at improving upon the reported 53% 1‐year retention rate in the Rio‐North American study, which studied a similar weight loss drug in patients with similar BMI but without diabetes in the USA and Canada, also over a 1‐year time period 1, 19, and even improved upon the retention rate of Phase 3 trials conducted with more recently approved weight loss agents 2, 3, 4, 5.…”

Section: Discussionmentioning

confidence: 99%

“…On average, one‐third to one‐half of participants drops out of these large trials by 1 year 1, 2, 3, 4, 5. Such high‐attrition rates result in missing data that limit the interpretation and generalizability of findings 6.…”

Section: Introductionmentioning

confidence: 99%

Maximizing retention in long‐term clinical trials of a weight loss agent: use of a dietitian support team

Delahanty

Riggs

Klioze

et al. 2016

Obesity Science & Practice

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SummaryObjectiveHigh‐attrition rates have been observed in long‐term clinical trials of weight loss agents. We evaluated the impact of an innovative retention programme on 1‐year retention.MethodsThree Phase 3 global multicentre clinical trials evaluated the efficacy and safety of a CB1 receptor antagonist in subjects with BMI ≥ or = 27 kg/m2. The impact of a multifaceted retention programme including a dietitian screening interview, a comprehensive culturally adapted lifestyle modification programme, and a dietitian support system to maximize lifestyle adherence, was evaluated in 4,410 subjects from four subpopulations (non‐US English‐speaking, non‐English‐speaking, US‐without dietitian screening and US‐with dietitian screening) comprising 208 centres from 15 countries.ResultsThe median proportion retained over the first year among subjects in three protocols was 82%. Non‐English‐speaking countries showed higher retention rates (89%) compared with the USA (73%) and non‐US English‐speaking (81%) countries. Within the USA, behavioural screening was associated with 29% reduction in dropout rate; for every five monthly teleconferences attended above 11, there was a 32% decrease in dropout rate.ConclusionsThis novel retention programme greatly improved upon reported retention rates of studies conducted with other weight loss agents in long‐term clinical trials. Its effectiveness should be confirmed in future trials.

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Effect of Rimonabant, a Cannabinoid-1 Receptor Blocker, on Weight and Cardiometabolic Risk Factors in Overweight or Obese Patients

Cited by 1,156 publications

References 29 publications

Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant

Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

Maximizing retention in long‐term clinical trials of a weight loss agent: use of a dietitian support team

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