Three very fat Turkish people, all cousins, got very lucky this year, when they spent a few months in Los Angeles getting injections of leptin, the “satiety” hormone discovered in 1994 and immediately hailed as the long-awaited magic bullet to cure obesity.
The three, a 27-year old man who weighed 312 pounds, a 35-year old woman who weight 253 pounds and a 40 year old woman who weighed 194 pounds, were all miserable.
The man was so fat, he said through an interpreter, that he couldn’t get a job, or a girlfriend. One woman had to work at home as a seamstress because people made fun of her if she went out. The other had given up her dreams of marriage, devoting herself to taking care of her parents.
By the time they headed back to Turkey in July after their treatments, they had each lost roughly half of their body weight, says the researcher who treated them, Dr. Julio Licinio, professor of psychiatry and medicine at the David Geffen School of Medicine at UCLA.
A pair of obese Pakistani cousins living in England, both born, like the Turkish family, with defective genes for leptin, also lost significant amounts of weight with leptin injections.
And that’s pretty much it, folks. That’s the good news: A handful of obese people who get better with leptin, and – let’s be generous here- maybe several thousand more helped modestly and temporarily by other drugs.
After all the hoopla, all the hype, all the hope and all the research, anti-obesity drugs, at least so far, have largely been a bust. And barring some secret miracle concoction now in development, there will simply not be a pharmaceutical fix for fatness in the near future.
It’s all rather depressing.
Two-thirds of Americans are now overweight, the latest government figures show, and one in every three is obese. Obesity is defined as having a Body Mass Index (BMI) of 30 or more and being overweight, by having a BMI of 25 to 30. (To calculate your BMI, multiple your weight in pounds by 703; then divide that number by your height in inches squared.)
Yet, aside from repeating the old mantra of diet and exercise, and maybe a mention of gastric bypass surgery, there’s still very little that doctors have to offer the millions of Americans stuck in weight loss hell.
“There is certainly nothing on the horizon in terms of a drug that will solve obesity,” says Dr. Eric Colman, medical team leader for the metabolic and endocrine division at the US Food and Drug Administration.
“It would be wonderful if there were something that was highly effective and without side effects. But nobody should be waiting for that pill to arrive,” adds Dr. Walter Willett, chairman of the department of nutrition at the Harvard School of Public Health.
The more researchers try to find a magic bullet for weight loss, the more they are discovering that the biochemical pathways in the brain that control appetite and weight maintenance are devilishly complicated.
At the moment, for instance, there are only two prescription weight-loss drugs on the market that are approved for long term use – Meridia (sibutramine) and Xenical (orlistat).
Meridia works promotes a feeling of satiety by increasing levels of serotoninn, norepinephrine and dopamine, chemical messengers in the brain. But, as the Harvard Heart Letter of March, 2002, notes, the drug only works as long as you take it, and even then, only modestly, resulting in a 5 to 10 percent weight loss. This amount of weight loss can help lower blood pressure and cholesterol but may not make a huge dent in what you see in the mirror.
Nor is Xenical a magic answer. It acts in the digestive tract to stop absorption of fat from foods by blocking enzymes called lipases. Like Meridia, it can result in a 5 to 10 percent weight loss, but all that unabsorbed fat can cause uncontrollable bowel movements, messy underwear and frequent passing of fatty gas.
There used to be more choices, but they weren’t terrific either. In 1997, the US Food and Drug Administration asked manufacturers to remove two highly popular anti-obesity drugs from the market, fenfluramine (part of the combination called “fen-phen”) and dexfenfluramine (Redux) because of an apparent increase in the risk of heart disease and serious lung problems.
There still are a few other weight-loss drugs on the market, including those containing phentermine (the “phen” of the old fen-phen combo). But these aren’t approved for long term use (which obese people need) and many are stimulants that can cause nervousness, rapid heartbeat and similar symptoms. These drugs can trigger brief spurts of minor weight loss, but they often lose their effectiveness over time.
So where does this leave the millions of Americans who are either overweight or obese? Still fat and still desperate.
Some people resort to gastic bypass operations – surgery to reduce the size of the stomach, which limits the amount of food a person can take in. In 2000, 40,000 Americans underwent this procedure, almost double the number performed five years earlier, reports Ellen Ruppel Shell, co-director of the Knight Center for Science Journalism at Boston University, in her highly-readable new book “The Hungry Gene.”
But the costs are high. “Gastric bypass surgery kills one out of every hundred patients on the operating table, and not everyone recovers from the complications,” notes Shell.
On the other hand, gastric surgery may work not just by limiting stomach volume – but biochemically as well, according to a recent paper in the New England Journal of Medicine.
Cells in the stomach produce a chemical called ghrelin that has been shown to stimulate feeding and obesity in animals. Unlike the weight loss induced by dieting, weight loss induced by gastric bypass may lead to longer term maintenance of weight loss because of reduced ghrelin levels, note Drs. Jeffrey Flier, an endocrinologist and chief academic officer at Beth Israel Deaconess Medical Center and Eleftheria Maratos-Flier, director of the obesity section at the Joslin Diabetes Center in Boston in an editorial accompanying the research. This suggests that a grehlin-blocking drug might work where others have failed.
And someday, there may be other pharmaceutical options.
Some scientists are hopeful that a drug now in clinical trials called CNTF, for ciliary neurotrophic factor, may work out.
Others are looking at a compound called MLN 4760, made by Millenium Pharmaceuticals in Cambridge, MA, which has been working on obesity drugs for years. So far, says Lou Tartaglia, vice president of metabolic diseases, none of the drugs in the works are yet ready for marketing, but MLN 4760 is now in early human safety trials. The company will not say exactly how it works except that it block an enzyme called carboxypeptidase.
Farther back in the Millenium pipeline is a drug that would activate a receptor molecule called MC4 that seems to act in the brain, at least in mice, to decrease body weig
Tartaglia thanks that the reason that drugs marketed so far have failed is that they are crude and act essentially “by hitting the brain with a hammer.” New drugs could work better because they are targeted to more specific molecules in the brain.
But even then, there are no guarantees. Take leptin, for exaple, a highly specific drug.
Amgen, a company based in Thousand Oaks, Calif., has been trying for years to develop a leptin-based drug, with no success. Company spokeswoman Barbara Bronson Gray says Amgen researchers have conducted several trials but the drug “did not achieve clinical or commercial hurdles needed for an obesity drug in this population.”
Why? For one thing, obese people often turn out to have perfectly normal or even higher than normal levels of leptin, which is made in fat cells and travels to the brain to deliver “satiety” or “I’m full, stop eating” signals.
The Turkish cousins were genuinely – and genetically – leptin-deficient, so giving leptin to them worked. But most obese people are not leptin deficient, perhaps in part because of the sheer number of their fat cells. These fat cells, which never go away, even when a person loses weight, keep cranking out leptin but, obese people, one current theory goes, may become resistant to their own leptin, much as people susceptible to diabetes can become insensitive to their own insulin.
Maybe, some day, the growing understanding of all the biochemistry involved in appetite and weight regulation will result in a magic pill.
Until then? It’s same old, same old: Diet and exercise. Turn off the TV and take a walk instead. Don’t adopt a “low fat” diet that allows you to eat endless carbohydrates. Eat more veggies and less processed junk. At the very least, if you are already overweight, don’t give up and let the problem get even worse.