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Weight-Loss Drug Rimonabant Increases Risk for Adverse Psychiatric Effects

A meta-analysis of 4 randomized controlled trials of the weight-loss drug rimonabant concurs with Food and Drug Administration (FDA) findings of an increased risk for serious adverse psychiatric effects — depressed mood disorders and anxiety — although depressed mood was an exclusion criteria.

The findings, are based on data from the 4 clinical trials in the Rimonabant in Obesity (RIO) program.

Rimonabant (Acomplia; Sanofi Aventis) was approved by the European Agency for the Evaluation of Medicinal Products in June 2006 and is available in Argentina, Austria, Denmark, Finland, Germany, Ireland, Norway, Sweden, Greece, and the United Kingdom. In June 2007, coinciding with the submission of this Lancet article, the Advisory Committee of the US FDA unanimously concluded that more detailed safety information about rimonabant was needed before the drug could be approved for use in the United States, and subsequent to that decision, Sanofi Aventis withdrew its new drug application in the United States.

Study author Arne Astrup, MD, said, "There’s no doubt that this is a serious matter because one should remember that the treatment must never be more harmful than the disease."

Rimonabant, a selective antagonist for the cannabinoid type 1 (CB1) receptor, is the first drug being marketed in this class of drugs that are involved in inhibiting the effect of food, cannabis, and tobacco on the central nervous system rewarding system.
The 4 RIO trails showed that rimonabant results in a weight loss that is 4 to 6 kg (8.8 – 13.2 pounds) greater than that with placebo, in 6 to 12 months, which is about the same as for the 2 other weight-loss drugs on the market, orlistat (Xenical; Roche) and sibutramine (Meridia; Abbott), the study authors write. Although rimonabant was generally well tolerated, individual trials showed trends to increases in depressed mood disorders, depression, and severe adverse effects.

The group aimed to perform a meta-analysis to obtain more robust data to determine the drug’s efficacy and safety, especially adverse psychiatric events. Only double-blind, randomized controlled trials using rimonabant for weight loss in patients with a body mass index (BMI) of 30 kg/m2 or greater or 27 kg/m2 or greater with 1 or more obesity-related comorbidities were eligible.

The 4 large, multicenter, double-blind RIO trials met the study requirements. These trials included 4105 participants who received 20 mg/day of rimonabant or placebo.

Compared with patients in the placebo group, patients taking rimonabant had a 4.7-kg greater weight reduction at 1 year, and they were 5 times more likely to achieve at least 10% weight loss.

Compared with patients receiving placebo, those in the rimonabant study groups had a higher risk of developing a serious adverse event (5.9% vs 4.2%) and a greater risk of discontinuing the study because of developing a depressive mood disorder (3% vs 1.4%) or anxiety (1% vs 0.3%).

In countries where rimonabant is being prescribed, clinicians need to be really aware that patients have an increased risk of developing depression or anxiety, said Dr. Astrup. It is also important to note that the clinical trials excluded patients who had existing or past depression or were taking therapies for depression. "We think the risk will be higher in clinical practice," he cautioned. Another reason these findings are important is that 4 or 5 major pharmaceutical companies are developing similar CB1 compounds that they are moving from phase 2 to phase 3, he added. "It is quite important for them to be aware of this problem with depression and anxiety so they will have a chance to do a better job of monitoring all these psychiatric symptoms. . . so we will have a much better idea of the severity of the problem."

The findings are significant because they "raise major questions about the safety of rimonabant in obese people, who are already at increased risk of depression, and suggests that phase III studies of CB1 antagonists should monitor psychiatric complications very carefully," they write, echoing the words of the study authors. In addition, they note that the link between depression and this CB1 blocker raises theoretical questions about a potential central role for the endocannabinoid system in normal and clinical mood states.

Practice Pearls

  • The use of rimonabant 20 mg daily for obese and overweight patients vs placebo for 1 year is associated with a greater weight loss of 4.7 kg and a 5 times higher likelihood of achieving at least 10% weight loss.
  • Rimonabant 20 mg daily for 1 year is associated with a 2.5 times higher rate of discontinuation because of depressive mood disorders and a higher rate of anxiety.

Published in a November 17 article in The Lancet by Robin Christensen, MSc, and colleagues at the University of Copenhagen in Denmark. Lancet. 2007;370:1671-1672, 1706-1713.

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FACT:
Post-challenge glucose and coronary atherosclerotic progression:
The next paper showed that post-challenge glucose is a strong independent predictor of coronary atherosclerotic progression in non-diabetic, post-menopausal women with coronary heart disease. According to the authors, these findings suggest that even modest post-challenge hyperglycaemia influences progression of coronary atheroscleroses. Further studies are needed to show whether interventions targeting post-prandial hyperglycaemia in subjects without diabetes can prevent further progression of their disease, an effect that has been previously documented in patients with impaired glucose tolerance. 
Diabetic Medicine,24 (1156-1159): Mellen P, Bittner V, Herrington D Post-challenge glucose predicts coronary atherosclerotic progression in non-diabetic, post-menopausal women