Cannabinoid-1 receptor antagonists in type-2 diabetes

Abstract

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...

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

“…Considering the complexity and the ubiquity of the EC system [6], CB1 antagonism strategy will lead to drugs probably not with magic bullet-like specificity but more likely with multiple actions targeting different facets of the system [5]. This may be a great opportunity in the management of multifaceted diseases such as obesity and the metabolic syndrome [16] or type 2 diabetes [21,23].…”

“…Such observations extend the potential use of CB1 receptor antagonists or inverse agonists, such as rimonabant (SR-141716A) and taranabant (MK-0364), for the management of abdominal obesity associated with multiple cardiometabolic risk factors, especially type 2 diabetes [18][19][20][21][22][23].…”

“…Considering that various organs with a key-role in diabetes-related hyperglycemia contain both ECs and CB1 receptors, the role of EC system and its therapeutic modulation deserve much attention in the pathophysiology and management of type 2 diabetes, respectively [21,23]. The aims of the present review are 1) to summarize the current knowledge of the EC system, especially the recently discovered numerous peripheral effects of ECs and the consequences of the blockade of CB1 receptors on energy control and metabolism regulation; 2) to analyze the rationale for use of CB1 receptor antagonists (or inverse agonists) in the management of overweight/obese patients with type 2 diabetes and other cardiometabolic risk factors; 3) to briefly describe the results obtained in randomized controlled clinical trials with rimonabant, a selective CB1 receptor antagonist, in non diabetic overweight/obese individuals and more particularly in patients with type 2 diabetes; 4) to succinctly present the ongoing trials with rimonabant and other CB1 receptor neutral antagonists or inverse agonists; and 5) finally to describe the benefit-risk profile of rimonabant and provide advice to target the right patient in clinical practice.…”

Once-weekly administration of dulaglutide, a glucagon-like peptide-1 receptor agonist, as monotherapy and combination therapy: review of the AWARD studies

“…За прошедшее десятилетие возможности лечения СД2 расширились с внедрением новых классов лекар-ственных препаратов, к которым относятся агонисты рецепторов глюкагоноподобного пептида-1 (аГПП-1), ингибиторы дипептидилпептидазы-4 (иДПП-4), ин-гибиторы натрий-глюкозного ко-транспортера 2 типа (иНГЛТ-2) [10][11][12]. Эти новые классы лекарственных препаратов расширяют возможности достижения целе-вых значений гликемии, положительно влияя на фак-торы сердечно-сосудистого риска (например, ожирение) и характеризуясь улучшенным профилем безопасности в сравнении со многими менее современными препара-тами.…”

The future of obesity: new drugs versus lifestyle interventions

“…Instead, antiobesity agents will be required to demonstrate health benefits beyond weight loss, such as improvement in adipocyte metabolism, and thus improvement in glucose metabolism, dyslipidaemia and blood pressure [7]. To this respect, the demonstration of favourable metabolic changes beyond weight loss with the selective CB1 receptor antagonist rimonabant, resulting at least in part from a significant increase in adiponectin levels, is promising [15,16]. The development of any new effective antiobesity agent ideally must not only reduce fat mass (adiposity), but also correct fat dysfunction ("adiposopathy") in order to maximize cardiometabolic health [17].…”