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Investigational drug ups HDL by 27% in one year: linked to weight loss, improved smoking cessation, reversal of metabolic syndrome.

MUNICH -- The investigational drug rimonabant, first in a new class of agents known as selective endocannabinoid type 1 receptor blockers, is looking more and more like the real deal: a potential blockbuster drug causing sustained weight loss in the obese, reversal of the metabolic syndrome, an improved cardiovascular risk profile, and increased success in smoking cessation.

Interim results of the randomized double-blind placebo-controlled 1,507-patient Rimonabant in Obesity-Europe (RIO-Europe) trial showed that after 1 year on 20 mg rimonabant/day, patients lost an average of 8.6 kg, reduced their waist circumference by 8.5 cm, boosted their cardioprotective HDL cholesterol levels by 27%, and lowered their triglyceride levels by 11%, Dr. Luc Van Gaal reported at the annual congress of the European Society of Cardiology.

"I have never before seen a 27% increase in HDL [cholesterol] with any drug--not statins, not even fibrates," observed Dr. Van Gaal, professor of internal medicine and diabetology at the University of Antwerp (Belgium).

At baseline, 42% of patients in the rimonabant 20-mg arm met criteria for metabolic syndrome, placing them at higher risk for cardiovascular disease. After 1 year of therapy in what will be a 2-year trial, the prevalence of the syndrome was cut by 53%.

RIO-Europe is a seven-nation study involving patients with a mean body mass index of 36 kg/[m.sup.2] and an average waist circumference of 110 cm. As is typical of obesity clinical trials, 80% were women.

Participants were encouraged by dietitians and counselors to modify their lifestyle by increasing physical activity and adopting a diet with a 600-cal/day deficit. One-fifth of subjects were randomized to placebo, while the remainder received either 5 mg or 20 mg of rimonabant daily.

The placebo response was high, which Dr. Van Gaal attributed to the counselors' dedication. Thirty-one percent of patients who completed 1 year of placebo therapy lost more than 5% of their initial body weight, and although that's an impressive figure, it is well below those of the rimonabant groups: 44% in the patients receiving 5 mg/day and a 67% rate in those receiving 20 mg/day.

Of patients on 20 mg/day rimonabant, 39% lost more than 10% of their initial body weight, as did 15% of those on 5 mg/day and 12% of those on placebo. It's known that a 10% loss in body weight coupled with an 8- to 10-cm decrease in waist circumference translates into a 25%-30% reduction in metabolically harmful visceral fat. A significantly improved insulin response on an oral glucose tolerance test was noted in patients on 20 mg/day rimonabant.

Earlier studies showed that weight loss on rimonabant is primarily due to decreased cravings for two food groups: sweets and fats, Dr. Van Gaal said.

The only side effects more common in rimonabant patients than placebo patients were mild transient nausea and diarrhea. Concern about possible psychiatric side effects raised in an earlier smaller study proved groundless.

About 40% of patients in each of the three study arms dropped out, primarily as a result of unmet expectations. Participants were counseled that a 5%-10% weight loss was both realistic and medically meaningful, but many still sought a 20%-25% weight loss. "They always hope for a miracle," Dr. Van Gaal observed.

RIO-Europe was sponsored by Sanofi-Aventis. The company is aggressively pursuing development of rimonabant in eight phase III clinical trials comprising more than 13,000 patients. The focus is on two separate indications: weight loss and smoking cessation. Previously presented smoking cessation studies showed that rimonabant doubled the quit-success rate, compared with placebo, while enabling patients to avoid the associated weight gain that often thwarts smoking cessation attempts.

Dr. Van Gaal said the remaining phase III rimonabant trials are slated for completion by year's end, including the 2,500-patient RIO-North America trial to be presented in November at the annual scientific sessions of the American Heart Association. He added that during the first half of next year Sanofi-Aventis plans to file for Food and Drug Administration marketing approval for the two indications.

Discussant Dr. Philippe Gabriel Steg of Bichat Hospital in Paris commented that in his view the most important finding in RIO-Europe was that weight loss accounted for only about half the improvement in HDL cholesterol and triglyceride levels. This implies the drug has direct metabolic effects beyond weight loss.

The endocannabinoid system is a recently discovered system involved in regulation of energy balance. "The system is often silent but can become overactive if stimulated by excess food intake or nicotine abuse," Dr. Van Gaal explained.

Rimonabant blocks the endocannabinoid type 1 receptor both centrally and peripherally. The central effect leads to decreased food intake and can help control nicotine dependence.

Peripherally, the drug acts on adipocytes to increase levels of adiponectin, which reduces insulin resistance and increases HDL cholesterol.

In a separate presentation, Dr. Alain Golay of University Hospital, Geneva, presented a new analysis of the previously presented 1,036-patient randomized RIO-Lipids trial showing that both the benefits and side effects of rimonabant were, reassuringly, essentially superimposable upon those of RIO-Europe.

For example, RIO-Europe showed a 53% reduction in the prevalence of metabolic syndrome after 1 year on 20 mg/day of rimonabant, while RIO-Lipids showed a 51% reduction in prevalence in the 53% of participants who met criteria for metabolic syndrome at baseline. HDL-cholesterol levels climbed by 27% and 23% in the 20-mg arms of RIO-Europe and RIO-Lipids, respectively, while triglyceride levels dropped by 11% and 16%.


Denver Bureau
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Author:Jancin, Bruce
Publication:OB GYN News
Date:Oct 1, 2004
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