Mixed Results in Clinical Trial of Weight Loss Drug Rimonabant on Slowing Progression of Coronary Disease

CHICAGO, April 1, 2008—The anti-obesity medication rimonabant showed mixed results in slowing progression of coronary artery disease in patients with abdominal obesity and pre-existing coronary disease, according to a new study in the April 2 issue of JAMA. The study is being released early online April 1 to coincide with its presentation at the annual conference of the American College of Cardiology.

“Abdominal obesity, even in the absence of type 2 diabetes, is associated with a constellation of metabolic and physiological abnormalities that amplify the risk for atheroslcerotic cardiovascular disease,” the authors write in background information for the article. Atherosclerotic disease, often commonly known as “hardening” of the arteries, occurs when deposits of plaques accumulate in the inner lining of the arteries. The researchers write that there are few treatment options to address the underlying cause of the metabolic syndrome – abdominal obesity. One promising approach is the use of the selective cannabinoid type 1 receptor antagonist rimonabant. Rimonabant has not been approved by the U.S. Food and Drug Administration, but is available in several other countries. Metabolic syndrome includes high triglyceride levels, a low HDL (good) cholesterol level, high blood pressure, and a high level of glucose (sugar) in the blood.

In this study called STRADIVARIUS, the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant – The Intravascular Ultrasound Study, ultrasonographic coronary imaging was used to assess atherosclerotic progression. Steven E. Nissen, M.D., of the Cleveland Clinic and the STRADIVARIUS investigators, conducted a randomized, double-blinded clinical trial from December 2004 to December 2005 comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe and Australia. The patients were randomly assigned to receive either rimonabant (20 mg daily) or a matching placebo for 18 to 20 months. Patients were eligible to participate in the study only if they also required a coronary angiography for a medical reason. The patients returned for scheduled clinic visits at 3, 6, 12, and 18 months following randomization. The main outcome the researchers were observing was a change in the percent atheroma volume (PAV) and the secondary outcome was a change in normalized total atheroma volume (TAV). PAV and TAV are different measurements of plaque build-up in an artery.

“In the rimonabant vs. placebo groups, PAV increased 0.25 percent vs. 0.51 percent, respectively, and TAV decreased -2.2mm3 vs. an increase of 0.88mm3,” the researchers report. “Rimonabant-treated patients had a larger reduction in body weight (-4.3kg [-9.5 lbs.] vs. -0.5 kg [-1.1 lbs.]) and greater decrease in waist circumference (-4.5 cm [-1.77 inches] vs. –1.0 cm [- 0.39 inches]). In the rimonabant vs. placebo groups, high-density lipoprotein cholesterol levels increased 5.8mg/dL (22.4 percent) vs. 1.8mg/dL (6.9 percent) and median (midpoint) triglyceride levels decreased -24.8 mg/dL (20.5 percent) vs. -8.9 mg/dL (6.2 percent).” However, LDL-C (“bad” cholesterol) levels and blood pressure changes did not differ significantly between treatment groups. “Psychiatric adverse effects were more common in the rimonabant group (43.4 percent vs. 28.4 percent),” the researchers note. Anxiety and depression were the most often reported adverse effects.

“Administration of rimonabant, 20mg, daily for 18 months did not significantly reduce the rate of progression of coronary disease for the primary IVUS (intravascular ultrasound) end point, the change in PAV,” the authors write. “However, the secondary endpoint, change in TAV, showed a statistically significant treatment effect favoring rimonabant.”

In conclusion, the authors write: “Because the current study failed to achieve a statistically significant effect for the primary efficacy measure, additional studies will be required to further define the role of rimonabant in the treatment of abdominally obese patients with coronary disease and metabolic risk factors.”
(JAMA. 2008;299[13]:1547–1560. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

EDITORIAL: THE HOPE AND FEAR OF RIMONABANT

The STRADIVARIUS trial, “reported by Nissen and colleagues in this issue of JAMA adds critical new information on the efficacy and safety of rimonabant,” writes John S. Rumsfeld, M.D., Ph.D., from the Denver Veterans Affairs Medical Center and the Department of Medicine at the University of Colorado, and Brahmajee K. Nallamothu, M.D., M.P.H., from the Ann Arbor Veterans Affairs Medical Center and the Department of Medicine, University of Michigan, in an accompanying editorial.

“This drug is clearly efficacious for weight loss, underscoring its promise as a therapeutic option for obesity. However, despite improvements in metabolic parameters, STRADIVARIUS demonstrated no efficacy of rimonabant for coronary artery disease progression while it simultaneously heightened concern about its safety profile.”

“The hopes for rimonabant ultimately may be realized if the drug is shown to have a favorable effect on mortality and cardiovascular events. In that case, clinicians will be grateful for a new weapon in the fight against the obesity epidemic but will have to remain vigilant for trade-offs in quality of life, an outcome of equal importance to survival and certainly more important than any surrogate measure.”
(JAMA. 2008;299[13]:1601–1602. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

Posted: April 2008

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