ADAGIO-Lipids gives promises but faces the setbacks.

The rapidly increasing global wave of obesity associated with cardiometabolic risk factors portends a daunting increase of cardiovascular disease. Consequently, the search for effective and safe drugs and new therapeutic avenues to fight obesity stands at the frontline because of a market with enormous opportunities. Rimonabant is a selective CB1 endocannabinoid receptor antagonist that was the first one authorized June 2006 by EMEA and marketed in 18 EU countries. The efficacy and safety of rimonabant had been evaluated in the extensive RIO program including more than 6000 overweight or obese subjects who received double-blind treatment with rimonabant 5 or 20 mg/d or placebo together with diet or lifestyle modification for 1 or 2 years.1–4 The results demonstrated the consistent and clear effects of rimonabant 20 mg/d not only on weight loss and reduced waist circumference but also on several markers of cardiometabolic risk especially on serum triglyceride and HDL cholesterol levels. Recently the efficacy of rimonabant was confirmed in the 2-year study of the RIO-Europe.5 The simultaneous improvement of several cardiometabolic risk factors by rimonabant raised enthusiasm and created expectations that have not been materialized. The promises were soon dimmed by concerns about its psychiatric side effects including depression, sleep disturbances, anxiety, and aggression. The FDA Advisory panel rejected the approval of rimonabant as a drug to treat obesity 2007. Growing concerns led EMEA to restrict the drug July 2007 in patients with depression or taking antidepressants. The final blow came October 2008 when EMEA concluded that the benefits of rimonabant did not outweight its risk and recommended the suspension of the drugs‘s marketing authorization across the EU (http://www.emea.europe.eu EMEA/537/53/2008). In the light of this development, from a promising success to the unexpected disaster, one asks what was going wrong.