From a patient's perspective, the principal questions about medical therapeutics are "Will I live longer or feel better?" and "What are the risks?" Until answers about the benefits of treatment on meaningful patient outcomes as well as about the attendant treatment risks are available, therapies have no role in the clinical armamentarium. Yet the answers to these deceptively simple questions often remain uncertain, even for some therapies commonly used in medical practice. The 2 faces of uncertainty for new therapeutics are hope and fear. The hope is that a treatment will provide meaningful benefits on patient outcomes. The fear is that, pending robust outcome studies, the only documented "benefits" of treatment may be for surrogate measures that may not translate into better outcomes or that any benefit will come at the expense of unacceptable risks.

Against this background is the obesity epidemic, in which approximately two-thirds of adults in the United States are overweight or obese based on body mass index.1 Obesity places these individuals at an increased risk of mortality and morbidity, not only from the obese condition (eg, reduced functional status) but also from a host of associated problems such as diabetes mellitus, hypertension, dyslipidemia, and coronary artery disease.2-3 The increasing burden of obesity in the United States and other countries has fueled the search for effective new therapies that could potentially be used by millions of individuals to improve the public's health.

One promising therapy for obesity is rimonabant, currently approved for use in Europe but not in the United States. Rimonabant is a selective antagonist of the cannabinoid type 1 (CB1) receptor, part of the endocannabinoid system that plays a significant role in regulating the drive for food ingestion.4 Previous studies have shown that rimonabant is effective for weight loss and improves metabolic parameters.5-7 However, it is equally clear that targeting the endocannabinoid system can yield neuropsychiatric adverse effects, including nausea, depression, and anxiety. Indeed, rimonabant may be considered an "antimarijuana"-like agent, because its effects are the opposite of the appetite-stimulating, antinausea, and euphoric effects of delta-9-tetrahydrocannabinol, the major active component of marijuana and a partial agonist of the CB1 receptor.

The Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—The Intravascular Ultrasound Study (STRADIVARIUS) trial, reported by Nissen and colleagues8 in this issue of JAMA, adds critical new information on the efficacy and safety of rimonabant. In this multicenter randomized clinical trial, the effect of rimonabant on progression of coronary atherosclerosis was evaluated over 18 months in 839 patients with coronary artery disease and abdominal obesity using intravascular ultrasound (IVUS). This technique measures the atherosclerotic plaque burden in coronary arteries and has been advocated as a tool for evaluating new antiatherosclerotic therapies.9 Consistent with prior studies, patients randomly assigned to receive rimonabant in STRADIVARIUS had greater weight loss as well as improvements in lipid profile and in levels of high-sensitivity C-reactive protein and glycated hemoglobin compared with patients receiving placebo. Disappointingly, however, no significant differences were noted between the 2 groups in the primary efficacy end point, change in percent atheroma volume by IVUS.

Despite the negative primary efficacy end point, additional aspects of STRADIVARIUS deserve attention. First, the investigators noted mixed results when examining other IVUS measures of atherosclerotic plaque burden, including changes in normalized total atheroma volume, an a priori secondary end point. This led the authors to conclude that rimonabant "continues to hold promise" with regard to the treatment of coronary atherosclerosis. While this promise remains, it certainly has faded. These results also reinforce caution about use of IVUS findings as surrogate markers of patient outcomes. Findings from IVUS have yet to be definitively linked to lower rates of death or myocardial infarction. In fact, the pattern of IVUS findings in STRADIVARIUS—no significant difference in percent atheroma volume but modest improvements in normalized total atheroma volume—closely mirror those reported for torcetrapib, a cholesteryl ester transfer protein inhibitor recently found to be associated with worse patient outcomes.10

Another major finding of STRADIVARIUS was the alarmingly high rate of psychiatric adverse effects, primarily depression and anxiety, among patients randomized to receive rimonabant as compared with those receiving placebo (43.4% vs 28.4%, respectively). While previous studies noted similar adverse effects with rimonabant treatment,11 the absolute rates were far greater in STRADIVARIUS, in which more than 1 in 7 patients developed psychiatric adverse effects attributable to the drug. A likely explanation is that STRADIVARIUS did not exclude patients with prior psychiatric disorders. This resulted in a less selected study population that may have more closely reflected the risks of depression and anxiety with rimonabant treatment in routine clinical practice. This is a particular strength of the study, and the STRADIVARIUS investigators should also be commended for amending their study protocol to better quantify neuropsychiatric effects.

Putting aside, for the moment, fears about the most serious psychiatric adverse events such as suicide, these results should give clinicians pause. Depression and anxiety exact a terrible toll at the individual level in terms of quality of life. Moreover, depression is associated with reduced adherence to lifestyle recommendations and medication regimens, and depressive symptoms are predictive of adverse outcomes and higher costs of care among patients with coronary artery disease.12 Given the known correlation between obesity and psychiatric comorbidity—as evidenced by the high prevalence of anxiety and depression in the placebo group of STRADIVARIUS—the potential for a medication that targets weight loss to cause depression is a major concern.

The investigators point out that the higher rates of depression and anxiety among patients receiving rimonabant therapy in STRADIVARIUS did not translate into significant differences in severe psychiatric adverse effects such as suicide, but this interpretation warrants caution. The study was not powered for evaluating these outcomes, any more than it was powered for evaluating cardiovascular death or myocardial infarction, and is thus inconclusive in this regard. Of concern, an analysis by the US Food and Drug Administration (FDA) of all randomized clinical trials evaluating rimonabant, including trials focused on smoking cessation, suggested that a 20-mg dose (as used in STRADIVARIUS) was associated with a 2-fold higher suicide risk (odds ratio, 2.0; 95% confidence interval, 1.2-3.4).13 The psychiatric adverse effect profile was the primary concern of the FDA's Endocrine and Metabolic Drugs Advisory Committee in unanimously recommending against rimonabant approval in 2007.14

What, then, is the current state of evidence for rimonabant therapy? 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. It is particularly worrisome to see a "safety signal" in a trial like STRADIVARIUS, given that safety concerns are often only recognized in larger trials or when therapies are used in clinical practice.

Therefore, pending data from ongoing outcomes trials like CRESCENDO (NCT00263042), the potential benefits of rimonabant therapy are offset by very real risks of depression and anxiety. 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.

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