Play an ADAGIO with a STRADIVARIUS: the right patient for CB1 receptor antagonists?

Description

It is increasingly recognized that an elevated amount of intra-abdominal (visceral) fat is associated with a diabetogenic and atherogenic metabolic profile that includes atherogenic dyslipidemia, altered glucose-insulin homeostasis, a pro-inflammatory and a pro-thrombotic state, and elevated blood pressure. Although often observed in obese individuals, this high-risk obesity phenotype is also frequently seen in overweight individuals. A growing body of evidence suggests that dysregulation of the endocannabinoid system plays an important role in the development of intra-abdominal obesity and its metabolic disturbances. This Viewpoint by Di Marzo discusses results of the two most recent clinical trials with the first CB1 receptor antagonist, rimonabant, and the effect of this drug on atherosclerosis and intra-abdominal fat accumulation (STRADIVARIUS and ADAGIO-Lipids). In the STRADIVARIUS trial, rimonabant 20 mg/day did not change percent atheroma volume (primary endpoint) to a greater extent than placebo-treated patients. However, rimonabant had a significant impact on total atheroma volume, which was greater than the effect observed with placebo. Moreover, since this study did not exclude patients with a previous history of psychiatric disorders, the adverse psychiatric effects that led to discontinuation of therapy were more frequent in rimonabant- than placebo-treated patients. On the other hand, the ADAGIO-Lipids study reported for the first time that rimonabant 20 mg/day generated a selective loss of intra-abdominal fat and a reduction in liver fat content. Moreover, given the association between extreme obesity and the risk of depression, Di Marzo believes that this new class of drugs might be safer and efficient in patients with a body mass index between 27-33 kg/m2 and who are simultaneously characterized by atherogenic dyslipidemia, a pre-diabetic state, and a large waist circumference. Additional studies are ongoing to further determine which patients would optimally benefit from this new class of drugs.