A Drug to Counteract Obesity -- Is Lorcaserin the Holy Grail?

Henry R. Black, MD


August 30, 2010

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Hi, I'm Dr. Henry Black from the New York University School of Medicine Center for the Prevention of Cardiovascular Disease and Immediate Past President of the American Society of Hypertension.

The Holy Grail in preventive cardiology and preventive medicine these days is to find some way to counteract the increasing obesity epidemic. Either most everything so far has failed, or any drug that we've had has turned out to be too toxic for general use.

If we take a somewhat historical perspective, back in the 1940s when we didn't have good antihypertensives, people were performing sympathectomies -- abdominal sympathectomies -- to treat hypertension that couldn't be treated otherwise. In the 1970s and 1980s, we performed ileal transpositions before we had statins to treat high cholesterol. And right now, we have surgical approaches to obesity, which are useful and have long-term data showing reductions in outcomes, but we still don't have an easy-to-take pharmacologic approach that we can consider for people who don't have the body mass indices in the range that we consider really necessary to be treated.

Now, there have been some pharmacologic approaches. There are 2 drugs on the market in the United States right now -- sibutramine and orlistat. Sibutramine has some cardiovascular toxicity and, in fact, has been withdrawn from the market in Europe and is currently being evaluated by the US Food and Drug Administration (FDA). Orlistat, which is also available in a low-dose over-the-counter, has some unpleasant side effects and is not all that effective, so we're looking for something that's going to work.

In the early 1980s, fenfluramine, dexfenfluramine, and phentermine were introduced and put together in a compound called Phen-Fen. It was quite popular and seemed to be working. These drugs both worked as serotonin agonists because the serotonergic system in the brain seems to affect our interest in eating. But a peculiar thing turned up. Cardiovascular valve abnormalities developed, which didn't seem to make sense until we realized that there were 3 receptors for serotonin: HTa, HTb, and HTc -- and HTb receptors were also present in the cardiac valves. This valvular abnormality was further investigated and the combination was removed from the market because it seemed to be responsible for the valve problems. This is nice in some ways because you have an idea of what the problem is, but it's got to have a pathophysiologic basis, not just some epidemiologic findings. However, in this case, there was a good pathophysiologic basis.

So, recently, the idea has been to develop a more selective serotonin HT antagonist for the brain, an HTc antagonist in particular. Now, there's a recent study and new drug called lorcaserin, which seems to possibly meet those criteria.

The BLOOM [Behavioral modification and Lorcaserin for Overweight and Obesity Management] study,[1] which has recently been published in The New England Journal of Medicine, is a long-term trial -- long-term by obesity standards -- of a 1-2 year study, which offered some promise about this idea. You hear of patients who were primarily women, and primarily in their early forties, who had body mass indices between 30 and 45 and didn't have any other cardiovascular disease, including diabetes, who were enrolled in this study in a 1-to-1 placebo-controlled trial that included lifestyle modification. They were asked to exercise 30 minutes a day every day and reduce their calorie intake by about 600 calories per day, which is easy to say and write about, but maybe not so easy to do.

At the end of 1 year, the people on the active drug, lorcaserin, had a weight loss of about 9 kg as opposed to about 4 kg in the people on placebo. While their primary endpoint was losing 5% of body weight, they also looked at how many people lost 10% of their body weight. At the end of a year, they did an interesting thing: People on placebo were continued on placebo, and people who were on the active drug were switched in a randomized fashion -- a 2-to-1 randomized fashion -- to take the active drug for another year or to be switched to the placebo. This is pretty common practice in obesity studies and was seen with rimonabant, a drug that had a great promise but turned out to have serious psychiatric side effects and was, in fact, withdrawn from the market in Europe and never approved by the FDA.

At the end of 1 year, the side effect profile was quite similar between the placebo group and the active group and even took into account a large number of dropouts, which we commonly see in obesity studies, but they took this into account when they planned it. And the number of valvular lesions was about 2.7% in the placebo group, and about 2.5% in the active therapy group, less than had been anticipated. When they followed this another year, this really didn't change. They did echocardiograms at baseline; they did echocardiograms at 24 weeks, at a year, a year and a half, and the end of the study. The echocardiograms were read independently in a blinded fashion by several observers, and there was about a 70% concordance between the observers.

So this is a promising idea. The editorialist for this paper pointed out that these drugs weren't any more effective than sibutramine or rimonabant were, or orlistat is, but they seem to be safer. So the real risk with any anti-obesity drug is that it will be approved for people who have obesity and its complications, but it will be taken by people who want to lose 10 pounds before a wedding or get into a bathing suit for the summer, which is the concern and the reason why it really must be safe.

I look forward to how this works out and to see whether we finally have something we can use that seems to be safe and effective to lose weight. Thank you very much.


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