After Fen-Phen

MARGE FRIEL HAS NEVER had much luck with diets. ""I can lose weight,'' she says, ""but keeping it off is more difficult. I lose my moti-vation.'' Fen-phen changed that. The 48-year-old secretary started taking the popular drug combination two years ago as part of a University of Pennsylvania weight-loss program that alsoincluded counseling. The weight on her5-foot-7-inch frame fell from 230 pounds to 160--and as long as she took her pills,it stayed there. But when Friel's doctors lowered her dose last winter to counter minor side effects, she promptly put on 15 pounds. She was still at 175 pounds in July, when researchers at the Mayo Clinic linked fenfluramine (the ""fen'' in fen-phen) to heart-valve abnormalities in two dozen patients. Concerned for her safety, Friel stopped taking the drugs altogether--and put on another 15 pounds in nine weeks. Her goal, for now, is to stay under 200,but she doubts she'll succeed on her own, and she can't help wondering whether she made the right decision. ""It's a trade-off,'' she says. ""I may be safer taking those drugs than I am being really, really heavy.''

Millions of dieters now face the same dilemma. Spooked by further reports of heart-valve trouble, the makers of fenfluramine (Pondimin) and dexfenfluramine (Redux) withdrew both blockbusters from the market last week. Though no one yet knows whether the drugs have actually harmed people, personal-injury lawyers are now suiting up for a litigation fest. Drugmakers, for their part, are racing to get other obesity treatments onto the market. And some obesity specialists are touting a new Prozac-based concoction as a safe alternative to fen-phen. Health experts agree that the questions surrounding fenfluramine were serious enough to warrant drastic action. But the withdrawal could cause harm as well as good. ""It's a fiasco for patients who have lost weight and improved their health,'' says Thomas Wadden, the psy-chologist who heads the University of Pennsylvania's weight and eating-disorders program. ""This potentially sets back obesity treatment many years.''

Redux and fenfluramine once seemed the answer to every dieter's dream. Like Prozac, they boost the effects of the brain chemical serotonin, curbing cravings and promoting feelings of satiety. Fenfluramine hit the U.S. market in 1973, but sales took off only recently, after researchers found that the stimulant phentermine could offset the fatigue fenfluramine induced. The combination was never reviewed for safety, but as word spread that it could zap fat, millions of Americans wanted prescriptions, and their doctors complied. Redux, a purified fenfluramine with fewer side effects, swept the country when the FDA approved it last year (chart).

Until this summer, there was no reasonto think the fenfluramines could affect people's heart valves. As far as anyone knew, the drugs' main hazard was a rare but deadly condition called primary pulmonary hypertension; untreated obesity posed greater risks than PPH, which affects only 18 to 46 of every million fenfluramine users. But the balance changed in July, when researchers start-ed identifying fen-phen users with waxy deposits on their heart valves. Though that condition often goes unnoticed, it can keep the valves from closing completely, compromising the heart's ability to pump blood. Alarmed by the reports, theFDA asked five clinics to perform echocardiograms (sonographic images that show theinside of the heart at work) on patients who'd taken Pondimin or Redux. When 92 out of 291 tests revealed valve abnormalities, the agency concluded that the drugs ""pre-sent an unacceptable risk at this time,'' leaving the makers little choice but to pull them.

Despite that dramatic step, it's not yet clear whether the drugs actually damage people's hearts or, if so, how. Diseased valves are rare among healthy young adults, but they may be more common in obese adults than anyone had previously realized. The patients in the FDA's survey didn't get echocardiograms before starting treatment, so before-and-after comparisons were impossible. Most experts believe the drugs are somehow to blame, since serotonin- producing tumors sometimes cause similar damage, but the evidence is still circumstantial. In coming weeks, researchers at Mayo and nine other centers will perform echo-cardiograms on 1,200 obese patients--400 who used fen-phen, 400 who took Redux and 400 untreated controls--to narrow the search for a culprit.

Pondimin has been sold in 85 countries for 32 years, and Redux has been circulating for 12 years. If the drugs were routinely destroying hearts, the problem would not have gone unnoticed for this long. But that won't keep people from suing. The Association of Trial Lawyers of America has already formed a 100-lawyer fen-phen group to press for damages. Paul Rheingold, the New York attorney who leads the group, accuses American Home Products (the conglomerate that makes Pondimin and distributesRedux) of failing to warn people of the drugs' possible hazards. That could be a hard sell, unless it turns out that the company knew of the problem. ""We had no evidence of it,'' says Marc Deitch, global medical director for Wyeth-Ayerst Laboratories, the American Home Products subsidiary responsible for the two drugs. ""In extensive clinical trials this problem never emerged.'' The lawyers also plan to go after individual doctors, whom Rheingold accuses of prescribing the drugs carelessly.

Lawsuits aside, the withdrawal will cost American Home Products an estimated $200 million to $300 million--not that big a blow to a company with annual sales of $15 billion. Many small weight-loss clinics will fail without pills to peddle. But analysts predict that such stalwarts as Weight Watchers and Jenny Craig will thrive as people who have relied on medication resume their struggles with diet and exercise. ""I think the public will have a very broad reaction against diet pills,'' says David Allen of Torrey Pines Securities, ""and that is sure to affect enrollment.'' The fenfluramine fiasco may also raise the bar for drugmakers seeking to market new obesity treatments. They'll face extra scrutiny from regulators, says Bill Fiala, a health-care analyst at Edward Jones. But with the fenfluramines out of the running, the potential jackpot is now ""bigger than anyone anticipated.''

Several drugs are already in the works. The first in line is Knoll Pharmaceuticals' Meridia (sibutramine), a compound that boosts serotonin less forcefully than the fenfluramines. The drug is now in the final stages of FDA review. A second candidate is Roche's Xenical (orlistat), which promotes weight loss by reducing intestinal absorption of dietary fat. A 1998 approval is possible. Other treatments are still at earlier stages of development. Scientists at Amgen Inc. and Millennium Pharmaceuticals are studying synthetic versions of leptin, a hormone that suppresses appetite when released by fat cells. Pfizer, meanwhile, is working on a drug that would block the action of neuropeptide-Y, a hormone that fosters feelings of hunger.

Any one of these drugs could be the next fen-phen, but some experts insist there is already a perfectly good alternative. They call it ""phen-Pro,'' for phentermine (the still-available appetite suppressant) and--you guessed it--Prozac. As a serotonin booster, Prozac can help diminish food cravings, and experts agree that it's not likely to damage heart valves, since it has a gentler effect on the serotonin system. Unlike fenfluramine, which forces cells to discharge more serotonin, Prozac and its cousins simply slow the removal of what cells have already released. None of these antidepressants has been approved as an obesity treatment, and many experts are leery of mixing them with phentermine. Eli Lilly, the maker of Prozac, says it has no plans even to study the phen-Procombination. But since both drugs are already on the market, any doctor can prescribe them together. Dr. Michael Anchors,a clinical professor of medicine at Georgetown University and author of a new book called ""Safer Than Phen-Fen,'' has treated 620 severely obese patients with phen-Pro. All but 10 have achieved significant weight loss, according to a report published in the Archives of Internal Medicine last June, and none has suffered serious adverse reactions.

Is phen-Pro the next wave? Nutri/System, a chain with 500 diet centers, gave up on fen-phen and Redux last month, but some of its doctors are now writing prescriptions for phen-Pro. And if half of their customers succeed the way University of Wisconsin patient Wendy White has, they're on to something big. The 45-year-old woman weighed 350 pounds when she started taking phen-Pro in June of 1996. Today she weighs in at 160. ""I'm constantly hungry without these drugs,'' she says, ""but they make it possible for me to succeed. They've saved my life.'' White is dismayed by the fenfluramine story--not because the drugs posed a hidden risk but because they were withdrawn so abruptly. Weighing 350 pounds can damage a lot more than your heart valves, she says. ""And if the treatment killed me, at least I would fit in my coffin.''

Phentermine and Pondimin (fenfluramine) were approved by the FDA decades ago, Redux (dexfenfluramine) in 1996. They seemed like quick fixes for the overweight-until this summer

July 8 Mayo Clonic reports valvular heart disease in 24 fen-phen users. The FDA issues an advisory to 700,000 doctors and clinics, asking them to report new cases.

Aug. 27 Mayo Clinic and Wyeth-Ayerst announce a study to investigate fen-phen and heart-valve disease.

Aug. 28 The FDA aks that prominent warnigns be added to the drugs-labeling.

Sept. 9 Flordia sets a 90-day ban on dual fenfluramine-phentermine prescriptions.

Sept. 15 The FDA requests a voluntary recall of fenfluramine and dexfenfluramine, but not phentermine. Wyeth-Ayerst complies, immediately pulling Pondimi and Redux from the market.