August 12th, 2010

CRESCENDO: The Fat Lady Sings for Rimonabant

The CRESCENDO (Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes) trial, which tested the effects of the endocannabinoid receptor blocker rimonabant for the prevention of cardiovascular events, was terminated early at the request of regulatory agencies in several countries following growing concern that people taking rimonabant were more likely to commit suicide. At the time of termination, 18,695 patients had been enrolled for a mean of 13.8 months. In a report in the Lancet, Eric Topol and colleagues report no significant difference between the rimonabant and placebo groups in the combined rate of cardiovascular death, MI, or stroke. There were 4 suicides in the rimonabant group and 1 in the placebo group. Gastrointestinal, neuropsychiatric, and serious psychiatric side effects occurred more frequently in the rimonabant group. In their conclusion, the investigators note that the trial has significant implications for clinical research and regulators: “The new precedent here is the capacity for such regulatory agencies to stop an ongoing clinical research project.”

In an accompanying comment, S. Matthijs Boekholdt and Ron J.G. Peters write that if the trial had been completed, “a large improvement in cardiovascular outcome could have outweighed a small risk of serious adverse events, in a similar way to, for example, the large cardiovascular benefits of statins outweighing a small risk of rhabdomyolysis. However, any mortality associated with cardiovascular preventive therapy is generally viewed as unacceptable.”

One Response to “CRESCENDO: The Fat Lady Sings for Rimonabant”

  1. This adds another drug to the long list of similar failed attempts to find a pharmaceutical therapy for obesity. It’s clearly a high-risk high-reward area, but the difficulty seems to be in trying to find a therapy that has the right neuromodulating effects (e.g. appetite suppression) without having off-target activity (e.g. psychiatric effects). As pointed out, risk of suicide is obviously way beyond even risk of rhabdo. Perhaps more basic advances need to be made in neuropsychiatry before this area can be safely pursued in the effort to reduce CV endpoints…