Feb 20 - FDA Issues Approvable Letter on Acomplia

Medication and diet may lead to weight loss.

STE-FOY, Quebec, Nov. 17 - An investigational drug, combined with a low-calorie diet, can lead to weight loss and improve a range of metabolic risk factors in patients with atherogenic lipid abnormalities, an international team of researchers says.

In a randomized, placebo-controlled trial, the selective cannabinoid-1 receptor (CB1) blocker Acomplia (rimonabant) significantly reduced weight and waist circumference, reports Jean-Pierre Despres, Ph.D., of the Quebec Heart Institute at Laval Hospital Research Center in Ste.-Foy, Quebec.

Also, Dr. Despres and colleagues wrote in the Nov. 17 issue of the New England Journal of Medicine, the drug improves a range of atherogenic markers, plasma triglycerides, plasma high-density lipoprotein (HDL) cholesterol, and adiponectin levels.

The study, by the Rimonabant in Obesity-Lipids Study Group, was one of two in the NEJM investigating issues surrounding the obesity epidemic.

In the Acomplia study, researchers randomly assigned 1,036 patients with a body mass index of 27 to 40 to one of three arms -- placebo, Acomplia at 5 mg daily, or Acomplia at 20 mg a day. All participants were placed on a low-calorie diet.

They were selected to have untreated dyslipidemia -- triglyceride levels greater than 1.69 to 7.90 mmol/L, or a cholesterol/HDL cholesterol ratio of greater than 4.5 among women or five among men.

After a year, patients at the high dose of Acomplia had a mean weight loss of 6.7 kg (all calculations by a repeated-measures method) and a mean reduction in waist circumference of 5.8 cm -- results that were statistically significant at the p<0.001 confidence level compared to placebo.

The high-dose patients also had a mean 10% increase in HDL cholesterol and a mean reduction in triglycerides of 13%. Also, the high-dose patients also saw an increase in plasma adiponectin levels of 57.7%. Again, the results were statistically significant at the p<0.001 confidence level compared to placebo.

There was no change in levels of LDL cholesterol. Levels of fasting plasma insulin, the one-hour and two-hour plasma glucose and insulin levels, decreased significantly in the group receiving 20 mg of Acomplia (p<0.01).

Weight loss and waist reduction generally took place in the first nine months of the study, after which the body shape stabilized and there was no evidence of regain, the researchers found.

The study provides additional evidence, the researchers said, that CB1-receptor blockade "may constitute a new, clinically relevant pharmacologic approach" that will improve the cardiovascular risk profile in overweight or obese patients with dyslipidemia.

On the other hand, they cautioned that "pharmacotherapy alone will not eradicate the epidemic of obesity" -- something that was borne out by the other obesity study in the NEJM.

In a one-year randomized trial, researchers in Philadelphia found that overweight patients taking the weight-loss drug Meridia (sibutramine) did better with group lifestyle counseling than on the drug alone.

In fact, just taking Meridia is the worst of four possible options -- the drug alone, the drug combined with brief counseling from a primary care provider, group lifestyle counseling, or Meridia combined with group counseling, according to Thomas Wadden, Ph.D., of the University of Pennsylvania and colleagues.

The results suggested that drug therapy must be combined with "a comprehensive program of diet, exercise, and behavior therapy" in order to be effective, Dr. Wadden and colleagues wrote.


In the study, researchers randomized 224 obese adults to:



15 mg/day of Meridia a day alone, delivered by a primary care provider in eight visits of 10 to 15 minutes each.

Lifestyle-modification counseling alone, delivered in 30 group sessions.

15 mg/day of Meridia a day plus 30 group sessions of lifestyle-modification counseling (dubbed "combined therapy").

Meridia plus brief lifestyle-modification counseling delivered by a primary care provider in during eight office visits of 10 to 15 minutes each.

The participants were prescribed a diet of between 1,200 and 1,500 kcal/day and an identical exercise regimen.


After a year, participants who completed the combined therapy had lost a mean of 12.1 kg. By contrast, those who had the drug alone lost 5 kg, those who just had group counseling lost 6.7 kg, and those who had the drug plus brief counseling lost 7.5 kg. The differences were statistically significant at p<0.001.


Meridia is one of two drugs approved for long-term use in treatment of obesity; the other is Xenical (orlistat).


While such advances in weight loss are welcome, the ultimate goal should be not simply to treat obesity but to prevent it in the first place, wrote Susan Yanovski, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.


In an accompanying editorial, Dr. Yanovski called for an "improved armamentarium of therapeutic approaches," but warned that new medications alone are likely to be problematic, especially if they are used on a long-term basis. As in the case of fenfluramine and phentermine, long-term use may expose adverse effects that were not seen in short-term clinical studies, she noted.


Also, she wrote, a medication that helps obese people lose weight is likely eventually to be used by people who are not clinically overweight, but simply want to improve their appearance.


"A careful assessment of the safety of anti-obesity medications may be even more important than for drugs used to treat other conditions," Dr. Yanovski said.



Primary source: New England Journal of Medicine