Cannabinoid-1 Receptor Antagonist, Rimonabant, for Management of Obesity and Related Risks

Gadde, Kishore M.; Allison, David B.

doi:10.1161/circulationaha.105.596130

Cited by 71 publications

(43 citation statements)

References 84 publications

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“…18, 47 The most impressive data arose from the RIO programme in overweight/obese individuals with or without comorbidities. 19,23,43 In this clinical research programme, two doses of rimonabant (5 mg and 20 mg) were compared to placebo, but only the dose of 20 mg has been commercialized (see below). …”

Section: Rimonabantmentioning

confidence: 99%

“…[16][17][18] For instance, it is reasonable to hypothesize that attenuation of EC-system over-activity would have therapeutic benefit in treating disorders that might have a component of excessive appetite drive, such as obesity and related disturbances. [18][19][20][21] Interestingly, whereas antagonism of CB1 receptors acutely reduces food intake, the long-term effects on weight reduction and metabolic regulation rather appear to be mediated by stimulation of energy expenditure and by peripheral effects related to adipose tissue, liver, skeletal muscle, and pancreas physiology. 14,22 Such observations extend the potential use of CB1 antagonists (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Cannabinoid-1 receptor antagonists in type-2 diabetes

Scheen

2007

Best Practice & Research Clinical Endocrinology & Metab

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Type-2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a risk of major cardiovascular disease. Several animal and human observations suggest that the endocannabinoid system is over-active in the presence of abdominal obesity and/or diabetes. Both central and peripheral endocannabinoid actions, via the activation of CB1 receptors, promote weight gain and associated metabolic changes. Rimonabant, the first selective CB 1 receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance index and C-reactive protein levels, and to increase high-density lipoprotein (HDL) cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in HbA1c levels was observed in metformin-or sulphonylurea-treated patients with type-2 diabetes and in drugnaïve diabetic patients. Almost half of the metabolic changes, including HbA1c reduction, could not be explained by weight loss, suggesting that there are direct peripheral effects. Rimonabant was generally welltolerated, and the safety profile was similar in diabetic and non-diabetic patients, with a higher incidence of depressed mood disorders, nausea and dizziness. In conclusion, the potential role of rimonabant in overweight/obese patients with type-2 diabetes and at high risk of cardiovascular disease deserves much consideration.Keywords: rimonabant ; obesity ; type-2 diabetes ; cardiovascular risk ; CB 1 receptor blocker ; endocannabinoid system. Type-2 diabetes frequently coexists with a cluster of other cardiovascular and metabolic risk factors -including abdominal obesity, low high-density lipoprotein cholesterol (HDL-C), high triglycerides, elevated blood pressure and silent inflammation -and is considered to be a cardiovascular disease (CVD) risk equivalent. 1,2 Being overweight or obese -abdominally obese in particular -increases the risk of type-2 diabetes and CVD. [3][4][5] Yet individuals with type-2 diabetes often have more difficulty in losing weight and experience weight gain associated with most antidiabetic medications. 6,7 The treatment of multiple cardiovascular and metabolic riskfactors is central to the management of diabetic patients 1,2,5,8,9 , and the importance of weight management is well recognized in type-2 diabetes. 7,10,11 Over the last two decades a new biochemical/physiological system, known as the endocannabinoid (EC) system, was discovered. 12,13 There is considerable evidence that the EC system plays a significant role in appetite drive and associated behaviours, but also in endocrine and metabolic regulation and energy balance. 14 Indeed, cannabinoid (CB) receptors, especially CB1 receptors, participate in the physiological modulation of many central and peripheral functions. 14 The tremendous advances in the understanding of the molecular basis of CB activity 15 has encouraged many pharmaceutical companie...

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Section: Rimonabantmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cannabinoid-1 receptor antagonists in type-2 diabetes

Scheen

2007

Best Practice & Research Clinical Endocrinology & Metab

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“…The tremendous increase in the understanding of the molecular basis of CB activity [4][5][6] has encouraged many pharmaceutical companies to develop synthetic CB analogues and antagonists, leading to an explosion of basic research and clinical trials [7][8][9][10][11]. For instance, it is reasonable to hypothesize that the attenuation of EC system overactivity would have therapeutic benefit in treating disorders that might have a component of excessive appetite drive, such as obesity and related disturbances [9,[11][12][13][14][15][16]. Interestingly, whereas antagonism of CB1 receptors acutely reduces food intake, the long-term effects on weight reduction and metabolic regulation rather appear to be mediated by stimulation of energy expenditure and by peripheral effects related to adipose tissue, liver, skeletal muscle and pancreas physiology [3,17].…”

Section: Introductionmentioning

confidence: 99%

The Endocannabinoid System: A Promising Target for the Management of Type 2 Diabetes

Scheen

2009

CPPS

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Conflict of interest :AJ Scheen is a consultant for sanofi-aventis, AstraZeneca, GlaxoSmithKline, and has received lecture fees from sanofi-aventis. 1 SUMMARY (Max 250 words : 250)Type 2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a high incidence of cardiovascular complications.Several animal and human observations suggest that the endocannabinoid (EC) system is overactivated in presence of abdominal obesity and/or diabetes, and contributes to disturbances of energy balance and metabolism. Not only it regulates the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, but it also intervenes in transport, metabolism and deposit of the nutrients in the digestive tract, liver, adipose tissue, skeletal muscle, and possibly pancreas. Activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes. Conversely, rimonabant, the first selective CB 1 receptor antagonist in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and to increase HDL cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin (HbA1c) levels was observed in metformin-or sulfonylurea-treated patients with type 2 diabetes and in drug-naïve diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared to placebo. New trials are supposed to confirm the potential role of rimonabant (and other CB1 neutral antagonists or inverse agonists) in overweight/obese patients with type 2 diabetes and high risk cardiovascular disease.

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“…The degree of weight loss with rimonabant is not markedly greater than that observed with sibutramine or orlistat. A recent analysis suggested it was approximately equal to sibutramine (3.4-5.4 kg compared with placebo for rimonabant in four large studies and 3.0-7.8 kg for sibutramine in five studies), although superior to orlistat (1.3-4.2 kg in 12 1-year-long studies) [10]. Taking the results of all four rimonabant trials together, Gadde and Allison [10] concluded that weight loss efficacy was modest but consistent.…”

Section: Editor's Commentsmentioning

confidence: 97%