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In fat war, doctors have few weapons

Though obesity is now the second-leading cause of preventable deaths in the United States, doctors face a surprising problem in fighting the battle of the bulge: To most patients, they don't have much to offer beyond advice about diet and exercise.

The only two drugs approved by the US Food and Drug Administration for long-term weight loss typically help patients trim 15 pounds or less, and one, orlistat, can cause severe indigestion.

The problem, say researchers, is that decades of seeing obesity as an aesthetic problem instead of a health crisis have left basic scientific questions unanswered about the process of getting and staying thin. As a result, the quest for a potent diet pill has been scattershot and sometimes tragic, from the addictive amphetamines prescribed in the 1930s to the popular fen-phen pills of the 1990s that caused heart problems.

"Not to disparage anyone, but this has been a backwater of science for many years," said Dr. Allen Spiegel, cochairman of the Obesity Research Task Force at the National Institutes of Health, which will spend 12 times more on studies of cancer than obesity this year.

But, with 64 percent of Americans considered overweight and 400,000 dying annually from obesity-related causes such as heart failure, the spotlight is starting to shine on the science of obesity.

"We're just too darned fat," declared Health and Human Services Secretary Tommy G. Thompson last month in calling on Americans to lose weight. To aid in the campaign, Spiegel's group is developing a research agenda for better understanding obesity while the Bush administration is seeking a 10 percent boost in NIH obesity research funding, to $440.3 million in 2005.

The research pace already has quickened from a decade ago, when very few researchers were dedicated to obesity studies, according to Russell Ellison, chief medical officer at the French pharmaceutical firm, Sanofi-Synthelabo. Today, at least 10 antiobesity treatments are being tested on humans, including Sanofi's drug rimonabant, which could help patients both lose weight and quit smoking by blocking the same molecular system that gives marijuana smokers "the munchies."

Most overweight Americans do not see a doctor about weight-loss strategies, turning instead to methods many doctors frown on, such as untested over-the-counter pills or controversial diets. A recent Harris Interactive survey found that 32 million Americans say they are on a low-carbohydrate diet, such as Atkins or South Beach, which many nutritionists say may be effective, at least in the short term, but may not be healthy.

The other method of weight loss gaining in popularity, stomach-reducing surgery, is generally reserved for people at least 100 pounds overweight, because the procedure carries a serious risk of death or complications. Yet the number of morbidly obese patients undergoing the procedure has tripled since 2000 to 103,200 last year, according to the American Society for Bariatric Surgery.

Prescription weight-loss drugs remain largely an afterthought, with sales dropping more than 30 percent since their peak year, 2001, according to statistics compiled by IMS Health, a health care consulting firm in Pennsylvania. They were outsold, 4 to 1, by over-the-counter diet pills last year. Doctors say the current prescription drugs have a limited role as part of a broader weight-loss program, but some say they are not worth the trouble. "People who take them can lose weight, but the losses are modest -- 5 to 10 pounds -- and we know if they stop taking the drug that they gain the weight back," said Dr. Mitch Gitkind, director of the Weight Center at UMass Memorial Medical Center in Worcester.

The lack of good medical options, say obesity specialists, reflects the fact that many medical professionals continue to view obesity as stemming from a lack of willpower rather than as a medical condition that leads to diseases the way high blood pressure and cholesterol do.

Even today, insurance companies are so reluctant to cover drugs strictly for weight loss that companies testing them tend to emphasize obesity-related conditions rather than weight loss. For instance, Ortho-McNeil's antiepilepsy drug Topamax appears to also help people lose weight, but the company says it is testing it only to help treat binge-eating disorder, a psychiatric condition that afflicts a minority of obese people.

Dr. George Blackburn, associate director of the Division of Nutrition at Harvard Medical School, argues that regulators subject weight-loss drugs to tougher safety standards than other drugs because they do not regard obesity as a true disease. For example, the FDA issued a warning about the safety of the two-pill combination fen-phen in 1997 after 43 women on the drug developed heart valve problems. Blackburn appealed for a chance to test the combination at a lower dose, but the FDA instead banned fenfluramine, the "fen" in fen-phen.

"If Tylenol were a weight-loss drug, no way would it be on the market with the number of deaths and liver diseases it had. You get into weight loss and you'd better be [as virtuous as] Caesar's wife because there's some major bias," said Blackburn.

Dr. David G. Orloff, director of the FDA's metabolic and endocrine drug products division, says that diet drugs face the same standards as other drugs, but his agency is very strict about the safety of products that will be taken over long periods. Almost any weight-loss drug would fall into that category, he said.

In recent years, moreover, the bigger issue has been the lack of weight-loss drugs coming to market at all. Though the pharmaceutical industry reports 10 or more drugs in some stage of human testing, none has come before FDA's commissioners for final approval since 1999.

"The FDA isn't holding anything up, and we haven't turned anything down," said Orloff.

At least one drug could come up for approval in the next year or two, with Sanofi-Synthelabo's rimonabant now in phase 3 human trials, the last stage before the company can seek approval to market the pill. People who took rimonabant for a year in an earlier study lost an average of 18.9 pounds.

But there have been so many disappointments in the search for an effective weight-loss drug that many researchers prefer not to focus on one prospect, instead stressing that the field has come a long way in a short time. They date the modern era to 1995, when Dr. Jeffrey Friedman at Rockefeller University isolated the gene for leptin, a protein that appears to prevent fat cells from being stored.

"The importance of leptin is not that it's going to be a treatment, but that it has opened up the field because it has proven that the fat cells are trying to send a message to the brain about how much fat is stored," said Dr. Louis J. Aronne, director of the Comprehensive Weight Loss Center at Weill Medical College of Cornell University in New York. In obese people, researchers have learned, these chemical messages lose their effectiveness, making it easier to gain weight than to lose it.

Since leptin's discovery, researchers have found many intriguing clues to the way metabolism works, including a protein called adiponectin, whose concentration tends to be low in overweight children. Understanding how these and other parts of human metabolism work together is key to developing drugs.

The other major frontier is the role of genes in shaping our bodies, said Dr. Osama Hamdy, an internist at the Joslin Diabetes Center. "Eating behavior and the response to eating is actually a very, very complex situation," said Hamdy. "The genetics still need to be discovered."

Scott Allen can be reached at allen@globe.com.

Drugs and surgery

As the obesity crisis deepens, more Americans are seeking weight-loss surgery, but sales of both prescription and overthe- counter diet drugs are declining. Some doctors complain that the prescription weight-loss drugs now on the market are only modestly effective.
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