In the 1990s, America's desire to be thin led to a craze for diet drugs -- including the infamous Fen Phen "cocktail." A brief look at the background of the Fen Phen fiasco and its impact.
Nov. 13, 2003
A Climate of Obesity
In the early 1990s, America was as it is now: coming to terms with its increasing waistline. Obesity, defined by an individual's Body Mass Index (BMI), became a horrifying buzzword. (BMI is calculated by dividing one's weight in kilograms by one's height in meters squared).
A 1992 National Institutes of Health (NIH) panel concluded that about a third of the population was considered "overweight" (a BMI greater than 27.8 for men and 27.3 for women), an eight percent increase over the previous ten years. (The panel acknowledged that they had no real standard for defining obesity, and a 1998 NIH panel set the standard, defining "overweight" as 25-30 kg/m2 and "obese" as 30 kg/m2.)
The 1992 panel linked obesity to a number of health risks, among them cardiovascular disease, hypertension, diabetes, high cholesterol, sleep deprivation, and cancer.
However, the NIH panel also noted that the psychological burden on an obese individual was potentially more detrimental than the medical consequences. In America's image-conscious society, svelte supermodels like Cindy Crawford and Naomi Campbell ruled pop culture, and spandex-clad "fly girl" dancers were a ubiquitous part of music performance and television. Meanwhile, Oprah Winfrey kept her viewers updated daily on her efforts to lose weight and her personal chef wrote a best-selling cookbook devoted to eating healthily.
Despite the nearly constant stream of body-perfect imagery and information, Americans were doing less and less to improve their weight. According to a 1990 Gallup Poll, "Mirror of America," although 62 percent of women and 42 percent of men said they had the desire to lose weight, only 18 percent were actively trying to diet -- a figure that had not changed in 40 years, despite a large increase in the percentage of people dissatisfied with their weight. The NIH panel cited data finding that people who did try dieting would regain one- to two-thirds of the lost weight after a year, and after five years nearly all of the weight would come back.
In 1990s America, women, in particular, were looking for a solution, and the food industry was quick to oblige with new low-fat varieties of consumer products, from potato chips to tomato soup. By 1994, Snackwells reduced-calorie chocolate creme sandwich cookies had replaced Oreos as the nation's most popular cookie. If dieting was doomed to fail, then perhaps switching to reduced-fat versions of junk food would succeed. After all, why go to the trouble of healthy eating and exercise to lose weight if there's a painless short-cut available?
Into this fat-conscious milieu came the release of an Institute of Medicine study which stated that obesity should be perceived as not merely a problem of will power but as a chronic condition like hypertension. The study, which was released on Dec. 5, 1994, found 30 million Americans to be obese and suggested that the condition be treated as doctors treat other genetic and biological diseases -- with extended drug therapy or surgery.
The Fen Phen Phenomenon
Diet drugs had not been high on the public's radar, perhaps due to the lingering stigma of the habit-forming, amphetamine-based weight-loss drugs of the 1960s. However, by 1994, Isomeride, a non-addictive drug containing a derivative of fenfluramine, was already on the market in Europe. Fenfluramine works by releasing into the body extra amounts of serotonin, a chemical linked to a number of brain functions, including a feeling of satiety. An older version of fenfluramine, Pondimin, had been on the U.S. market since 1973, but according to former FDA drug reviewer Dr. Leo Lutwak, it had not been very successful because its moderate results were overshadowed by uncomfortable side effects, including drowsiness and altered moods. "Pondimin was not widely used. It just didn't make people feel that good," says Lutwak. The fact that the drug resulted in an excess of serotonin, a chemical often associated with psychological events, also concerned Lutwak. "To this day, I remain concerned about the neuropsychiatric side effects -- mood changes, memory loss, and so on. I don't think it ever has been fully explored."
In 1983, a University of Rochester pharmacologist named Michael Weintraub postulated that fenfluramine could be combined with the diet drug phentermine, a stimulant which would counter-balance Pondimin's negative effects. He ran a four-year study, funded in part by the NIH, on 121 subjects averaging 200 pounds, and found that the combination led to the loss of about 32 pounds on average. By 1992, the medical community was formulating its stance on obesity as a chronic disease, and in the wake of the study's report in the Journal of Clinical Pharmacology that same year, doctors began prescribing the fenflurmine-phentermine cocktail, or "Fen Phen," as an "off-label" combination (meaning it was not approved by the FDA).
In Dispensing with the Truth (2001), Alicia Mundy's book about the eventual Fen Phen disaster and ensuing legal battles, the author tracks the impact of Weintraub's findings after his results finally became public. "Reprints land in doctors' offices around the country and on the desks of health writers at major newspapers and magazines," Mundy writes. "It goes mainstream in February 1995 with an article in Allure, a woman's magazine. Then it's reprinted in Reader's Digest. Pondimin (and phentermine) come back from the dead." By 1995, Fen Phen had the attention of a mass American audience.
With the patent on Pondimin set to expire and the demand for Fen Phen increasing, the pressure was on to get a new drug, Redux, approved in the United States. A European version of the drug was already on the market overseas; the French pharmaceutical company Servier had formulated the treatment, stripping levofenfluramine (thought to be causing the drowsiness) from the Pondimin molecule and packaging the remaining dexfenfluramine, the active ingredient, as their version of Redux.
At an advisory committee convened by the FDA to discuss Redux's approval, there was contentious debate on the drug's safety. Critics cited data from the forthcoming release of the International Primary Pulmonary Hypertension Study (IPPHS) that linked derivatives of fenfluramine to primary pulmonary hypertension, a disease that thickens the capillaries in the lungs and makes breathing very difficult.
"What was particularly shocking to me was that on the heels of reporting that this drug caused a fatal, incurable disease in Europe, the company was planning to put it on the American marketplace," says Dr. Stuart Rich, who co-authored the pulmonary hypertension study. Despite testimony from Dr. Rich and the opinions of two experts on neurotoxicity, the FDA approved dexfenfluramine in April 1996. "Just three months after the introduction of Redux, doctors are writing 85,000 prescriptions a week," Time Magazine reported in a cover story titled "The New Miracle Drug?" The article also reported that 58 million Americans were clinically obese.
Given the risks associated with the drugs, some doctors cautioned that only those categorized as moderately to severly obese should take Fen Phen, but their recommendations were scarcely heard in the frenzy that followed Redux's approval and its ensuing $52 million marketing campaign. The drug was not only easy to obtain by prescription, but also accessible in weight-loss clinics and over the Internet. If the drug combination was banned in certain states, as it was in Tennessee for a time, then people simply drove across state lines to buy the drugs. In 1996, sales for Pondimin and Redux drew in $300 million for American Home Products (which has since changed its name to Wyeth), the company marketing them in the United States. The Wall Street Journal projected that Redux could gross $1 billion for the company in the coming years.
In reality, neither Pondimin nor Redux was very effective. The combination with the stimulant Phentermine put patients in a better mood, keeping them on the drug longer and away from indulgent comfort food, but a clinical trial for Redux found that people using the drug experienced only a 3 percent weight loss on average. Nonetheless, prescriptions for the drug combination topped 18 million in 1996.
In August 1997, an article in The New England Journal of Medicine by Dr. Heidi Connelly of the Mayo Clinic, revealed her experience treating women with pulmonary hypertension and heart-valve abnormalities. "We report 24 cases of unusual valvular disease in patients taking fenfluramine-phentermine," Connelly wrote. Her patients had been taking the drugs for as little as one month and for as long as 28, but each presented symptoms in various stages that Connelly attributed to the excess of serotonin in their systems.
As a result of these findings at the Mayo Clinic, and another 75 cases of heart-valve disease reported to the FDA in 1997, both Pondimin and Redux were withdrawn from the market on Sept. 15, 1997. American Home Products had turned a profit of $200 million by the time of its voluntary withdrawal of the two drugs. The FDA inferred from its data and from Dr. Connelly's study that 30 percent of the patients evaluated were presenting unusual echocardiagram results.
The heart-valve problems caused by Fen Phen can require risky heart surgery, and primary pulmonary hypertension is a devastating disease for which there is no cure. A story in the Sept. 1, 2003, issue of Forbes ("Bad Medicine") reports that Wyeth has paid $13 billion in claims related to Redux and Pondimin. However, lawsuits have been slowed in recent months due to the allegations that some of the tens of thousands of claims are bogus, a result of faulty echocardiogram readings by law firm-appointed doctors. According to an Oct. 7, 2003 story in The New York Times, ("Tough Questions are Raised On Fen-Phen Compensation") only a third of the 37,000 most serious claims have been addressed by the compensation trust set aside by Wyeth.
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At the Institute of Medicine's annual meeting in October 2000, obesity was the focus. In his remarks to the audience, Surgeon General David Satcher used a PowerPoint presentation to track the prevalence of obesity in the U.S. from 1990 to 1999. The maps show a steady increase of states reporting at least 15 percent of their populations to be obese. As of Jan. 1, 2003, only Colorado still fell under the 15 percent mark, and a USA Today article on Oct. 14, 2003 ("A Nation of Obesity") states that 65 percent of Americans are overweight or obese, with obesity defined as 30 pounds over a healthy weight.
Dr. George Bray, M.D., a professor at Louisiana State University, made remarks to the IOM meeting regarding the risks and benefits of current drug treatments. He stressed that because obesity is a stigmatized condition, it is unique from other diseases like hypertension for which people take medication. "The cosmetic purposes set a higher standard for safety than for drugs for which the cosmetic purpose doesn't exist," said Dr. Bray. He found that most physicians opt to treat the medical conditions that are associated with or caused by obesity, rather than the condition itself, because the available treatments for those are better. The two diet drugs on the market at that time, orlistat (Xenical) and sibutramine (Meridia), could achieve results of up to 10 percent weight loss -- the highest one can expect from any weight-loss treatment other than surgery, according to Dr. Bray. He estimated that no more than 2 percent of the obese population was taking anti-obesity drugs.
Similar to fenfluramine in that it affects serotonin levels in the body, Meridia was approved about two months after Redux and Pondimin were pulled from the market in 1997. At the time of its approval, it was known to be associated with high blood pressure and increased heart rate. On Sept. 3, 2003, Public Citizen called on the FDA for a second time to withdraw Meridia and sent out a press release citing evidence, culled from the FDA's database, of 49 cardiovascular deaths and 124 adverse cardiovascular reactions in people taking Meridia. The group also says Meridia has an impact on developing fetuses. As America continues to struggle with obesity, it appears the search for a healthy diet drug continues.
Editor's Note (11.17.03): Due to an editing error, the original version of this article did not include the fact that Meridia's manufacturer, Abbott Laboratories, disputes the claims made by Public Citizen, saying in a March 2002 press release that the group's original petition calling for the removal of the drug "is based on incorrect conclusions regarding both the efficacy and the safety profile of Meridia and is without merit." In addition, the original paragraph on Meridia stated that Public Citizen's press release cites deaths and adverse reactions "associated with the drug." In fact, Public Citizen said the deaths and adverse reactions occurred "in people using Meridia." According to Abbott Laboratories, a causal link between Meridia and the deaths or adverse reactions cited by Public Citizen has not been scientifically established. Click here to read Public Citizen's original petition filed with the FDA on March 19, 2002; click here to read Public Citizen's supplemental petition filed on Sept. 3, 2003. Abbott Laboratories' response to the supplemental petition can be downloaded here (in PDF format).
Kate Cohen is the editorial research assistant for FRONTLINE's Web edition.