Predictions that a new prescription weight-loss pill will attract millions of frustrated dieters have some doctors worrying about a potential side effect that is worse than fat -- a deadly lung disease called primary pulmonary hypertension.
Lung specialists concede they have not proved that the drug, to be sold as Redux, triggers the disease. Even if the link is proved, the risk may be very small for the individual patient taking the medication.
But they said the affliction is so serious that the drug should be prescribed only for the truly obese -- and even then, with extreme caution. Primary pulmonary hypertension (PPH) is usually fatal and is treated with radical measures such as lung transplants or continuous infusions of medication by a portable pump.
"The risk is small but the magnitude of the disease once someone develops it is overwhelming," said Dr. Lewis J. Rubin, head of pulmonary care at the University of Maryland Medical Center and a leading authority on PPH.
Rubin warned that physicians could begin seeing an upsurge of the disease if Redux wins a large following not just among the obese, but also among people wanting to shed a few pounds.
Last month, the Food and Drug Administration approved Redux for people who are at least 30 percent over their desirable weight. The FDA said the lung complication was rare and that another suspected side effect, nerve damage, was not shown in humans.
Dexfenfluramine, the chemical name, was the top-selling prescription drug in France until authorities restricted its sale a few years ago. The action followed reports that large percentages of the country's PPH patients had taken the diet suppressant.
Wyeth-Ayerst Laboratories, which is marketing the drug in the United States, maintains that the drug's potential to relieve a growing national problem -- obesity -- overshadows any danger. The company contends that obesity itself poses a significant risk of sickness and death.
"The last thing I'd want to do is deprive people of a drug that has a much greater chance of doing good than harm," said Dr. Gerald Faich, a former Food and Drug Administration official who is serving as a spokesman for Wyeth.
Pulmonary hypertension is an extremely rare disease, occurring in about 250 new patients a year in the United States. Doctors don't know what causes it, but its features are well known.
Small arteries inside the lungs thicken and constrict, raising the lung's internal pressure and causing an increased resistance to blood flow. In turn, the heart weakens as it struggles to pump blood into the adjacent organ.
Patients become short of breath and cannot perform simple tasks without feeling exhausted. Many die of heart failure.
Rubin sees an unusually large number of these patients because he gets referrals from around the world. A few years ago, he noticed that many of his patients had taken two generic diet suppressants: phenteramine and fenfluramine. This coincided with the exploding popularity of the pills, which are prescribed singly or in a combination known as phen-fen.
In the past year, 12 of 55 pulmonary-hypertension patients treated by Rubin reported taking one or both diet drugs. Some had taken them for only a few weeks before getting sick, others for several months.
Now, he fears a sharp upturn in the deadly disease when dexfenfluramine makes its U.S. entry next month. Redux is chemically similar to its older cousin, fenfluramine, but is expected to become a bigger seller because it is approved for longer-term use.
With 50 million adults considered overweight or obese, the U.S. market potential is tremendous. The drug will cost $2.40 a day.
"I fear that we may be witnessing only the tip of the iceberg," Rubin said. "We're going to see a lot more patients who want this drug."
Redux and fenfluramine both work by increasing the availability of seratonin, a brain chemical that is associated with feeling "full."
Although the link between the drugs and PPH remains unproved, Rubin said his suspicions grew last year when he observed that one of the patients got better as soon as she stopped taking the medications. He had made the same observation in a patient a few years earlier.
Rubin, who has studied PPH for 20 years, said the improvements were extraordinary because the disease is irreversible when it occurs spontaneously.
"It was positively sudden," Lois Keil, 54, said of her recovery. The Greenbelt woman was hospitalized and placed on oxygen last fall when she could not walk across a room without feeling winded. She had been taking fen-phen for about four months.
Doctors discussed the possibility of an organ transplant, but that became unnecessary once they took her off the weight-loss pills.
"I could get up. I could walk. I could take a bath," Keil said. Discharged from the hospital, she returned to her job in Silver Spring.
Keil, who is 100 pounds overweight, said she had tried stomach stapling, intestinal bypass surgery and diets before taking the appetite suppressants. Now, she participates in a diet-and-exercise program.
"If her pulmonary hypertension hadn't reversed, she would either need to be on prostacyclin and/or be transplanted within the next year, or she'd be dead," said Rubin. Prostacyclin is a drug that is pumped into the bloodstream.
Other PPH patients face an uncertain future, their disease either getting worse or temporarily controlled. One had a lung transplant.
In France, Dr. Francois Brenot reported an experience similar to Rubin's. Over a five-year period, 15 percent of the PPH patients seen at the Hospital Antoine Beclere outside Paris had taken fenfluramine, dexfenfluramine or both for weight control.
Both doctors say they worry about a repeat of a pulmonary hypertension epidemic that occurred in Western Europe in the 1960s after the release of an amphetamine-like diet pill called aminorex. When the drug was banned, the epidemic disappeared.
"The risk of developing this disease is probably fairly low in the general population, but we consider this drug and maybe others as triggers for susceptible people," Brenot said. "Unfortunately, we don't know who is susceptible."
Faich, the Wyeth spokesman who runs a private consulting firm outside Philadelphia, said aminorex and Redux should not be compared because they work on different systems in the brain.
Debate expected to intensify
The debate is likely to intensify with the pending release of a large European study. Researchers compared the dexfenfluramine use among two populations: people with pulmonary hypertension and people not suffering from the disease.
The full study is embargoed until its publication, but a principal author outlined major details before the FDA advisory panel that reviewed Redux.
People taking dexfenfluramine were 23 times more likely to develop the disease than were people who didn't take the pills.
Rubin, who declined to comment directly on the study until its publication, said Wyeth overreached when it concluded that people taking Redux face just a 1 in 50,000 chance of developing PPH. No study has tracked the incidence of PPH among a population of people taking the weight-loss pill, he said.
Two area doctors who prescribe fen-phen said weight-loss drugs can be safely used if doctors closely monitor patients.
"We see people once a month -- if they have exercise intolerance or shortness of breath, we stop the medication early on," said Richard Rothman, a Baltimore doctor who treats obesity, addictions and depression.
"If you stop the medication at the emergence of a problem, it could prevent a serious problem."
Rothman, who considers the PPH risk to be remote, said he discontinued the drugs a few times when patients became short of breath. None, however, had developed the deadly lung disease.
Dr. Pietr Hitzig, a Timonium doctor who has built a large practice around fen-phen, said serious complications can be avoided by striking a balance between the two pills that make up the combination. An imbalance can trigger an excess of seratonin, as can the use of fenfluramine alone, he said.
"Never have I said that these medications are things you can throw around like candy," Hitzig said.
Pub Date: 5/28/96