GIRTH CONTROL PILLS
Diet pills had a heyday in the ‘50s and ‘60s, when housewives around the country were downing amphetamines in the morning and barbituates to put them asleep at night. For a while, people all over the country were optimistic that a cure for obesity had been discovered. As Newsweek put it in February, 1949, “Many drugs have been used to correct obesity but only a few are safe and effective. One of the best is Benzedrine.” In 1952, three billion ten-milligram amphetamine tablets were being produced annually in this country. By 1970, eight percent of all prescriptions were for these “mother’s little helpers.” But diet pills fell out of favor when it became clear that the effects of amphetamines were sometimes disastrous: many women became addicted to the drugs, which rev up the nervous system, increase the heart rate and blood pressure, and cause anxiety, insomnia, nervousness, and often addiction. Long-term use led to heart damage, stroke, kidney failure, and psychosis in some cases. In 1979, the FDA reclassified appetite suppressants as dangerous drugs. For many years, most respectable doctors shunned the use of diet pills.
Now, however, diet pills are becoming popular again among physicians — if only by default. “We’ve tried everything,” explains obesity expert Jules Hirsch. “Nothing works, and people are desperate, so we’re going back to drugs.”
The pendulum started to swing back with a vengeance after a 1992 study showed that a combination of two diet drugs — fenfluramine and phentermine — are more effective than diet and exercise alone at taking weight off. Since that study, done at the University of Rochester by pharmacologist Michael Weintraub, Wyeth-Ayerst has been unable to keep up with the demand for fenfluramine, even with its workers on 24-hour shifts; pharmacists all over the country have reported running out of the drug. New prescriptions for fenfluramine and phentermine have increased 14-fold since 1991, with an estimated one million Americans taking the drugs now, spending over $100 million a year their prescriptions. By all accounts a new obesity dexfenfluramine, which is related to fenfluramine, is on the verge of FDA approval; industry analysts predict the market for dexfenfluramine alone could reach $1 billion by 1999. But the worry among some weight loss experts is that this new era in diet drugs will end as the old one did: in disillusionment.
These diet drugs have become so popular that even commercial diet centers have gone into the business of prescribing them. In 1995, Nutri/System became the first diet center in the country to pass out prescriptions for appetite suppressants along with pep talks and prepackaged meals. To qualify for the program, most patients must be 20 percent heavier than insurance charts of desirable weights; a 5’5” woman, for instance, would need to weigh at least 157 pounds to enroll (a weight some obesity researchers would still call healthy).
So far, clients at these programs seem pleased to be able to get prescriptions for diet pills at their local mall. Andrea Wagner, for instance (not her real name), has been through the doors of her local Nutri/System weight loss center in suburban Philadelphia before. The first time she tried the low-calorie diet program, she felt constantly hungry. After four months, she went off the diet and gained back what little she had lost — “Plus more,” she says. That wasn’t unexpected: At 5’4″ and 154 pounds, the 47-year-old lab technician had tried just about every commercial diet program in the book, with no lasting success.
This time, things are different. Now, in addition to seeing her regular weight loss counselor at each visit, she goes down the hall every few months to a physician who gives her a quick check-up — and a prescription for diet pills. Since she began taking the fen/phen combination, as it’s called, Wagner says she’s experienced few side effects, suffering only the occasional dry mouth, a little nervousness at first, and vivid dreams. And she says she’s found what every frustrated dieter dreams of. “You can be around food, and you just don’t have the desire to eat it,” she says. “You don’t even think about food.”
Fenfluramine tones down Wagner’s craving for food by increasing the amount of serotonin in her brain. Serotonin is a chemical messenger that helps regulate not just appetite but impulsiveness, sexual feelings, and mood. The more serotonin, the calmer and more satisfied people feel. “What I hear from my patients, is that they feel normal for once,” says John Foreyt, a psychologist and obesity researcher at the Baylor College of Medicine in Houston who is paid to be on NutriSystem’s scientific advisory board. “They still have to struggle with eating right, exercising, and managing stress, but these pills give them more control.”
Dexfenfluramine, awaiting FDA approval, also increases serotonin levels. Actually, with fenfluramine too, it’s dexfenfluramine that is doing the work. Used on its own in Europe since 1985, dexfenfluramine is available here only as one of two mirror-image compounds that make up fenfluramine; the other part of the fenfluramine package, a compound called levofenfluramine, can make patients feel drowsy. To counteract the snooziness and further suppress the appetite, physicians here give patients phentermine, an amphetamine-like drug that speeds up the nervous system.
There’s no question that fen/phen and dexfenfluramine make dieters feel like they can lose weight more easily; cookies lose some of their interest while stomach crunches take on a new appeal. But some obesity researchers wonder whether that feeling really translates into weight loss over the long term, and others worry that the benefits of the drugs may not be worth the risks — particularly if a patient isn’t seriously obese.
“We don’t know anything about the long-term safety of these drugs,” says obesity researcher David Levitsky. There have been no studies, he says, on whether it may be harmful to use the drugs over several years. When the FDA approved fenfluramine and phentermine, the agency recommended that both drugs be used only on a short-term basis. Generally, that’s been interpreted by state regulatory agencies as meaning about three months. But the trend among many physicians is to think of obesity as a chronic disease, one that may require long-term medication, so many doctors are flouting the rules. “We know there’s more prescribing,” says Weintraub, who now works for the FDA. “Most of the state boards of medicine are taking it easy and not chasing too many physicians.” According to Nutri/System vice-president Joe DeBartolomeo, the NutriRX policy is to prescribe the drugs for up to two years.
Even with short-term use, fenfluramine and dexfenfluramine both raise the risk of pulmonary hypertension, a condition in which the blood vessels that feed the lungs tighten up. The heart must work so hard to pump the blood through the constricted vessels that it can fail. The condition is often fatal, but it is rare: Servier, Ltd., which markets dexfenfluramine in Europe, has reported just 101 cases among the drug’s ten million users. Some researchers worry, however, that some cases of pulmonary hypertension may have been overlooked. Ron Innerfield, an endocrinologist with the National Diabetes Center who was formerly a medical officer in the division of the FDA that regulates weight loss drugs, says the condition, which reveals itself through subtle complaints of weakness, shortness of breath, and debilitation, is very difficult to diagnose. “This is a tip-of-the-iceberg phenomenon,” he says. “For every patient you pick up with this, there must be 100 more you’re missing.”
Another possible risk is more insidious. There are suggestions that with long-term use, fenfluramine and dexfenfluramine can cause subtle brain damage. Lewis Seiden, a pharmacologist at the University of Chicago, is one of several scientists who has studied the drugs in rats and monkeys. He, like others, has found that at high doses, the drugs burn out the brain axons that release serotonin. The axons regrow, but in odd tangles. No one is sure what it means to have tangled neural axons, but it doesn’t sound good. As fat activist Lynn McAffee put it at the FDA hearings on dexfenfluramine, “I don’t like having tangles in my hair, much less in my brain.”
Seiden suspects that the long-term result could be depression, anxiety, sleeplessness, and other mood disorders. European users haven’t complained of such problems, but they’re just the sort of symptoms that might escape detection or be attributed to other causes. “If these drugs cured cancer, they would be worth the risk,” Seiden says. “But when millions of people are taking the drug, many of whom are only slightly above their ideal weight, some of them are going to get hurt.”
Johns Hopkins neurologist George Ricaurte, who showed that monkeys given high doses of the drug for just four days suffered substantial damage to the neural axons and that the damage lasted for as long as a year and a half, says the drug’s effect on the brain is similar to the kind that results from using the recreational street drug MDMA, better known as Ecstasy. People would take the diet drugs much more frequently, presumably, than they take MDMA, which is illegal because the Drug Enforcement Agency considers it dangerous and addictive. Ricaurte says that while it may be possible to prescribe a dose of fenfluramine or dexfenfluramine that is low enough that no damage would occur, no one yet knows what a safe dose would be — only that the line between safe and dangerous is, according to the animal studies, probably very narrow. “We have a need for a good appetite suppressant,” says Ricaurte. “But when the animal data raise the possibility of neurotoxicity in humans, we have to be cautious.”
The animals in these studies were given relatively large doses of the drugs, Richard Atkinson, an obesity researcher at the University of Wisconsin, points out, so the findings may have no bearing on humans. But while he believes the drugs can be useful, he, too, urges caution. In his studies involving over 2,000 patients on fenfluramine and phentermine, he’s seen significant mood changes, concentration problems, short-term memory loss, fatigue, and loss of libido. He also doesn’t believe the drugs should be used on people who only want to lose a few pounds. Says Atkinson, “It’s a little scary to say everybody who’s a little overweight ought to go take these things.”
People who are struggling with recalcitrant pounds may be willing to take the risk of rare and unconfirmed ailments in exchange for a sure way to lose weight. But according to Jules Hirsch, the drugs are hardly the magic bullets they’ve been made out to be. In the short run, the fen/phen combination is as good as any diet: About a third of patients will lose five to ten percent of their body weight. In the long run, they’re just as bad, because most of those patients will regain the weight. The results of the Weintraub study, which prompted the run on diet drugs, were really quite modest, Hirsch points out. In that study, after nearly four years of drug therapy, not all of the 121 patients lost weight, and some even gained a considerable amount. Fifteen percent dropped out because they couldn’t tolerate the side effects, including sleep disturbances, nervousness, tension, increased blood pressure, and heart palpitations. Only one-fifth of those who began the study succeeded in keeping off ten percent of their weight.
Hirsch says there are times when these drugs may be useful, but he’s wary of how frequently they’re being prescribed. He warns that physicians must be careful to tailor obesity treatment to individuals, according not just to their weight, but to their complete medical picture — other health risks, their history, their reasons for being obese. He questions whether physicians working for commercial weight loss programs will be able to do that. “In any new commercial weight loss program where physicians are under orders to follow company guidelines for prescriptions rather than judgments for individualized medical treatment,” he says, “I would consider this to be bad medical treatment.”
Some researchers expect that after the buzz quiets, the drugs will turn out to be truly useful only for a relatively small group of dieters: for those, say, who are very fat, have related medical problems such as diabetes, are already eating healthfully and exercising, and yet still have tremendous food cravings. One 1996 study suggested that for people who abdominal obesity (the “apples” among us), dexfenfluramine may help redistribute fat to a safer location on the hips and thighs. When Sharon Marks and her colleagues in Oxford, England, and Australia used magnetic imaging to measure how dexfenfluramine affected ten slightly overweight men with diabetes for twelve weeks, they found that the drug, in combination with their regular diabetic advice and medication, caused a 31 percent reduction in the abdominal fat surrounding the organs, compared with an 11 percent reduction in the fat under the skin (which is likely to be stashed away on the hips and thighs). The drug also improved the insulin sensitivity of the subjects, which could improve their overall health. Obesity researcher Claude Bouchard, of Quebec’s Laval University, said the study, if reproducible, could pave the way for selectively treating the most dangerous type of fat.
But it’s unlikely that physicians will be so selective in prescribing these drugs. The trend, in fact, is to medicate everyone society considers cosmetically overweight. Both researchers urging caution and fans of prescription diet pills agree on one thing: The pendulum in drug treatment for weight loss has further to swing. “People are desperate,” says obesity researcher Steven Heymsfield, who helped develop the NutriRx program. “They’ve failed on every program, they want to lose weight, and they want to keep it off. So there will be more and stronger drugs developed, the FDA will approve them, and more people will take them.”
Andrea Wagner, a few pounds away from her goal weight of 123 pounds, is pleased with how her daily dose of diet drugs has worked. The only thing worrying her now is what will happen when she stops taking the drugs. “I hope I won’t gain the weight back, but I wouldn’t be surprised if I did,” she says. “I’m terrified about going off the medications.”
If she does regain the weight, she’ll go right back on the drugs. And if her NutriRX doctor stops prescribing them to her? “I’ll just find another center,” she says, “and another doctor.”
Instead of attacking appetite, the drug called orlistat is meant to work after you’ve eaten — by interfering with the body’s metabolism of fat. Though still in the experimental phase and years from FDA approval, gossip columnist Liz Smith has already called orlistat a “dream drug,” and Self magazine hailed it as “the miracle drug we’ve all been waiting for.” The promise of orlistat is that it would allow us all to be on a low-fat diet without having to eat any less fat. It’s the drug that does to the body what olestra does to food — both make it impossible for fat to be absorbed into the body.
Under normal circumstances, fat in food is broken down by an enzyme that allows it to pass through the intestinal walls and into the bloodstream, where it’s either used as energy or sent along to convenient storage areas (like the thighs). Orlistat interferes with that enzyme — called pancreatic lipase — so that about one-third of the fat you take in passes through the body undigested.
It’s an elegant idea, if you don’t think it all the way through. But there may be some uncomfortable side effects to blocking fat. “If you have more fat in the large intestine, you’ll have more fat in the stool,” says Xavier Pi-Sunyer, an obesity expert at St.-Luke’s Roosevelt Hospital in New York City. The effect, he said, would be bulky, greasy, foul-smelling stools. Anyone who has had weight loss surgery to shorten their intestines, so that fat is not absorbed into the body, can attest to how nasty this particular side effect can be. There may also be health risks: Robert Eckel, a professor of medicine at the University of Colorado, speculates that the increase in fat could heighten the risk of colon cancer. (One theory has it that fat in contact with colon cells explains the well-known association of high-fat diets with this cancer.) Another potential problem is that when fat isn’t absorbed in the body, fat-soluble vitamins are lost, too.
Finally, it’s likely that many patients on the drug would simply eat more fat. When people eat fake fat, which is now used in many foods, like ice cream and cookies, they don’t lose weight — they eat more to make up for the loss. The same thing would likely happen with fat blockers, says Callaway “The fallacy here is that people are fat simply because they eat too much, and all you have to do is reduce food intake or digestion of a certain nutrient.”
The human body is much more complex than that, and not likely to be fooled by such a crude trick as blocking fat. Over the millennia, the human body has learned to fight to hold on to its store of food; our survival has depended on it. “There are always compensatory mechanisms,” says Callaway.
Until scientists understand more about the underlying causes of obesity, dieting with drugs is likely to be hit-and-miss. Despite all the optimistic reports about new diet pills, we’re a long way from having a pill that would make us thin.
© Laura Fraser