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A Weight-Loss Drug for Atherosclerosis?

Rimonabant reduced some cardiovascular risk factors — but not disease progression — among obese patients in a prospective, placebo-controlled trial.

Obesity is associated with a constellation of risk factors for atherosclerosis. But can treatment for obesity slow the progression of cardiovascular disease? To test whether the weight-loss and metabolic benefits of rimonabant, an inhibitor of the cannabinoid type 1 (CB₁) receptor, would be effective against atherosclerosis, investigators conducted the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant — The Intravascular Ultrasound Study (STRADIVARIUS), an industry-funded, prospective study of 839 adults with abdominal obesity and coronary artery disease enrolled at 112 centers in North America, Europe, and Australia between 2004 and 2005.

Patients (65% men; mean age, 58; mean waist circumference, 46 inches) were randomized to either 20 mg of rimonabant daily or placebo for 18 to 20 months. Intravascular ultrasound was used to measure artery narrowing at baseline and a minimum of 320 days after randomization. No major differences in baseline characteristics were observed between patients in the two treatment groups or between the 676 patients who completed both ultrasound exams and the 163 patients who completed only the baseline exam.

Rimonabant did not significantly alter coronary disease progression according to the primary efficacy parameter, change in percent atheroma volume, which increased 0.25% in the rimonabant group versus 0.51% in the placebo group (P=0.22). However, the drug had a favorable effect on the secondary efficacy parameter, total atheroma volume, which was reduced 2.2 mm³ in the rimonabant group and was increased 0.88 mm³ in the placebo group (P=0.03). Patients assigned to rimonabant lost more weight and had greater reduction in waist circumference than those assigned to placebo. The rimonabant group also had improved hemoglobin A_1c, HDL, C-reactive protein, and triglyceride levels. No significant between-group differences were seen in LDL and blood-pressure changes or in the composite endpoint of cardiovascular death, MI, stroke, hospitalization, revascularization, and transient ischemia. Adverse effects included psychiatric disorders, which occurred in 43.3% of rimonabant patients versus 28.4% of placebo patients (P<0.001).

Comment: Rimonabant’s effect on percent atheroma volume did not differ significantly from that of placebo. Treatment with the CB₁ antagonist reduced body weight and waist circumference and improved lipid profiles, as in prior research (Journal Watch General Medicine Dec 19 2006), but was associated with adverse effects, notably a worrisome increase in psychiatric problems. Until further large-scale, long-term studies of clinical outcomes of rimonabant treatment are undertaken, the drug is unlikely to have any role in secondary prevention of cardiovascular events.

— Joel M. Gore, MD

Published in Journal Watch Cardiology April 1, 2008

Citation(s):

Nissen SE et al. for the STRADIVARIUS Investigators. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: The STRADIVARIUS randomized controlled trial. JAMA 2008 Apr 2; 299:1547. (http://dx.doi.org/10.1001/jama.299.13.1547)

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