Even better would be to be able to predict what will work best for a given person. "There are three reasons to eat: hunger, reward, and stress," says Robert Lustig, a pediatric endocrinologist and the director of the Weight Assessment for Teen and Child Health program at the University of California–San Francisco. And, he says, different areas of the brain are involved with each of those reasons: A region of the hypothalamus is tied to hunger, the nucleus accumbens to reward, and the amygdala to stress. An individual might have problems with one, two, or all three. "Until you determine which is the problem, you're not going to know how to target therapy appropriately," he says. Trouble is, there's no good screening tool to help doctors prescribe the correct treatment for patients.
In the interim, Madelyn Fernstrom has some basic suggestions. Orlistat, for example, only blocks the absorption of fat. So if your vice is fat-free SnackWells or soda, it's not likely to be helpful. On the other hand, if you eat out a lot and consume a lot of hidden fat, it may be just the ticket. If the root of your problems comes down to mood, a drug that includes bupropion may help. And sibutramine, she says, can really help you get better control of your eating if you're the type of person who gets very hungry and, as a result, makes poor food choices. It's not clear who might benefit best from the drugs in development; obviously, the companies would like everyone to use them. (Experts say Qnexa, with greater weight loss but questions about the side effects of its components, might be used by doctors in the seriously obese.)
So what's next with weight-loss drugs? Perhaps weight loss can be extended if we can get beyond or delay the current plateaus. "The reason that's happening is that the body is smarter than the brain," says Lustig. You can fool the brain with drugs into thinking that you're full, but "the body know there's less food coming in and reduces its rate of energy expenditure." (It's the same thing that happens when you go on a crash diet.) The mechanism behind that, says Lustig, is the body's response to leptin, a hormone produced by fat that tells the brain, "Enough food already; I've got enough food on board and stored." But when calories drop and fat is lost, leptin levels decline below a certain level, hunger persists (making it tough to resist food), and the body slows movement to conserve energy. Lustig believes one strategy—at least for a subset of people—is to reduce insulin, persistently high levels of which he believes block leptin's satiety action.
A company called Amylin is working on an injectable drug that combines metreleptin, a slightly modified version of leptin, and pramlintide, a modified version of a hormone secreted by the pancreas that is involved with satiety. The two working in concert produced weight loss in animals and then in human studies, says Christian Weyer, vice president of medical development at Amylin. (Leptin alone hasn't proved successful as an obesity treatment.) "With the exception of very heavy individuals, we were able to see a marked reduction in body weight," he says. It's not yet clear whether the drug's effects might persist longer than those of others. The drug is heading for phase III trials.
Leibel, one of the scientists who discovered leptin in 1994, wonders if the entire approach to drugs might be tweaked. The hard part, as everyone knows, is not so much losing the weight via diet, exercise, or drugs but keeping it off. Key may be studying and then addressing the physiology of that weight-reduced state, he says, where the body is screaming with hunger and ratcheting down its energy expenditures. Cowley agrees. "A more fruitful avenue is to cause weight loss through diet and exercise and then use a drug to help maintain the loss," he says.