According to a recent study published in JAMA, a clinical trial testing how well the anti-obesity medication rimonabant slowed the development of coronary artery disease in patients with abdominal obesity and pre-existing coronary disease resulted in mixed conclusions. Called STRADIVARIUS (the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant – The Intravascular Ultrasound Study), the trial was conducted by Steven E. Nissen, M.D. (Cleveland Clinic) and several STRADIVARIUS investigators.
Nissen and colleagues write that, “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 atherosclerotic cardiovascular disease.” Some examples of metabolic syndrome are high triglyceride levels, low HDL (good) cholesterol levels, high blood pressure, and high blood glucose (blood sugar) levels.
Atherosclerotic disease is more commonly known as “hardening” of the arteries, and it occurs when the inner walls of the arteries accumulate plaque deposits. Abdominal obesity is a fundamental cause of atherosclerotic disease, but currently there are few treatment options available for the condition. The drug rimonabant, a selective cannabinoid type 1 receptor antagonist, is one possible treatment option. Lacking the approval of the U.S. Food and Drug Administration, the drug is only available in other countries.
To compare rimonabant against placebo, the researchers designed a randomized, double-blinded clinical trial that included 839 patients at 112 centers in North America, Europe, and Australia selected from December 2004 to December 2005. For 18 to 20 months after random assignment, participants received either 20 mg daily of rimonabant or a matching placebo. Part of the selection process maintained that patients were eligible only if they needed coronary angiography for medical reasons. After randomization, participants scheduled clinic visits at 3, 6, 12, and 18 months. The STRADIVARIUS researchers were chiefly concerned with the change in the percent atheroma volume (PAV) and secondarily concerned with the change in normalized total atheroma volume (TAV). Both PAV and TAV indicate how much plaque has built-up on the inner lining of an artery. These markers of atherosclerotic progression were measured by ultrasonographic coronary imaging.
“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,” write the researchers. “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).”
The investigators also found, however, that changes in the level of “bad” cholesterol (LDL-C) and changes in blood pressure were not significantly different between groups. “Psychiatric adverse effects were more common in the rimonabant group (43.4 percent vs. 28.4 percent),” with anxiety and depression being the most commonly reported adverse side effects.
In the authors’ words: “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.” Although, “The secondary endpoint, change in TAV, showed a statistically significant treatment effect favoring rimonabant.”
“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,” the authors conclude.
An accompanying editorial by John S. Rumsfeld, M.D., Ph.D. (Denver Veterans Affairs Medical Center and the Department of Medicine at the University of Colorado) and Brahmajee K. Nallamothu, M.D., M.P.H. (Ann Arbor Veterans Affairs Medical Center and the Department of Medicine, University of Michigan) notes that the STRADIVARIUS trial is critical to understanding the effectiveness and safety of rimonabant.
“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,” write Rumsfeld and Nallamothu.
They conclude: “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.”
Effect of Rimonabant on Progression of Atherosclerosis in Patients With Abdominal Obesity and Coronary Artery Disease: The STRADIVARIUS Randomized Controlled Trial
Steven E. Nissen; Stephen J. Nicholls; Kathy Wolski; Josep Rodés-Cabau; Christopher P. Cannon; John E. Deanfield; Jean-Pierre Després; John J. P. Kastelein; Steven R. Steinhubl; Samir Kapadia; Muhammad Yasin; Witold Ruzyllo; Christophe Gaudin; Bernard Job; Bo Hu; Deepak L. Bhatt; A. Michael Lincoff; E. Murat Tuzcu;
JAMA (2008). 299[13]:1547-1560.
Written by: Peter M Crosta