In late August, one of the nation's most respected drug researchers, Dr. Richard J. Wurtman, dropped a bombshell on the diet-drug industry. He presented new evidence that could explain why the once wildly popular obesity drug combination known as fen-phen seemed to cause serious heart problems. Because of these problems, fenfluramine, one of the drugs in the combo, was voluntarily pulled off the market a year ago. Phentermine, the other half of the pair, is still available and is now commonly used in combination with the antidepressant Prozac to treat obesity. But Wurtman warned that the Pro-phen combination could be just as dangerous as fen-phen.
That warning alarmed obesity experts because, unlike previous studies, it implicated phentermine. Wurtman suggests that phentermine's label should have been changed long ago to say that the drug alters the blood's chemistry by inhibiting the action of an enzyme known as MAO. The labels of fenfluramine and Prozac both carry express warnings that they should not be taken with drugs that act as MAO inhibitors.
Wurtman's claims have been furiously attacked by some diet-drug companies, already under siege from lawsuits related to the fen-phen combination. His research is "blatant, unsupported advocacy," said Medeva Americas Inc. It's "incorrect and totally misleading," complained SmithKline Beecham plc. "There is no evidence that phentermine is an MAO inhibitor of clinical significance in humans." Wurtman, director of Massachusetts Institute of Technology's renowned Clinical Research Center, and co-author Timothy J. Maher, a professor at Massachusetts College of Pharmacy, were accused of conflicts of interest and of supporting "junk science."
The conflict-of-interest charges arise because Wurtman is a co-developer of a competing diet drug--Redux, a form of fenfluramine. He is also co-founder of Cambridge (Mass.)-based Interneuron Pharmaceutical Inc., which made Redux. Wurtman dismisses the criticism, pointing out that Interneuron pulled Redux from the market worldwide last year and has no interest in trying to reintroduce it. Interneuron on Sept. 6 also negotiated a settlement of all lawsuits alleging harm from Redux.
Wurtman says phentermine's makers were irresponsible in failing to uncover the problem themselves. "I would hope that Medeva conducted their own research," he says. "The fact is, this should have been stated on the label." Medeva responds that the earlier research on phentermine "demonstrated that phentermine's MAO inhibitory potential is very weak."
WHOSE JOB? The controversy over phentermine highlights a long-standing problem at the Food & Drug Administration (FDA). The agency's top priority is to clear the way for the marketing of new drugs. Few of its resources are aimed at monitoring and updating the labels of older drugs. That job is left largely to the drugmakers, which must file yearly reports with any new information on their drugs. Medeva and SmithKline both say the FDA was notified of the earlier research on phentermine.
Why didn't the FDA act? Dr. James Bilstad, director of one of the agency's drug-evaluation offices, would not comment on the possible dangers of the phentermine combination or on whether the FDA considered changing the label. "There are hundreds of articles published on drugs all the time and not everything merits mentioning in the label," he said.
Wurtman and Maher maintain their work confirms research on phentermine that was first published in the early 1970s. That information, they say, should have been added to the drug's label back then. Maher agrees with the manufacturers that the early literature characterizes phentermine as a weak MAO inhibitor. But "the labels of [fenfluramine and Prozac] say `never give these drugs with an MAO inhibitor,"' he says. "They don't say `never give with an MAO inhibitor unless it's weak."'
This is a high-stakes battle. Phentermine, an amphetamine-like drug, has been a popular treatment ever since its approval as a short-term appetite suppressant in 1959. A generic version has been available since 1976. Sales soared in 1992 when doctors discovered that a combination of phentermine and fenfluramine worked better than phentermine alone. In 1996, sales of phentermine totaled $124 million but fell to $25 million in the first half of 1998 after fenfluramine was pulled off the market.
Wurtman claims it's the combination that is the problem. Fenfluramine and Redux, as well as anti-depressants such as Prozac, raise levels of a brain chemical called serotonin that affects appetite and mood. Many scientists believe that if too much serotonin is released, it may damage heart valves and lead to a serious lung condition called primary pulmonary hypertension. The companies say the link between serotonin and heart damage has not been proven.
The body has two ways of mopping up excess serotonin--by absorbing it into blood platelets or soaking it up with the MAO enzyme. Phentermine inhibits the action of MAO; Prozac, fenfluramine, and Redux prevent the platelets from soaking up serotonin. When phentermine is given in combination with one of the other drugs, the body has no way to soak up excess serotonin, Wurtman says.
DATABASE DISCOVERY. Maher first decided to investigate the fen-phen combination in the spring of 1997. "I am always concerned about combination drugs because combinations are not approved by the FDA," he says. He did a database search of previous studies and found several from the 1970s suggesting that phentermine is an MAO inhibitor. He alerted Wurtman, but the two did little to follow up, because fenfluramine had been taken off the market.
They took a second look this summer, after Maher learned that obesity clinics are now regularly prescribing the Pro-phen combination. Wurtman, meanwhile, was curious as to why fenfluramine and Redux had caused heart problems in the U.S. but few cases had been reported in Europe, where the drugs were not normally taken with phentermine. He gave phentermine to 17 healthy mit students and was surprised to discover that their serotonin levels almost doubled. "That's when I remembered something that Tim had told me almost a year ago--that phentermine is an MAO inhibitor," he said.
The two scientists assembled a team of researchers to conduct experiments on rats. They discovered that phentermine did indeed block MAO in the animals in much the same way researchers had reported in the 1970s. Maher and Wurtman put together a presentation for the International Congress of Obesity in Paris in early September and announced their findings to the press.
The drug's manufacturers saw red. Medeva issued a five-page statement arguing that Wurtman and Maher merely presented "a hypothesis in search of facts." Dr. Arthur E. Weyman, an adviser to American Home Products Corp. and professor of medicine at Harvard Medical School, also questions the researchers' conclusions, saying: "Nobody even knows that it is serotonin that is involved in the heart-valve problems."
"WE NEED GUIDANCE." Wurtman and Maher insist that they made no final conclusions. Their report says that phentermine "probably increases serotonin" when given with fenfluramine or Prozac. "I think we need guidance on this from the FDA," says Maher.
The two scientists have moved on to other research, and Wurtman says he hopes other studies will more closely examine the implications of taking phentermine in combination with Prozac. But the FDA is famously short of resources to keep track of new information on drugs already approved. "These drugs are tested on only a couple hundred people, and the rare complications only occur when they are used on hundreds of thousands of people," says Dr. Alan L. Hillman, director of the Center for Health Policy at the University of Pennsylvania. "Unless some horrible thing happens, the drugs stay labeled that way."
Wurtman's work doesn't explain all the diet-pill problems. Studies just published in the New England Journal of Medicine found that Redux and fenfluramine can be linked to heart valve damage even when taken alone. Meanwhile, obesity clinics continue to prescribe Pro-phen, figuring the benefits outweigh the risks. That may be so, but the patient might still like to see those risks pointed out on the label.