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Effects of Rimonabant on Metabolic Risk Factors in Overweight Patients with Dyslipidemia
Després J-P, Golay A, Sjöstöm for the Rimonabant in Obesity–Lipids Study Group. N Engl J Med. 2005;353:2121-2134.
Lifestyle modification, focused on improving nutrition and increasing physical activity, is central to therapeutic approaches that combat obesity. However, pharmacotherapy that targets metabolic and cardiovascular risk factors may also be appropriate. The recently discovered endocannabinoid (EC) system, comprised of endogenous cannabinoids (endocannabinoids) and the CB1 receptor, has been implicated in appetite control and energy utilization, making its components potential pharmacotherapeutics target in the battle against obesity. Rimonabant is a selective CB1-receptor blocker in clinical development. The Rimonabant in Obesity–Europe (RIO-Europe) trial demonstrated the efficacy of rimonabant in promoting weight loss and improving diabetes and cardiovascular disease risk factors among obese patients. The RIO-Lipids study, described in this literature summary, examined the potential benefits of rimonabant in a population of patients at higher risk for cardiovascular disease–obese patients with dyslipidemia. In addition to weight loss and traditional cardiovascular risk factors, metabolic risk markers for cardiovascular disease, such as plasma levels of C-reactive protein and adiponectin, were also evaluated.
The RIO-Lipids study was a 12-month, randomized, double-blind, placebo-controlled trial designed to assess the effect of rimonabant (5 mg or 20 mg), in combination with a hypocaloric diet, on body weight in overweight or obese patients (body-mass index [BMI] 27-40), 18-70 years of age, with untreated dyslipidemia and no diabetes. Exclusion criteria included, but were not limited to, disease in any of a number of major organ systems; systolic or diastolic blood pressure higher than 165 or 105 mm Hg, respectively; severe depression; and less than 80% compliance with a hypocaloric diet and placebo during the 4-week, postscreening, run-in period. A total of 1036 patients were enrolled and assigned to treatment groups as follows: placebo (n = 342), 5 mg rimonabant (n = 345), 20 mg rimonabant (n = 346). Outcomes were measured in terms of change from baseline. The primary study outcome was weight loss, with secondary measures for high-density lipoprotein (HDL) cholesterol, triglycerides, plasma glucose and insulin, and prevalence of metabolic syndrome. Metabolic syndrome was diagnosed according to criteria in the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATPIII). Additional efficacy markers included waist circumference and leptin, adiponectin, and C-reactive protein levels. Data were analyzed using both repeated-measures (RM) and last-observation-carried-forward (LOCF) methods.
Study results indicated similar baseline characteristics among the 3 treatment groups. In each of the groups, the dropout rate was approximately 40%, with a higher rate due to adverse events in the 20 mg rimonabant group. The most common adverse events leading to study discontinuation in the rimonabant groups included depression, anxiety, and nausea. Decreases in weight and waist circumference were significant at both rimonabant doses (P<.001 for weight loss at 5 and 20 mg; P<.03 and P<.001 for decreased waist circumference for 5 and 20 mg, respectively). Also at both doses, HDL increased (P<.03 and P<.001 for 5 and 20 mg, respectively) and leptin levels decreased (P<.002 and P<.001 for 5 and 20 mg, respectively) significantly. Adiponectin levels increased at both doses, with a clearly significant effect at 20 mg (P<.001). The effect at the 5 mg dose was significant based on RM, but not LOCF, analysis (P = .049 for RM analysis). For other outcomes, only the effect at 20 mg rimonabant reached statistical significance. These outcomes included: decreased triglycerides (P<.001), decreased fasting insulin (P = .011 to .016), decreased C-reactive protein (P = .02), and decreased blood pressure (P<.05 and P<.02 for systolic and diastolic, respectively). Plasma insulin and glucose levels assessed during oral glucose tolerance tests also decreased significantly in the 20 mg rimonabant group. In addition to the findings above, the number of patients meeting criteria for metabolic syndrome decreased from 52.9% to 25.8% and 51.9% to 41% in the 20 mg rimonabant and placebo groups, respectively. The change in the 20 mg rimonabant group was significantly greater than in the placebo group (P<.001).
Based on the results of the RIO–Lipids study, rimonabant improved cardiovascular risk profiles, including dyslipidemia, in overweight, dyslipidemic patients. Additional benefits included improvement of markers for insulin resistance and abdominal obesity. Effects were generally more pronounced at the 20 mg dose of rimonabant than at the 5 mg dose. The increased adiponectin levels were attributed, in part, to weight loss-independent activity of rimonabant. This finding is consistent with rimonabant’s observed ability to alter metabolic activity and increase adiponectin gene expression in adipose tissue. Although the benefit of targeting metabolic syndrome, beyond addressing classic cardiovascular risk factors, has been debated, the ability of rimonabant to decrease metabolic syndrome prevalence may support its use in the treatment of metabolic syndrome.
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