Obesity
Geoffrey P. Webb in Nutrition, 2019
Rimonabant is a new type of anti-obesity agent that was licensed for a short period for use in the UK. This compound blocks the endocannabinoid receptors in the brain where active ingredients of cannabis (cannabinoids) bind and where endogenously produced cannabinoids also bind. Endogenous cannabinoids and those taken in the form of cannabis are known to increase appetite – the increased appetite associated with cannabis use is sometimes referred to as “the munchies”. This drug was licensed in 2006 in the UK after successful clinical trials in the USA and in Europe and was for a time licensed for use in over 50 countries. A Cochrane review by Curioni and Andre (2006) included a meta-analysis of four controlled trials of rimonabant for weight loss. A daily dose of 20 mg of rimonabant for a year resulted in around 5 kg more weight loss than a placebo and improved several cardiovascular risk factors. A 5 mg dose had much less effect upon weight loss and cardiovascular risk factors. At the higher dose, there were significant numbers of adverse effects reported which were mainly psychiatric and gastrointestinal problems. Rimonabant was withdrawn from sale in 2008 and its approval withdrawn because its beneficial effects did not outweigh its adverse effects, particularly its adverse psychiatric effects.
Future Directions in Obesity and Weight Management
James M. Rippe in Lifestyle Medicine, 2019
Following those failures, two developments marked a significant shift in the environment for obesity drug development. First, the FDA responded to th e safety issues raised by dexfenfluramine’s withdrawal by raising the safety threshold for approving new drugs targeted for use in weight loss. Sanofi had completed its full clinical drug development program for rimonabant and obtained approval to market in Europe. But the FDA balked at approving it for the U.S. because of concerns about depression and suicide. Then the agency turned down the next three drugs it reviewed for obesity—phentermine/topiramate, bupropion/naltrexone, and lorcaserin.43
Medical Management of Uncomplicated Obesity
Susan L. McElroy, David B. Allison, George A. Bray in Obesity and Mental Disorders, 2006
Rimonabant is a cannabinoid receptor antagonist which has shown promise in phase 2 trials and is now in phase 3 trials. No trial data has thus far been published on the use of rimonabant. However, unpublished data from the Rimonabant in Obesity (RIO) Lipids trial was presented in 2004 (43). This one-year placebo-controlled trial of 1036 subjects with dyslipidemia and a BMI of 27 to 40 showed that 20 mg of rimonobant produced greater weight loss than placebo. Perhaps more importantly, subjects who received rimonobant also showed significant improvements in high-density lipoprotein, triglycerides, and C-reactive protein.
The function of the endocannabinoid system in the pancreatic islet and its implications on metabolic syndrome and diabetes
Published in Islets, 2023
Edgardo Cortes-Justo, Sergio H Garfias-Ramírez, Alonso Vilches-Flores
However, rimonabant was discontinued after undesired side effects reported, including dizziness, psychiatric disorders, symptoms of depression, anxiety, and the development of suicidal intention.66,67 In the last decades two different CB1 receptor antagonists have been synthetized, BAR-1 and Ibipinabant.42,68–70 In isolated pancreatic islets from rats, BAR-1 increased insulin, glucokinase, PDX-1 and CB1r gene expression, and basal insulin secretion was modified, in opposition to AEA effect.42 BAR-1 treatment of prediabetic and diabetic mice reduced oral glucose tolerance without effect on HbA1c and triglycerides; glucose-stimulated insulin secretion was enhanced, but gene expression for insulin, glucagon, PDX-1 and some elements of ECS showed significant decrease.68 Streptozocin-induced diabetic mice presented a discrete increase in islets mass and insulin-positive cells after BAR-1 exposure, suggesting a protective effect against apoptosis.68 Ibipinabant is another rimonabant analog tested in animal models that improved glucose tolerance, insulin sensitivity, weight loss, triglycerides in blood, and induced a significant reduction in beta-cell lost.69,70
Novel therapeutic and drug development strategies for tobacco use disorder: endocannabinoid modulation
Published in Expert Opinion on Drug Discovery, 2020
Kevin Butler, Bernard Le Foll
Arguably one of the most promising candidates for smoking cessation in recent years was rimonabant, an anti-obesity drug and inverse agonist at the cannabinoid (CB) receptor 1. Indeed, abstinence at the end of 10 weeks of treatment with rimonabant (20 mg/day) and at 48 weeks follow-up was higher than placebo in a pooled analysis of three randomized double-blind controlled trials [17]. However, the high rate of psychiatric side effects, notably the induction of anxiety and depression and risk of emergence of suicidal ideation [18], led to the voluntary withdrawal of rimonabant from the European market in 2008 [19]. Nevertheless, there is an increasing understanding of the role of the endocannabinoid system in reward processing and addiction [20,21] suggesting that there may still be potential tobacco smoking cessation candidates found that work via endocannabinoid modulation.
The limits and challenges of antiobesity pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2020
Kishore M Gadde, Katelyn D Atkins
In 2007, the FDA issued an updated guidance which also recommended that new antiobesity drugs be tested in a dedicated phase 3 trial of overweight/obese patients with T2D [15]. Between 1997 and 1999, sibutramine and orlistat were approved for long-term obesity treatment. In 2006, rimonabant, a cannabinoid receptor-1 (CB-1) antagonist, failed to win FDA advisory committee recommendation due to high incidence of psychiatric adverse events [16], although it was already approved by the European Medicines Agency (EMA). In 2008, rimonabant was withdrawn from Europe and other markets as more reports confirmed the increased risk of depression and suicidal ideation with the drug [17]. Sibutramine was withdrawn in the US and several countries in 2010 following review of the results of a cardiovascular outcomes trial (CVOT) among patients with preexisting CVD or those at high risk. The results of this trial revealed a slightly increased risk of major adverse cardiovascular events (MACE) in the drug group compared with the placebo group (11.4% vs 10.0%; hazard ratio, 1.16; 95% CI, 10.3–1.31; P = 0.02), corresponding to approximately 4 excess events per 1,000 patient years [18]. Nevertheless, sibutramine remains legally marketed in a few countries, e.g., Russia [19]. In 2010, three new antiobesity drugs – phentermine plus topiramate, lorcaserin, and naltrexone plus bupropion – failed to win FDA approval, but were subsequently approved between 2012 and 2014 along with liraglutide 3.0 mg (higher than the 1.8 mg dose approved for T2D).
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