Istanbul, Turkey - A new rimonabant (Acomplia, Sanofi-Aventis) study presented this week confirmed key changes in HDL cholesterol and triglyceride levels as well as improvements in HDL- and LDL-cholesterol particle size, inflammation, and key components of the metabolic syndrome. Investigators also showed that the drug reduced visceral adipose tissue, the type of abdominal obesity that contributes to big waistlines and type 2 diabetes.

The two new analyses, from An International Study of Rimonabant in Dyslipidemia with Atherogenic Risk in Abdominally Obese Patients (ADAGIO-LIPIDS), were presented here this week at the 77th European Atherosclerosis Society Congress.

"We've demonstrated very clearly that the CB1-receptor antagonist rimonabant represents a very relevant approach to the pharmacological treatment of visceral obesity and ectopic fat in patients who are high risk with atherogenic dyslipidemia," said Dr Robert Ross (Queen's University, Kingston, ON), who presented computed-tomography (CT) data showing significant reductions in visceral adipose tissue with rimonabant.

Dr Jean-Pierre Després (Université Laval, Quebec City, QC), the lead investigator of ADAGIO-LIPIDS, a randomized, double-blind, placebo-controlled multicenter study, stressed that this was not a weight-loss study, but rather an investigation into changes in lipid parameters with rimonabant. In the phase 3 studies with the drug, patients in both the treatment and placebo arms altered their diets to reduce caloric intake in the run-in period, and this resulted in both groups losing weight, reducing their waist circumference, and increasing HDL-cholesterol levels before active treatment began.

The purpose of this study, explained Després, was to determine the net effect of rimonabant on HDL-cholesterol and triglyceride levels and on the cardiometabolic profile of weight-stable overweight/obese patients with atherogenic dyslipidemia. The CT analysis was conducted to measure how much subcutaneous and visceral fat was lost on rimonabant as well as to determine whether rimonabant could reduce liver fat. In total, 370 patients were randomized to rimonabant 20 mg and another 370 patients to placebo. Both groups reduced daily caloric intake 600 kcal after randomization to treatment and were followed for 12 months.

At one year, treatment with rimonabant increased HDL-cholesterol levels 9.7% and reduced triglycerides 15.5%, both of which were significantly greater than placebo. Changes in apolipoprotein levels also improved with rimonabant, as did HDL- and LDL-cholesterol particle size. Blood pressure was reduced 3.3 mm Hg with rimonabant, significantly greater compared with placebo, and inflammation levels measured by CRP were also reduced. Weight and waist circumference were also favorably improved with the CB1-receptor antagonist.

In the CT analysis, Ross showed that rimonabant treatment resulted in significantly greater reductions in total adipose tissue, visceral fat, and subcutaneous fat at 12 months compared with placebo. The fatty liver index, a measure of hepatic steatosis, was also improved.

"Clinicians have an arsenal of pharmacological strategies for the treatment of longstanding comorbidities and risk factors, but with respect to cardiometabolic risk, there may be a residual effect of the metabolic syndrome, perhaps caused by excessive abdominal obesity, in this case visceral and ectopic fat," said Ross. "We have not—until now—had a compound that acts directly on this phenotype."

Earlier in the week, Després said there is a need for greater concern about how patients are putting on weight and called large waist circumferences the clinician's new battle for the 21st century. However, he stressed that, despite the reductions in abdominal cavity fat, rimonabant and other similar drugs that might follow in its footsteps still have a long way to go.

"I think the field of pharmacologic therapy for weight loss is in the minor leagues compared with pharmacologic therapies for dyslipidemia," said Després. "Rimonabant is not a miracle drug, and patients with a weight problem shouldn't be taking it to look good in a swimsuit." The drug, he added, has a very serious side-effect profile and should be reserved only for those who are unable to reduce abdominal obesity through dietary and lifestyle modification.

ADAGIO-LIPIDS was conducted in patients with no history of psychiatric and/or depressive illness, and as a result, discontinuation of therapy due to adverse events was significantly less than has been reported in other studies. Psychiatric adverse effects are the largest hurdle Sanofi-Aventis faces in the US, with the drug rejected by the Food and Drug Administration in 2007 because of concerns about side effects such as anxiety and depression. Rimonabant has been approved in Europe since 2006 for obese or overweight adults, but European regulators recently stated that the drug must carry stronger safety warnings about psychiatric side effects.

In terms of gaining a US approval, an intravascular ultrasound study presented last month at the American College of Cardiology Scientific Sessions in Chicago, IL provided a bit of a double-whammy for the drug.

In the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant-the IVUS Study (STRADIVARIUS) study, run by Dr Steven Nissen (Cleveland Clinic, OH) et al and conducted in patients with abdominal obesity and coronary artery disease, treatment with rimonabant failed to show any benefit on progression of atherosclerosis. Moreover, significantly more patients in the rimonabant group reported adverse psychiatric effects (43.4% vs 28.4% in the placebo group, p<0.001). It should be noted, however, that STRADIVARIUS investigators enrolled patients whether or not they had a history of psychiatric illness, and some 20% of patients were on antidepressants at baseline.