Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial

Topol, Eric J.; Bousser, Marie‐Germaine; Fox, Keith A.A.; Creager, Mark A.; Després, Jean‐Pierre; Easton, J. Donald; Hamm, Christian W.; Montalescot, Gilles; Steg, Philippe Gabriel; Pearson, Thomas A.; Cohen, Éric A.; Gaudin, Christophe; Job, Bernard; Murphy, James; Bhatt, Deepak L.

doi:10.1016/s0140-6736(10)60935-x

Cited by 231 publications

(140 citation statements)

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“…However, the commercial development of CB 1 receptor antagonists, including studies with rimonabant (CB 1 K i = 12 nM), taranabant (CB 1 K i = 9-10 nM) and otenabant (CB 1 K i = 1 nM) (Howlett et al, 2002), was halted due to adverse neuropsychiatric effects (Janero and Makriyannis, 2009). However, many thousands of people have safely taken and tolerated a dose of a CB 1 receptor antagonist /inverse agonist (Van Gaal et al, 2008;Topol et al, 2010). The adverse events, notably depression, anxiety and a low risk of suicide, which prompted withdrawal of rimonabant from the market (Janero and Makriyannis, 2009), were not considered to be acceptable to justify its long-term use against what may be considered lifestyle, food and tobacco issues (Doggrell, 2008;Janero and Makriyannis, 2009).…”

Section: Discussionmentioning

confidence: 99%

Antidote to cannabinoid intoxication: the CB₁ receptor inverse agonist, AM251, reverses hypothermic effects of the CB₁ receptor agonist, CB‐13, in mice

Pryce

Baker

2017

British J Pharmacology

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BACKGROUND AND PURPOSECannabis is a recreational drug leading to intoxication, following stimulation of cannabinoid CB 1 receptors. However, more recently, herbs mixed with synthetic cannabinoids sometimes known as 'Spice' and 'Black Mamba' have been increasingly used, and their high CB 1 receptor affinity has led not only to marked intoxication but also life-threatening complications and an increasing number of deaths. Although many studies have indicated that prophylactic treatment with CB 1 receptor antagonists can block cannabimimetic effects in animals and humans, the aim of this study was to determine whether CB 1 receptor antagonism could reverse physical cannabimimetic effects. EXPERIMENTAL APPROACHCannabimimetic effects, measured by the hypothermic response following sedation and hypomotility, were induced by the synthetic CB 1 receptor agonist CB-13 (1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone) in Biozzi Antibody High mice. The CB 1 receptor antagonist/inverse agonist AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) was administered 20 min after the injection of CB-13 and its effects on the cannabimimetic responses were assessed. KEY RESULTSIn this study, the CNS-related cannabimimetic effects, as measured by the hypothermic effect, induced by the CB 1 receptor agonist were therapeutically treated and were rapidly reversed by the CB 1 receptor antagonist/inverse agonist. There was also a subjective reversal of visually evident sedation. CONCLUSIONS AND IMPLICATIONSCannabinoid receptor antagonists have been widely used and so may provide an acceptable single-dose antidote to cannabinoid intoxication. This use may save human life, where the life-threatening effects are mediated by cannabinoid receptors and not offtarget influences of the synthetic cannabinoids or non-cannabinoids within the recreational drug mixture. In animals, cannabimimetic effects have been associated with a tetrad of behavioural effects including catalepsy, analgesia, lack of locomotor activity and thermoregulation, mediated mainly by THC within cannabis and by CB 1 receptors expressed within the CNS (Zimmer et al., 1999;Varvel et al., 2005;Croxford et al., 2008). These behavioural effects induced by THC and synthetic cannabinoids can be blocked by CB 1 receptor antagonists (Varvel et al., 2005;Marshell et al., 2014). Likewise, behavioural and physiological effects of cannabis can be blocked by CB 1 receptor antagonists/inverse agonists in humans (Huestis et al., 2007). Therefore, receptor blockade could act as an antidote to limit potentially life-threatening intoxication.Although there are claims that inverse agonists of CB 1 receptors can reverse cannabimimetic effects of synthetic cannabinoids (Taffe et al., 2015), on closer analysis, it is evident that these antagonists/inverse agonists are typically applied before the cannabinoid agonist. Therefore, it is an inhibition of the development of cannabimimetic effects rather than a reversal of established cannabimimet...

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Section: Discussionmentioning

confidence: 99%

Antidote to cannabinoid intoxication: the CB₁ receptor inverse agonist, AM251, reverses hypothermic effects of the CB₁ receptor agonist, CB‐13, in mice

Pryce

Baker

2017

British J Pharmacology

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“…However, rimonabant increased the risk of psychiatric adverse events 63 . The CV outcome study CRESCENDO (Rimonabant for prevention of cardiovascular events) was stopped prematurely because of a higher risk of suicide in the rimonabant 20 mg group compared to placebo 64 , leading to the withdrawal of the drug from the market.…”

Section: Rimonabantmentioning

confidence: 99%

Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

Scheen

Gaal

2014

The Lancet Diabetes & Endocrinology

175

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New glucose-lowering therapies, especially glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors, offer advantages over traditional antidiabetic agents by promoting weight loss while improving glucose control. . The present review will explore the overlapping pathophysiology and also how the various therapies can, alone or in combination, combat the 'dual burden' of obesity and T2DM. Word count: 249

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“…15 Rimonabant for Prevention of Cardiovascular Events (CRESCENDO), a long-term cardiovascular outcomes trial, was terminated after revealing an increased rate of serious psychiatric side effects including suicide at mean follow-up of 14 months. 16 Sibutramine, a selective serotonin and norepinephrine reuptake inhibitor, combined 2 previously effective but potentially dangerous mechanisms. Approved by FDA regulators in 1997, sibutramine induced weight loss and improved lipid profile and glucose tolerance, but it also increased BP and pulse rate in clinical trials.…”

Section: The Checkered History Of Obesity Pharmacotherapymentioning

confidence: 99%

“…These trials observed annual placebo group MACE rates of 2.9% and 3.5%, respectively. 16,18 This strategy may limit the generalizability of results to the larger population of young, low-risk patients.…”

Section: Standard Of Safety: Regulatory and Clinicalmentioning

confidence: 99%

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

Cunningham

Wiviott

2014

Clinical Cardiology

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Obesity is a major correlate of cardiovascular disease. Weight loss improves cardiovascular risk factors and has the potential to improve outcomes. Two drugs, phentermine plus topiramate and lorcaserin, have recently been approved by the US Food and Drug Administration for the indication of obesity; a third, bupropion plus naltrexone, is under consideration for approval. In clinical trials, these drugs cause weight loss and improve glucose tolerance, lipid profile, and, with the exception of bupropion plus naltrexone, blood pressure. However, their effect on cardiovascular outcomes is unknown. In defining appropriate roles for these drugs in preventive cardiology, it is important to remember the checkered history of drugs for obesity. New weight-loss drugs share the serotonergic and sympathomimetic mechanisms that proved harmful in the cases of Fen-Phen and sibutramine, respectively, albeit with significant differences. Given these risks, randomized cardiovascular outcomes trials are needed to establish the safety, and potential benefit, of these drugs. This review will discuss the history of pharmacotherapy for obesity, existing efficacy and safety data for the novel weight-loss drugs, and issues in the design of postapproval clinical trials. IntroductionAdvances in prevention-smoking-cessation campaigns, statin therapy, and tight blood pressure (BP) control, among others-have contributed to decreases in the burden of coronary artery disease over the past several decades. However, the increasing prevalence of obesity and obesityassociated diseases like type 2 diabetes mellitus (T2DM) have tempered these gains. 1 Despite recent data suggesting a plateau, rates of obesity remain substantially higher than a few decades ago. 2 Intensive lifestyle interventions have produced clinically relevant weight loss, 3 but modest interventions that are feasible in the primary-care setting are less successful. 4 Many efforts to develop an effective and safe weight-loss pill have failed. In fact, the history of obesity pharmacotherapy has been notable for cardiovascular side effects, not benefits. In 2012, the US Food and Drug Administration (FDA) approved 2 medications for weight loss, the selective 5-HT 2C agonist lorcaserin and the combination pill phentermine plus topiramate; a third, bupropion plus naltrexone, is under consideration for approval at the time of this writing. 5 The mechanisms of

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Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial

Cited by 231 publications

References 13 publications

Antidote to cannabinoid intoxication: the CB₁ receptor inverse agonist, AM251, reverses hypothermic effects of the CB₁ receptor agonist, CB‐13, in mice

Antidote to cannabinoid intoxication: the CB₁ receptor inverse agonist, AM251, reverses hypothermic effects of the CB₁ receptor agonist, CB‐13, in mice

Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

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Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial

Cited by 231 publications

References 13 publications

Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB‐13, in mice

Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB‐13, in mice

Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

Contact Info

Product

Resources

About

Antidote to cannabinoid intoxication: the CB₁ receptor inverse agonist, AM251, reverses hypothermic effects of the CB₁ receptor agonist, CB‐13, in mice

Antidote to cannabinoid intoxication: the CB₁ receptor inverse agonist, AM251, reverses hypothermic effects of the CB₁ receptor agonist, CB‐13, in mice