Weighty Problems

FOR A WHILE THERE, IT SOUNDED great. Take a couple of pills, get rid of those pesky 10 pounds hanging around since last Christmas. The drugs - a tongue-twisting pair called fenfluramine and phentermine, or fen-phen - were intended to treat serious obesity, not cosmetic insecurity. And sure, there were risks. But it's easier than hitting the gym or eating another salad, right?

So it seemed until last week, when doctors at the Mayo Clinic and the MeritCare Medical Center in Fargo, N.D., released a series of case studies that suggested fen-phen might have a potentially fatal side effect, a rare malfunction of the valves inside the heart. The studies aren't anywhere near conclusive - they describe only 24 long-term fen-phen users, and the Food and Drug Administration has found nine others. But the news has the weight-loss community worried. Last year prescriptions for fen-phen and another anti-obesity drug, Redux, were in the millions (chart), up more than 200 percent since 1995. These numbers were boosted by the drugs' use in diet centers.

Fenfluramine and phentermine have been around for more than two decades, and both are FDA-approved appetite suppressants. But it wasn't until 1984 that their combined effects were recognized. Doctors prescribe them together to minimize side effects (fenfluramine induces fatigue, and phentermine amps people up). But both the FDA and fenfluramine maker Wyeth-Ayerst have warned against this off-label use. ""Fenfluramine... is only indicated for the short-term treatment of obesity,'' says Philip de Vane, U.S. medical director at Wyeth-Ayerst. ""And it's not recommended in combination.''

No one knows how fen-phen might cause valvular disease. The case-study patients' heart valves were coated with a white, waxy substance that kept them from closing fully. Blood leaked back into their hearts, forcing them to pump too hard. The valves looked as if they'd been damaged by high blood levels of the neurotransmitter serotonin, says Heidi Connolly, a Mayo cardiologist and lead author of the paper. Fen-phen (and Redux, which wasn't implicated) increases brain serotonin, producing feelings of satiety. But heart valves would only encounter plasma serotonin, which fen-phen actually decreases.

Connolly admits that her group's findings, appearing in the New England Journal of Medicine next month, are far from definitive. (She, the FDA and Wyeth-Ayerst are developing a more detailed study.) The patients were all women, and 23 out of 24 lived within 200 miles of each other, so the results may be explained by a statistical quirk, or something in the women's environment. Also, case studies don't indicate the size or extent of a hazard - though that didn't stop a class-action suit against Wyeth-Ayerst and the various makers of phentermine filed last week. Co-plaintiff Natalie Gardner, a 35-year-old Head Start worker in San Diego, believes her high blood pressure and other cardiopulmonary problems resulted from fen-phen. ""I want doctors to stop issuing these two drugs together like candy,'' she says. Wyeth-Ayerst expects to ""contest vigorously.''

All drugs have side effects. The question is, how does the risk-benefit equation balance out? For those who are more than 20 percent overweight, the risk of adult-onset diabetes is clear and present. For the merely pudgy, the cost-benefit analysis should shift considerably. Until the pills' effects are better understood, the gym and that salad may be the way to go.

The number of prescriptions for diet pills phentermne and fenfluramine continues to rise. Pill sales in 1996 alone: $312 million

DRUG PRESCRIPTIONS, IN MILLIONS Phentermine Fenfluramine 1994 2.87 .37 1195 4.72 1.92 1996 11.21 7.03 1997* 5.49 3.25

*Jan.-May. Source: IMS America