In the wake of this week's world-wide recall of two hugely popular diet pills, scientists are grappling with a perplexing medical mystery: How could Redux and Pondimin, which work on the brain to control appetite, produce potentially severe heart and lung problems?
Nobody knows the answer. Indeed, experts from several scientific disciplines say it isn't yet proved that the big-selling diet drugs cause the lung-disease side effects or the troubling heart-valve problems that led the U.S. Food and Drug Administration to ask for the drugs' withdrawal.
One other perfectly plausible hypothesis: Because everyone taking Redux and Pondimin was presumably overweight, their obesity could be the cause of their heart problems.
On the other hand, researchers say that if the weight-loss drugs are to blame, a likely link is their highly potent effect on serotonin, a brain chemical that regulates moods and emotions.
Several psychiatric drugs, including the antidepressant Prozac, also work by manipulating the brain chemical -- but in such complex and different ways that there's no evidence the diet drugs' side effects implicate other serotonin drugs. Indeed, scientists believe Redux's and Pondimin's effects on serotonin are more potent and wide-ranging than other serotonin-based drugs.
Even as scientists race to untangle the serotonin-heart valve link, new evidence emerging this week suggests the research that led to last week's recall may be flawed. That research showed that 32% of 291 people who used the diet pills had heart-valve abnormalities identified by a diagnostic test called an echocardiogram.
But Richard Bowen, a diet doctor from Naples, Fla., says that a number -- he doesn't know exactly how many -- of the 200 patients he contributed to the FDA report were tested specifically because he had observed heart murmurs in them. "My group was a biased sample. I told them [the FDA] that."
The FDA confirmed that Dr. Bowen contributed a large number of patients, but declined to say how many. The agency's Web site (http://www.fda.gov/cder/news/slides/index.htm) says he contributed 122 of the 291 patients in the diet-drug sample, making him the largest of the five contributors. Asked about the doctor's concern that the sample was biased, Janet Woodcock, director of the agency's center for drug evaluation, said "that's not our understanding from him."
While many scientists feel there is strong evidence that the diet drugs do cause some damage, it's unclear how extensive the damage is, or whether it's reversible once the drugs are stopped. Many questions remain unanswered about the original Mayo Clinic report in July that linked the drugs to a troubling thickening of heart valves, as well as about the echocardiogram results.
"The women who have come to the FDA's attention in the five centers that were studied may be in some way different from the millions of women who took these drugs. A controlled trial is needed," says Marcia Angell, executive editor of the New England Journal of Medicine.
Researchers say that one way to solve the controversy is understanding precisely how serotonin is affected by Redux, the drug approved by the FDA last year and sold by American Home Products Corp. It is also affected by "fen-phen," the combination of the older American Home Products' drug, Pondimin, and another medicine called phentermine. The FDA recall affected Redux and Pondimin, also known as fenfluramine.
Serotonin is one of a large number of chemical substances, called neurotransmitters, that carry messages between nerve cells. It's implicated in the regulation of appetite, mood swings and depression, and even migraine headaches. It is also found outside the brain in the blood and gut. Many drugs besides Redux and Pondimin work through serotonin, including certain anti-migraine medicines. So do Prozac, sold by Eli Lilly & Co., and its chemical cousins, Zoloft, sold by Pfizer Inc., and SmithKline Beecham PLC's Paxil.
Heidi M. Connolly, a clinical cardiologist at the Mayo Clinic and the lead author of the New England Journal of Medicine report published on Aug. 28 that helped spur the massive diet-drug recall, says the 24 cases of heart-valve damages reported in the article (another 75 have since come to light) are unusual.
In each case, the valves have a "bizarre" thickened appearance that look strikingly like damage to valves in patients with a type of rare cancerous tumors that release serotonin into the blood. The valve damage is also similar to that caused by an old migraine drug, ergotamine, which may mimic the actions of serotonin.
But how the damage happens is unclear. "It's a mystery," says Glaxo-Wellcome PLC serotonin expert Michael Tyers "It is difficult to see how the drugs" [action on] serotonin in the brain can affect the heart."
Some top brain researchers speculate the unusually broad and potent actions Pondimin and Redux have on serotonin -- which are much different from other serotonin-based drugs -- may be responsible. Prozac and similar antidepressant drugs merely enhance the normal function of serotonin, explains George Aghajanian, a serotonin expert at Yale University in New Haven, Conn. By contrast, the diet drugs "come in like a sledgehammer and release serotonin in large quantities in all parts of the body," something that doesn't normally happen.
"The two drugs [Prozac and Redux] affect serotonin quite differently," says Steven Paul, the psychiatrist who runs research at Eli Lilly & Co.
Dr. Connolly of the Mayo Clinic also believes it's "unlikely" Prozac could cause heart-valve disorders but believes someone should study the matter. Five of the patients in her New England Journal study were on Prozac and other antidepressants as well as on the diet drugs.
But that isn't necessarily significant because so many Americans take Prozac. "In the past, we've said so many millions of people have taken [Prozac-like drugs], you'd think any problems would have come to light," she says. "But millions of people were taking these [diet] medications and it didn't come to light until now."
Scientists from Eli Lilly and Pfizer strongly defend the safety of their serotonin drugs. "As far as we're concerned, the chance [of heart-valve side effects] from Zoloft are nonexistent," says Joseph Feczko, vice president for medical and regulatory operations at Pfizer, referring to the company's Prozac-style antidepressant.
Officials from both Pfizer and Eli Lilly say they have not seen any reports of abnormal heart-valve problems in side-effects reports from tens of millions of patients who are taking the antidepressant drugs over many years.
Serotonin's normal function is to transmit messages between nerve cells. Once the message is sent, the serotonin is pumped back into the nerve cells so it can be used again. Prozac blocks some of these pumps, keeping serotonin present in nerve junctions.
However, Prozac's effects are self-limiting: The drug cannot increase serotonin levels in nerve junctions, or synapses, where serotonin is not already present.
By contrast, fenfluramine is believed to act indiscriminately on nerve cells, platelets and other places where serotonin is stored, squeezing out supplies of serotonin from their storage sites in cells.
Because serotonin is stored in many places in the body and performs a large variety of functions, this action could have an effect outside the brain. Some researchers speculate that Redux or Pondimin may release serotonin stored in blood platelets, where it somehow interacts with heart-valve tissue and harms it.
"Drugs like fenfluramine overstimulate serotonin in a way that Prozac [and similar medicines] cannot, says Steven Hyman, director of the National Institute of Mental Health. In particular, he supports the much-disputed assertion that fenfluramine kills the nerve cells that produce serotonin. "In animals, it's fairly clear that it can kill serotonin neurons," he says.
American Home says that evidence that nerve cells can be harmed is controversial, and the company has never seen adverse brain effects in millions of humans who have taken the drug.
Meanwhile, questions remain about the data linking the diet pills to heart-valve problems. For instance, none of the people with abnormal echocardiogram results had a baseline test before they used the drugs. So it's unclear whether they had previous valve troubles.
Moreover, most of the reported cases involved users of fen-phen-raising the question of whether the combination, rather than fenfluramine alone, could be responsible.
"We just don't know," says Dr. Woodcock of the FDA. "We're only saying this finding is alarming enough to pull the drugs off the market. We're going to learn much more in the next several months."
The FDA is now developing a standard procedure for physicians across the country to report cases quickly and efficiently. Meanwhile, American Home is setting up a rigorous clinical trial to try to get at the truth.
The company, in connection with ten research sites nationally, will give echocardiograms to 400 patients who have taken Redux, 400 who took fen-phen and 400 people of similar age, weight and other demographic factors who never took the drugs. "This should happen quickly," says Marc Deitch, global medical director for the company's Wyeth-Ayerst unit. "We're already up and running, and in two to three weeks all the patients should be echoed." Analyzing the results will take longer but "we're moving as rapidly as we can," he says.
A look at the patients who didn't take fen-phen, the so-called control group, will answer the question many people have been asking: What is the incidence of abnormal echocardiograms in the general population? Cardiologists estimate it would be anywhere from 1% to 5% in people who didn't take diet drugs -- but that's a pretty rough estimate.
Perhaps the most pressing question as yet unanswered is whether the damage -- if, indeed, caused by diet drugs -- is reversible. A Mayo patient who stopped taking fen-phen drug before surgery on defective heart valves, developed more disease in another valve two months later and her condition has continued to worsen. "We don't understand why that happened," says the Mayo's Dr. Connolly. "It's so early in this new disease, and we just don't know its natural history."
The FDA has two as-yet unconfirmed reports of patients who seemed to get better after stopping the drugs. Dr. Bowen, the Naples, Fla., doctor, contributed one of those patients: a 61-year-old from Sarasota who stopped taking the drug in December. "If her echo came across my desk today," he said, "she would still have some abnormalities but nothing like what we saw initially."
Material presented on this home page constitutes opinion of the author.
Copyright © 1997 Steven J. Milloy. All rights reserved. Site developed and hosted by WestLake Solutions, Inc.