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.

ADAGIO-LIPIDS Not a Weight-Loss Study

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."

What About the Psychiatric Effects?

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.

EAS 2008: The 77th European Atherosclerosis Society Congress.
Presented April 29, 2008.