Weighing In With a New Pill
Xenical, the new prescription fat-fighting pill due to arrive this week in pharmacies nationwide, is already getting mixed reviews. Many who are trying to lose a lot of weight are understandably eager to take the pill, approved by the Food and Drug Administration last month, because it blocks an enzyme in the gastrointestinal tract and decreases absorption of dietary fat by about 30%.
Obesity specialists, although generally predicting a brisk business for Xenical (orlistat), don’t expect it to beat out other options to become the only, or even the leading, star in the war on obesity. The real hope for effective obesity treatment, experts say, lies not with Xenical or any other single drug but with the host of drugs yet to come that will ultimately make up the smorgasbord necessary to best treat a complicated disease.
The next new obesity drug is probably two years, perhaps four, from FDA scrutiny, observers say. Among the contenders are drugs that suppress appetite or rev up metabolism.
Most often mentioned as a fat-fighting advance is leptin, the so-called anti-obesity hormone. First discovered in mice, leptin is made in fat cells and then circulates in the body and is believed involved in food intake and body weight regulation. In lab studies, mice deficient in leptin became obese and then shed weight when given leptin.
Amgen Inc., in Thousand Oaks, conducted widely publicized human studies of leptin. But ultimately, very few humans were genetically deficient in leptin. So Amgen and other companies are changing research direction.
The problem, says Lou Tartaglia of Millennium Pharmaceuticals in Cambridge, Mass., may be one of leptin resistance in the body. Now, Millennium is working to develop leptin in pill form to activate the leptin receptor in a way that the leptin of some obese people can’t, so appetite can be suppressed and metabolic rate boosted.
Late last month, Amgen announced it is abandoning its development of the first form of leptin it studied and moving on to second-generation molecules. Also under study is enterostatin, a substance produced in the pancreas that signals the brain that one is full and may curb an appetite for high-fat foods.
Researchers at Pennington Biomedical Research Center at Louisiana State University suspect that lean people secrete more enterostatin than do obese people and have recently begun human studies of the peptide, says Dr. George Bray, an obesity specialist there.
Companies Working
on ‘Exercise’ Pill
Many companies are hoping to develop a drug--in pill form--that would prevent neuropeptide Y, a powerful appetite stimulant in the brain, from sending its hunger signal, says Larry Brenkus, senior director of strategic planning for Millennium who tracks obesity research. And many companies are looking to beta3agonists. Beta3agonists are substances that activate receptors involved in thermogenesis, boosting fat-burning. If an effective beta3agonist is found, it could be a kind of “thermostat” or “exercise” pill, Brenkus says.
Obesity treatment research must take endless twists and turns, experts say, because it is clear there’s no single cause for obesity.
“There are genetic factors, as well as psychological, environmental, ethnic and behavioral,” says Dr. Morton H. Maxwell, UCLA clinical professor of medicine and director of the UCLA University Obesity Center. “You don’t know what the mix [of factors] is for each patient. A treatment that works for patient A doesn’t always work for patient B.”
Then there are societal pressures.
“In our culture, every time two people get together there is either food or drink or both,” Maxwell says. “It’s hard not to get fat.”
Obesity Increased
Greatly in the ‘90s
About 97 million U.S. adults are either overweight or obese, according to the National Heart, Lung and Blood Institute of the National Institutes of Health. From 1960 to 1994, the percentage of obese U.S. adults has risen from 13% to 22.5%, and most of the increase has occurred in the 1990s, with frequent restaurant meals and larger portions seen as contributing factors. For some obese people, Xenical might help. Doctors say others will be wary, remembering all too well the withdrawal in 1997 of fenfluramine, the fen part of the popular fen-phen diet combination, after it was linked with heart valve damage.
“There’s a general fear of obesity drugs” in the wake of fen-phen, says Dr. Richard Atkinson, an obesity specialist at the University of Wisconsin, Madison, who explains to patients that Xenical works in the gut, not the brain.
Xenical is meant for those with a body mass index (a measure of weight in relation to height) of 30 or more, or those with a body mass index of 27 or greater who have medical problems made worse by obesity, such as high blood pressure, diabetes or elevated cholesterol. (A person 5 feet, 5 inches who weighs 180 pounds has a body mass index of 30.) Patients are instructed to eat a calorie-reduced diet with no more than 30% of calories coming from fat and to take one pill with each fat-containing meal. Doctors say they don’t expect to be begged for a Xenical prescription by those needing to lose 10 pounds for swimsuit season, as many did with fen-phen, partly because Xenical can have some inconvenient side effects, such as oily spotting, fatty or oily stools and frequent bowel movements. (But Xenical, on the market in 17 other countries, is widely sold online via Internet Web sites by foreign pharmacies, sometimes after a physician approves information supplied by the patient.)
Study Indicated
Small Weight Loss
In Southern California, Xenical is expected to cost about $1.35 a pill, more at some pharmacies, and to cost a typical patient $120 a month. So how much weight loss is possible for that investment, which probably won’t be covered by insurance plans?
“We participated in one of the early trials,” Maxwell says. “It’s a rather small [weight loss] effect.”
In a study of 880 patients supported by a research grant from Hoffman-La Roche and published in January in the Journal of the American Medical Assn., the Xenical-treated patients lost on average a little more than 19 pounds while on a reduced-calorie diet; the placebo-treated group shed nearly 13 as they also reduced calories.
During the second year of the study, when the focus shifted to preventing weight regain rather than on additional loss, those on Xenical maintained about two-thirds of their loss; those who were switched to placebo for year two regained most of the weight lost while on the drug.
“Based on the published scientific studies, it doesn’t seem to be much more or less effective than what’s out there,” says David F. Williamson, senior biomedical research scientist in the diabetes division of the federal Centers for Disease Control and Prevention familiar with the research. The average weight loss with Xenical, he says, is comparable to that seen with Meridia (sibutramine), an appetite suppressant that became available last year.
Xenical might work best, says Maxwell, as a behavioral therapy, referring to the gastrointestinal effects that can happen to patients on Xenical, especially when they go overboard on fatty foods.
“We will use it in combination with phentermine or with Meridia,” says Atkinson of the University of Wisconsin.
“[Xenical is] a fabulous tool, but it’s not a miracle cure,” says Dr. Peter D. Vash, executive medical director of Lindora Medical Clinics who serves on the Hoffman-La Roche advisory speaking board. He expects that up to 25% of patients treated at his 32 Southern California clinics may benefit from the drug. Generally, patients can expect a 10% to 15% loss of total body weight over four to six months, he says.
“We found about a 10% weight loss,” adds John Foreyt, director of the Nutrition Research Clinic at Baylor College of Medicine, Houston, one of the testing sites for the two-year study published in JAMA.
Early Concerns About
Breast Cancer Mollified
Earlier concerns about a possible increased breast cancer risk with Xenical use have been put to rest, according to Dr. Jonathan Hauptman of Hoffman-La Roche, after an independent panel determined that virtually all of the cancers existed before the women began to take Xenical.
But even the most effective obesity medication can’t do it all. Sensible eating, regular exercise and a behavioral modification component are also crucial for weight loss success. Every Saturday morning, for instance, the UCLA University Obesity Center conducts patient consultations, support group meetings and lectures on such topics as how to order sensibly in a restaurant. Leah, a 50-something Los Angeles homemaker, wouldn’t dream of skipping it, crediting the Saturday sessions for much of her success in dropping 60 pounds. She takes in the lectures, participates in support groups and looks forward to positive feedback from the administrators. It takes up the whole morning, but it’s worth the time investment, she says.
“For me, it’s everything.”
*
* Times reference librarian Peg Eby-Jager contributed to this story.
* * Kathleen Doheny can be reached at kdoheny@compuserve.com.
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The Present and the Future
Ultimately, experts say, the successful obesity treatment won’t hinge on a single medication but a host of them, enabling physicians to tailor treatment to the individual. The following are medications in common use now and drugs under study. They work by suppressing appetite, boosting metabolism or blocking digestion.
Name: Meridia (sibutraamine)
Status: Available now
Action: Appetite suppressant
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Name: Xenical (orlistat)
Status: Available this week
Action: Blocks absorption of dietary fat
*
Name: Leptin
Status: Under study
Action: It’s a complicated process, but eventually a leptin pill might help overcome leptin resisitance and suppress appetite
*
Name: Enterostatin
Status: Under study
Action: Sends signal to the brain that you are full
*
Name: Beta agonist
Status: Under study
Action: Activates receptors involved in thermogenesis to boost fat burning
