America's pop culture can send a dizzying blur of mixed signals. On the one hand, its massive restaurant and food industries serve up an abundance of calorie laden, often unhealthy processed meals that have turned Americans into the most overweight people in the world.
America's pop culture can send a dizzying blur of mixed signals. On the one hand, its massive restaurant and food industries serve up an abundance of calorie laden, often unhealthy processed meals that have turned Americans into the most overweight people in the world. On the other hand, fashion designers and other purveyors of style pound home images of lean and muscular men and waiflike women, creating a national yearning for body types that rarely approach the reality of what most of us will ever look like.
Mediating between these two contradictory forces is a burgeoning weight-loss industry whose own feeding frenzy consumes billions of dollars each year. According to a report last summer in the Washington Post, Americans spent nearly $500 million on prescription and over-the-counter diet drugs in 1996. Meanwhile, they disgorged another $30 billion annually on diet programs and products, according to a National Task Force on the Prevention and Treatment of Obesity. The cost of excess isn't only economic-an estimated 300,000 people die each year from obesity-related causes.
But a combination of serendipity and science last summer threw the medicine and business of weight reduction into turmoil. As researchers scurried to determine what mechanisms in a combination of weight reduction drugs cause cardiac damage to millions of people, Eli Lilly and Co., the manufacturer of Prozac (fluoxetine), landed in the center of a controversy, though one not of its own making. Pitted against Nutri/System Weight Loss Centers, which is heavily marketing Prozac in combination with phentermine (Adipex, Fastin) as a weight-loss drug, Lilly now finds itself in a public relations, legal and public health quagmire as physicians and consumers agonize over what to do next.
A mere five years ago, it seemed as if researchers had discovered a magic bullet that could decimate fat and bring relief to millions who had fought the battle of the bulge unsuccessfully. A combination of phentermine and fenfluramine (Pondimin), according to University of Rochester investigators, caused people to lose more weight and keep it off for longer periods of time than those taking placebo. Weight-loss companies, always hungry for new injections of capital and for a sharper marketing angle, jumped on the bandwagon, and the "phen-fen" diet blossomed into a fad that swept the country. Last year alone, doctors wrote 18 million prescriptions for the combination. In the 14 months since the Food and Drug Administration narrowly approved Redux (dexfenfluramine), a more refined version of fenfluramine, physicians have written approximately 4.2 million prescriptions.
Even earlier concerns about side effects, the most troubling of which was a connection to primary pulmonary hypertension (PPH), did not stem the growing tide of individuals willing to manage weight with pills. And despite warnings that phen-fen should not be used for long periods of time and only in patients who met medical criteria for obesity, the combination nevertheless became a panacea for moderate weight gain.
In July, when the Mayo Clinic first reported that fenfluramine and dexfenfluramine were linked to heart valve defects in women who had used the drugs, the bottom began to fall out of the phen-fen craze. As more and more doctors began to back off the combination, the FDA intensified its investigation into the disturbing reports, ultimately withdrawing the drugs from the market in mid-September. Weight-loss centers had to consider options.
Nutri/System turned to Prozac. Hanging its hat on claims made by two physicians, it replaced the "fen" portion of the phen-fen combination with Prozac. By the end of the summer, it was marketing its newly revised NutriRx program that featured "phen-Pro," a combination of phentermine and Prozac it claimed was a "clinically tested prescription medication that targets the source of the problem, the part of the brain that controls hunger."
In a media blitz that included advertising and extensive press coverage, Nutri/System did something Lilly could never do because of strict federal laws prohibiting manufacturers from making off-label claims about prescription drugs. The weight-loss company, with over 500 locations in 47 states, began touting an off-label use for Prozac, at one point even suggesting that Lilly found the combination of its antidepressant and phentermine to be "very promising." Despite the view of many experts that the data supporting the "phen-Pro" combination was largely anecdotal, Nutri/System promoted its NutriRx program as a "medical breakthrough" offering "proven medications."
In a stinging letter sent in September to Nutri/System's Joseph DiBartolomeo, Ph.D., vice president for scientific affairs, Lilly officials denounced the use of Prozac in combination with phentermine for weight loss. Observing that Prozac "is not authorized for the treatment of obesity or weight control by the U.S. Food and Drug Administration," the letter accused Nutri/System of embarking "on a public campaign-including direct-to-consumer television advertising-that misrepresents the antidepressant Prozac."
Referencing statements attributed to DiBartolomeo during a Sept. 18 interview on ABC's "Good Morning America," the letter said that "Lilly has not indicated a belief that the combination of fluoxetine plus phentermine is 'very promising,' nor does Lilly have data from adequate controlled clinical trials that would characterize the combination as 'very safe' or 'something that could be very effective for people to lose weight with.'"
And in a final, more ominous warning that signaled that the dispute between the two companies has more to play out, Lilly alleged that the weight-loss company's "references to Prozac and Lilly for Nutri/System's commercial gain are violations of federal and state trademark law..." that "infringe Lilly's rights and misappropriate Lilly's good will." The letter then charged that "Nutri/System's advertising campaign creates potential public health issues and could mislead consumers."
In an interview with Psychiatric Times, DiBartolomeo, whose doctorate is in health education, nutrition and weight management, defended the off-label use of Prozac, arguing that there is no FDA prohibition against physicians using any approved drug for any purpose. He added that Nutri/System physicians prescribed the drugs only after customers met certain medical criteria.
Although he would not provide a copy of his company's protocols, calling them a "trade secret," DiBartolomeo said that individuals needed to weigh at least 20% more than their recommended body weight before receiving the drugs. In addition, he said, consumers undergo a complete physical exam and history before a physician determines the drugs are appropriate.
To support his company's use of the "phen-Pro" combination, DiBartolomeo relied on the reports of two physicians: Richard L. Atkinson, M.D., at the University of Wisconsin-Madison Medical School, and Michael Anchors, M.D., Ph.D., a Rockville, Md., family practitioner and a Georgetown University Medical School professor of medicine.
Atkinson's study, conducted several years ago, but reported in an abstract published in the March 1996 issue of FASEB Journal, involved 68 patients who took either Prozac and phentermine, or fenfluramine and phentermine over a 20-week period. The 42 patients who received Prozac lost 8.9% of their baseline body weight compared to 12.2% for the 26 individuals taking fenfluramine. Based on these results, Atkinson concluded that "in combination with phentermine, both fluoxetine and fenfluramine produce weight loss and improvement in complications of obesity, but fenfluramine is more effective."
In an interview with Psychiatric Times, however, Atkinson, a professor of medicine and nutritional science and director of the medical school's clinical nutrition program, denied that his study justified giving the phentermine/Prozac combination on a mass basis. "I feel uncomfortable in the position of senior author on this [abstract] if it is used as a justification for much of anything," he said. "[This] is clearly an anecdotal abstract, and I think it would be hazardous to draw any great conclusions about the safety or effectiveness from that. And this is, to my knowledge, the only thing in the literature that has used phentermine and Prozac."
Atkinson balked when told Nutri/System described his study as one "conducted at a major university medical school" that "determined that a combination of two medications made participants feel more full and less hungry."
"It's pretty scary, to say that," Atkinson said. Although the investigation was done with careful follow-up, he added, "what's in that abstract was not designed as a formal scientific protocol. It was a collection of cases and a comparison...I do feel uncomfortable with my abstract-not even a paper, an abstract-being cited as evidence for the safety and efficacy of this combination."
Calling some of Nutri/System's ad claims a "lot of hype," Atkinson lamented the commercialization of the treatment of obesity. "I'm sorry that medicine and physicians for so many years neglected obese people [to the extent] that obese people feel they have to go to a shopping mall to get their really severe disease treated," he said. "This is America. If there is a demand, whether it's for marijuana, or crack cocaine, or obesity treatment, people will seek it, and people will supply it. And that's what's going on here. I don't approve of using the tiny little abstract that I had, which was not even a formal study. I think they [Nutri/System] are vastly overblowing the data."
Anchors' claims for the phentermine/Prozac combination are the subject of his just-released book called Safer than PhenFen. A description of his clinical experience with more than 500 patients who were prescribed the Prozac combination over the past two years, Anchors' book concludes that "obesity is a biochemical problem in the brain and it can only have a chemical answer." In a letter published in the June 9 issue of Archives of Internal Medicine, Anchors concluded that "fluoxetine and some other selective serotonin reuptake inhibitors are just as effective and probably safer than fenfluramine in the combination with phentermine in the medical treatment of exogenous obesity. They should be used exclusively, instead of fenfluramine, until the results of large randomized, double-blind trials of both drugs become available."
It is this reliance on preliminary, largely anecdotal reports, lacking the scientific rigor of long-term, double-blind, placebo-controlled research, that has some experts seething at the mass marketing of the phentermine/Prozac combination. Even DiBartolomeo concedes that there is no long-term data. "What I anticipate happening is that now that there is some data on phen-Pro short term, that it's very effective and without side effects...we'll find that more researchers will begin to test this on a longer-term basis. But we do not have very long-term data at this point," he said, although he denies that using the drugs now is an inappropriate off-label treatment regimen.
But Paul Hamburg, M.D., an assistant professor of psychiatry at Harvard Medical School, and associate director of the eating disorders program at Massachusetts General Hospital in Boston, disagrees. "The thought that anyone's response to this surprise [the discovery of valvular heart disease]-which is going to result in death and a tremendous amount of morbidity, especially for obese patients who can least afford to have open heart surgery-should be to plunge ahead and try another untested combination of drugs, even for the medically obese... is the height of foolishness."
Peter D. Kramer, M.D., a Providence, R.I., psychiatrist and Psychiatric Times columnist whose best-selling book Listening to Prozac helped turn the antidepressant into a household name, agrees. "This is one of many approaches you'd rather have studied than just done for large numbers of people," he said. "When you see that there's a side effect that can occur in a large percentage of people-there were up to 30% of the people on phen-fen [who] had suffered some change in the heart valve-you really know that there can be less frequent side effects that only emerge from systematic study. So it does seem difficult to recommend this. It does seem worrisome. These are powerful medicines."
Despite the lack of studies, Anchors discounts the potential for side effects similar to those encountered by phen-fen users. Arguing in his book that, since its introduction in 1987, Prozac has been connected to only eight instances of PPH out of 19 million users worldwide, he surmises that the differences in the way Prozac and fenfluramine affect serotonin levels account for the prevalence of cardiac effects in phen-fen users. But even Anchors can't be sure.
Although controlled studies are already underway to determine the actual cause of the cardiac effects, results are months, if not years, away. American Home Products, through its subsidiary Wyeth-Ayerst Laboratories, manufacturer of the withdrawn drugs, has already begun a clinical trial aimed at targeting the cause of the valvular damage.
Nutri/System's nationwide campaign to boost sales of phentermine/Prozac combinations, without waiting for the hard, scientific data, according to Thomas Wadden, Ph.D., professor of psychology and psychiatry at the University of Pennsylvania School of Medicine, is "terribly irresponsible." Wadden, also director of the school's weight and eating disorders program, provided some of the subsequent data the FDA used to justify withdrawing fenfluramine and dexfenfluramine from the market. Rather than marketing a new, largely untested product, he said, Nutri/System ought to be giving echocardiograms to customers who got their phen-fen through its weight loss programs.
When Stanley Hertz, M.D., director of the eating disorders center at Schneider's Children's Hospital, at the Long Island Jewish Medical Center, first heard of the Mayo Clinic results at a Harvard conference over the summer, he immediately stopped prescribing the phentermine/Prozac combination.
"We don't know what the pathogenesis of the cardiac effects are of serotonin agonist medications and phentermine. So I, in good conscience, could not see giving it to patients...I took all of my patients off of it three months ago," Hertz said. "What is the mechanism that causes the cardiac effect? I would rather be conservative and do nothing from a lack of knowledge than be cavalier and do something."
The American Medical Association has also taken a cautious approach; acknowledging the physician's right to prescribe Prozac and phentermine for uses they deem appropriate, but at the same time warning doctors that there should be separate indications for each drug. If there were reasons to prescribe phentermine and Prozac to a single individual, for instance to treat obesity and depression, then the AMA would support it, said John C. Nelson, M.D., an AMA trustee. "But the combination of the two for weight loss we couldn't support. The reason we couldn't support it is because there's no clinical evidence for that...no studies done."
Nutri/System's marketing plan has its risks. Already, more than 100 lawsuits have been filed by individuals claiming injuries from phen-fen, and there are likely to be substantially more. Estimates are that the potential claims could reach over $3 billion as lawsuits spread beyond the manufacturers of phen-fen and Redux, to distributors, weight loss companies and physicians. DiBartolomeo declined to respond to questions regarding potential liability issues, including those claims asserted by Eli Lilly in its letter, despite numerous requests.
Four years ago, Nutri/System entered into a consent decree with the Federal Trade Commission (FTC) after it charged several weight loss firms with deceptive advertising by making unsubstantiated weight-loss and weight-loss maintenance claims. By the terms of the settlement, Nutri/System agreed not to misrepresent the performance or safety of any future weight-loss program, and was required to have scientific data to back up future claims about weight loss and maintenance.
"I can't confirm or deny whether we are looking at any company for possible order violations, but I can say that we monitor compliance very carefully," said FTC spokesperson Bonnie Jansen. "We monitor [weight- loss] program claims in general, and we've really focused on this area in recent months," she added. The FTC is empowered to seek monetary penalties of up to $11,000 per day, per violation.