Topol EJ, Bousser MG, Fox KA, Creager MA, Despres JP, Easton JD et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 376: 517-523
Blockade of the endocannabinoid receptor reduces obesity and improves metabolic abnormalities such as triglycerides, HDL cholesterol, and fasting blood glucose. We assessed whether rimonabant would improve major vascular event-free survival.
This double-blind, placebo-controlled trial was undertaken in 974 hospitals in 42 countries. 18,695 patients with previously manifest or increased risk of vascular disease were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). Randomisation was stratified by centre, implemented with an independent interactive voice response system, and all study personnel and participants were masked to group assignment. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke, as determined via central adjudication. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00263042.
At a mean follow-up of 13.8 months (95% CI 13.6-14.0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3.9%) patients assigned to rimonabant and 375 (4.0%) assigned to placebo (hazard ratio 0.97, 95% CI 0.84-1.12, p=0.68). With rimonabant, gastrointestinal (3038 [33%] vs 2084 [22%]), neuropsychiatric (3028 [32%] vs 1989 [21%]), and serious psychiatric side-effects (232 [2.5%] vs 120 [1.3%]) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide.
The premature termination of this trial has important lessons for drug development. A drug that was being marketed for weight loss, but being tested for improving cardiovascular outcomes, induced a level of serious neuropsychiatric effects that was deemed unacceptable by regulatory authorities, and both the drug and the trial were abruptly terminated.
"In fact, a meta-analysis of the four major clinical studies performed with rimonabant found that there was approximately a threefold increase in the emergence of anxiety symptoms in patients receiving rimonabant versus a placebo, and these studies were all performed on individuals who had no history of psychiatric illness
. The largest multi-center trial for rimonabant (involving over 18,000 patients in 42 countries) similarly found that there was a significant increase in neuropsychiatric side effects (in approximately one-third of patients treated with rimonabant) and serious psychiatric side effects (which developed in roughly 1 in 40 individuals treated with rimonabant) following CB1 receptor antagonism
. One case report even discusses the de novo emergence of a profound bout of melancholic depression, which occurred following administration of rimonabant, and subsided following cessation of drug administration
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence over the past decade has highlighted an important role of the endocannabinoid (eCB) system in the regulation of stress and emotional behavior across divergent species, from rodents to humans. The general findings from this work indicate that the eCB system plays an important role in gating and buffering the stress response, dampening anxiety and regulating mood. Work in rodents has allowed researchers to determine the neural mechanisms mediating this relationship while work in human populations has demonstrated the possible importance of this system in stress-related psychiatric diseases, such as post-traumatic stress disorder, generalized anxiety and major depression. These stress-protective effects of eCB signaling appear to be primarily mediated by their actions within corticolimbic structures, particularly the amygdala and the prefrontal cortex. The aim of this review is to provide an up-to-date discussion of the current level of knowledge in this field, as well as address the current gaps in knowledge and specific areas of research that require attention.
Biology of Mood and Anxiety Disorders 10/2013; 3(1):19. DOI:10.1186/2045-5380-3-19
"c o m / l o c a t e / i j c a r d doxorubicin-induced myocardial dysfunction   , this may not be the case for conventional CHF induced by myocardial ischemia or pressure overload. In fact, a recent large-scale clinical trial (RESCENDO) showed that rimonabant did not improve major cardiovascular eventfree survival in obese patients with a previous history or increased risk of vascular disease at a mean follow-up of 14 months . Moreover, there is new evidence that slight downregulation of CB1 expression in the myocardium of CHF patients may reflect maladaptive changes . "
[Show abstract][Hide abstract] ABSTRACT: Background:
The endocannabinoid system is known to play a role in regulating myocardial contractility, but the influence of cannabinoid receptor 1 (CB1) deficiency on chronic heart failure (CHF) remains unclear. In this study we attempted to investigate the effect of CB1 deficiency on CHF induced by pressure overload and the possible mechanisms involved.
Methods and results:
A CHF model was created by transverse aortic constriction (TAC) in both CB1 knockout mice and wild-type mice. CB1 knockout mice showed a marked increase of mortality due to CHF from 4 to 8 weeks after TAC (p=0.021). Five weeks after TAC, in contrast to wild-type mice, CB1 knockout mice had a higher left ventricular (LV) end-diastolic pressure, lower rate of LV pressure change (± dp/dt max), lower LV contractility index, and a larger heart weight to body weight ratio and lung weight to body weight ratio compared with wild-type mice (all p<0.05-0.001). Phosphorylation of the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (P38 and ERK) was higher in CB1 knockout mice than that in wild-type mice. In cultured neonatal rat cardiomyocytes, a CB1 agonist reduced cAMP production stimulated by isoproterenol or forskolin, and suppressed phosphorylation of the EGFR, P38, and ERK, while the inhibitory effect of a CB1 agonist on EGFR phosphorylation was abrogated by CB1 knockdown.
These findings indicate that cannabinoid receptor 1 inactivation promotes cardiac remodeling by enhancing the activity of the epidermal growth factor receptor and mitogen-activated protein kinases.
International journal of cardiology 05/2012; 167(5):1936-44. DOI:10.1016/j.ijcard.2012.05.033 · 4.04 Impact Factor
"Drug development in the diabetes and metabolic field has been a ground-breaking and most active area during the last couple of years, but we must not forget that the metabolic and diabetologic drug development community has had to cope with several especially severe backslashes. For the indication of anti-obesity treatments, the selective CB 1 receptor antagonist rimonabant, initially celebrated as groundbreaking innovation, and the monoamine reuptake inhibitor sibutramine have had their market authorization suspended due to increased incidence of serious adverse events [Topol et al. 2010; Sayburn, 2010]. Approval applications for the combination phentermine/ topiramat, the selective 5-HT 2c receptor ligand lorcaserine and the combination bupropion/ naltrexone have been recently rejected by the US Food and Drug Administration (FDA) due to safety concerns. "
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