Given the size of the obesity problem in the United States—and, increasingly, around the world—you'd expect the weight-loss drug market to be, well, huge. It's not. According to the market research firm Datamonitor, while the global market for drugs to combat diabetes will hit a projected $37 billion by 2018, the obesity drug market is likely to come to just $600 million. The reasons? A history of drugs haunted by sometimes dangerous side effects (including, most recently, the risk of heart problems associated with sibutramine, sold under the Meridia name in the United States, for some people with health issues) and the complex physiology of weight regulation.
Yet, ever cognizant of the market opportunities that would greet a safe, effective drug, manufacturers are teeing up new attempts. Two companies have filed for Food and Drug Administration approval for their medications, and another is expected to file this year. Other drugs are further back in the pipeline. And researchers are urging the exploration of new avenues that may lead to entirely different pharmaceutical approaches to making weight loss easier (although probably never easy).
Shouldn't the obese lose weight the old-fashioned way, through diet and exercise? In an ideal world, probably, but that approach hasn't been particularly successful over the years (see Do Program Diets Work? Rarely—Here are 7 Tips to Shed Pounds). But if willpower alone isn't the answer, neither is treating obesity as a chronic illness to be managed solely through medical means. Behavior and biology both contribute, says Madelyn Fernstrom, director of the nutrition and weight management program at the University of Pittsburgh Medical Center and author of The Real You Diet. Medications, she says, can help make healthful lifestyle choices a bit easier.
But there's not much ammo in currently available prescription options. Phentermine is an appetite suppressant approved by the FDA only for short-term use (up to 12 weeks). It's a stimulant—it was the "good" half of the infamous fen-phen combination that led to dangerous heart and lung damage—and has a powerful but short-lived effect, says Fernstrom. Another drug that muffles appetite, diethylpropion, is also potent but even shorter-acting. Sibutramine is a long-acting appetite suppressant that was initially studied as an antidepressant, but recent data suggest it may cause cardiovascular problems in people with uncontrolled high blood pressure or who have had previous heart attacks or strokes. (The FDA requested a stronger label warning; the European Medicines Agency recommended the drug not be used at all.) Finally, a drug called orlistat (sold over the counter as Alli and by prescription, in a higher dosage, as Xenical) acts not on appetite but by inhibiting a fat-digesting enzyme and causing some of the fat in meals to pass through the digestive tract without being absorbed. If a person eats too much fat, he or she can experience gas, diarrhea, and other unpleasantries. And those are the survivors among weight-loss products; fen-phen spectacularly crashed and burned, while the much-hyped rimonabant was never approved in the United States and faltered in Europe after reports of depression and suicidal thoughts in users. A host of other drugs were abandoned during early studies and never even submitted for approval.
With all the drugs, weight loss tends to top out at about 4 to 6 percent of body weight, on average, and then plateaus. Stop taking the drug, and the weight usually comes back. It's not surprising that it's so tough to make the body give up pounds, says John Fernstrom, a professor of psychiatry and pharmacology at the University of Pittsburgh and director of research for the school's Weight Management Center. Fernstrom, who is Madelyn's husband, has researched weight-loss drugs. Like other physiological processes such as blood pressure, the balance of energy taken in from food and burned off through activity is fairly tightly regulated, he says. (Even if you gain 20 pounds over as many years, all it means is that your body isn't accounting for about 3,500 calories a year, or about 10 calories a day.) But things are lopsided; the body probably has a preference for fat accumulation, allowing weight to creep up far more easily than it creeps down, he says. Our bodies evolved in feast-or-famine conditions; when humans were hunter-gatherers, there was plenty of food available at some times of the year but not at others. So, he says, the pattern was to overeat during times of plenty, store fat, and then burning the fat when food wasn't readily available. Now, of course, conditions are different.
Keeping the percentage of body fat above some critical minimum level is one of the most important biological aspects of our existence, says Rudolph Leibel, a professor of medicine and pediatrics and codirector of the New York Obesity Research Center and the Diabetes and Endocrinology Research Center at Columbia University. Without enough body fat, survival is impaired. So is fertility: Women need enough energy on board to feed themselves and nourish a growing fetus and then, through breast milk, a child. No wonder the body has so many mechanisms in place to protect against too much change in the downward direction. "If you perturb the system in one way, it will compensate in another," says Leibel. "It's very hard to trick Mother Nature."
Will the new drugs currently being developed for the U.S. market work any better or have fewer side effects? Two of them—Contrave, made by Orexigen Therapeutics, and Qnexa, made by Vivus—are actually combinations of existing drugs prescribed for other purposes but married with an eye to boosting effectiveness, reducing side effects, or both. Contrave, expected to be submitted for FDA consideration this year, has bupropion (the ingredient in the antidepressant Wellbutrin and the antismoking therapy Zyban) combined with naltrexone, already prescribed for drug and alcohol addiction. Bupropion seems to stimulate the brain's so-called POMC cells, with the ultimate effect of "decreasing food intake and boosting energy expenditure," says Dennis Kim, senior vice president of medical affairs at Orexigen. Naltrexone, meantime, blocks beta-endorphin, a chemical that normally ratchets down the activity of POMC. The combination leads to "longer and greater weight loss," he says.
Qnexa, which was submitted to the FDA in late December, has produced the largest weight loss in trials. It combines low doses of topiramate, an antiseizure drug, with phentermine. In higher doses, both have side effects—cognitive dulling and fatigue for topiramate and high blood pressure in phentermine—but Peter Tam, president of Vivus, says the combination of the drugs at lower doses reduces those side effects and leads to greater weight loss. (The phentermine is similar to an amphetamine, acting as a stimulant and prompting the release of a neurotransmitter that is linked to appetite suppression. The mechanism behind topiramate isn't understood.)
Lorcaserin, made by Arena Pharmaceuticals, is a new drug that stimulates the serotonin 2C receptor, found mostly in the hypothalamus. This receptor is involved in appetite and food intake. (Fenfluramine, the "bad" half of fen-phen, stimulated the closely related 2B receptor that is found in the heart, with ill effects.) "It's targeting one specific [receptor] subtype that's in a part of the brain which should only affect food intake suppression," says Dominic Behan, cofounder and chief scientific officer of Arena. The drug also seems to have few side effects. Safety will be key for the FDA, given that an obesity drug is likely to find its way into the medicine cabinets of people who may only want to lose 10 to 15 pounds; for them, the risks of carrying the extra weight aren't large, so the risks of the drug better be extremely low, says Donna Ryan, president of the Obesity Society and associate executive director for clinical research at Pennington Biomedical Research Center in Baton Rouge, La. (Her financial relationships with drug and weight-loss companies ended in 2008.)
It's important to have more options, says Michael Cowley, developer of Contrave and a professorial fellow in the department of physiology at Monash University in Australia. He and others use the analogy of the antidepressant market to describe what more drugs would likely mean: a range of different options that work well in some people and not in others—so you try something, see if it works, and move to something else if it doesn't.
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.
And we may fundamentally have to adjust our expectations and focus on attainable medical benefits such as improvements in the level of "good" cholesterol and blood sugar. Even modest weight loss translates to real benefit in terms of how well the body metabolizes sugar; it takes only about a 7 percent weight loss to see as much as a 58 percent improvement in the risk of progressing from prediabetes to the full-blown disease, says Ryan. And even with future drugs, weight loss of just 10 percent may be the most reasonable target. "These drugs are not for cosmetic reasons," she says. "They're not for being the Biggest Loser."
[Read about the potential hazards of over-the-counter weight-loss products.]