Healthy Skepticism Library item: 6334

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Publication type: news

Goetz T.
The Thin Pill
Wired Magazine 2006 Oct 14
http://www.wired.com/wired/archive/14.10/thin.html?pg=1&topic=thin&topic_set

Full text:

The Thin Pill
75 million Americans may have something called metabolic syndrome. How Big Pharma turned obesity into a disease – then invented the drugs to cure it.
By Thomas Goetz

FOR PATIENTS, disease puts a name to an affliction. It answers that question we all face at one time

A month after the ADA statement, the AHA fired back with a response (written primarily by Grundy) rejecting Kahn’s analysis and reasserting the syndrome’s value. Reaven weighed in with a paper titled “The Metabolic Syndrome: Is This Diagnosis Necessary?” (No, he concluded, siding with Kahn.) Kahn came out with another paper, titled “The Metabolic Syndrome (Emperor) Wears No Clothes.” Grundy followed, declaring that “the common clustering of metabolic risk factors in obese persons is a fact of American medicine.” As the spitballs flew, the medical community gawked at the spectacle of two of the world’s largest and most powerful medical organizations engaged in a highly public dispute.

To some degree, Kahn’s gambit has worked. The ADA statement “really put the brakes on things,” says Donny Wong, a drug industry analyst who specializes in metabolic and obesity markets. The lack of consensus means some physicians and insurers aren’t on board – that, Wong says, prevents pharmaceutical companies from maximizing the metabolic syndrome market, which he estimates could be as big as $18 billion annually. But Kahn’s crusade hasn’t doused enthusiasm altogether. Time and again, physicians – scientists! – brush off his data with a hem-haw reply that the concept helps get people’s attention. At the ADA’s annual meeting in June, Kahn took the “con” side in a debate over metabolic syndrome. His data and presentation impressed, even intimidated, the audience. Until one doctor piped up that, whatever the data, his patients find the syndrome a useful concept. Kahn was clearly exasperated: “You can’t invent something just so you can treat patients,” he appealed to the crowd. “Medicine isn’t supposed to work that way.”

And yet it does. Clearly, there’s something about taking high blood pressure and obesity and calling it metabolic syndrome that makes it different – even if it’s unclear what that difference is. For Karen Cunningham and thousands like her, terminology matters. Likewise for physicians. In a doctor’s office, Grundy says, “physicians see a patient with diabetes or hyperglycemia and they focus so much on that, there is a real danger they will ignore blood pressure or lipids. It becomes tunnel vision. By saying that these all go together as metabolic syndrome, some of us believe it leads doctors to look at the whole patient and this patient’s total risk.”

Eager to paper over their dispute, executives at the ADA and the AHA have found common ground by focusing on obesity. In a joint statement released this past summer, they referred to “many unresolved scientific issues” about the syndrome, but emphasized that the core risk factors stem from the upsurge in obesity. “The growing prevalence of this condition,” the statement concluded, “threatens to undermine all of our recent gains to prevent and control chronic disease.”

But obesity is an old saw. No matter how many times obesity makes the covers of Time and Newsweek, it’s been impossible to change the public’s impression that being fat is simply a lifestyle issue, one that comes down to personal responsibility. If obesity is a health care crisis, the thinking goes, it’s one of our own making.

That’s what makes metabolic syndrome so compelling: It takes personal responsibility out of the equation. Turning the epidemic of obesity into a slightly smaller epidemic of metabolic syndrome puts it in the province of science, not lifestyle. With science, we’re not confined to a futile path of diet and exercise. With science, we get drugs.

What is a disease?

FOR THE PHARMACEUTICAL INDUSTRY, it’s a business model. Disease offers an opportunity to develop and market drugs that help people get better and, along the way, help companies make a profit.

In the late 1980s, researchers at the St. Louis University School of Medicine were investigating a question that had inspired decades of dorm-room symposia: Why do pot smokers get the munchies? The answer, the researchers discovered, is that the active ingredient in marijuana, THC, attaches itself to specific receptors in the brain, stimulating appetite. These receptors form what became known as the endocannabinoid system – a body-wide network that interacts with pain, memory, and hunger. Soon, pharmaceutical companies began developing endocannabinoid blockers, under the hypothesis that if engaging the receptors stimulates appetite, then blocking them would curtail it.

In 1996, the French pharma Sanofi-Synthelabo (now Sanofi-Aventis) began animal trials testing an endocannabinoid antagonist known as rimonabant. The results were encouraging: Obese mice given rimonabant ate less and lost 18 percent of their body weight. Then, in 2001, Sanofi began four human trials involving more than 6,600 patients; these were the largest obesity drug trials in history. The results were again impressive: Patients who took rimonabant for two years, combined with some diet and exercise, lost an average of almost 14 pounds – about 10 pounds more than those with the same routine taking a placebo.

What’s more, rimonabant doesn’t just promote weight loss. It improves HDL cholesterol and reduces insulin resistance. In other words, it’s an ideal match for metabolic syndrome. Rimonabant has side effects – some patients reported increased depression and moodiness – but it’s still hailed as the blockbuster drug of the decade. “We’ve been working on this problem for 20 years; we went through dozens and dozens of candidates,” says Lou Aronne, director of the Comprehensive Weight Control Program at Weill Cornell Medical Center in Manhattan and a lead investigator in one of the rimonabant studies. “Rimonabant hits the right receptors for the right problem. It’s no different than finding the statins,” the class of drugs developed for cholesterol treatment.

The cholesterol analogy is apt in many ways. For 50 years, high cholesterol was simply one of several risk factors for heart attack and stroke, along with high blood pressure, smoking, and stress. You treated it by changing your lifestyle. But the discovery of statins in the mid-1990s gave physicians a way to control cholesterol levels, and high cholesterol became more like a disease (now called hypercholesterolemia). Today, statins are the biggest drugs in the pharmaceutical industry; Lipitor sales alone will hit $13 billion this year. Metabolic syndrome is in a similar position today. Should the right drugs come along, the metabolic syndrome market “promises to be as big or bigger” than cholesterol, Pharmaceutical Executive magazine predicted a couple of years ago. And rimonabant, also known by its brand name, Acomplia, may well be the first of those drugs. JP Morgan analysts predict that rimonabant sales could hit $5 billion a year.

That potential has spurred Sanofi, the third largest pharmaceutical firm in the world, to launch a two-tiered campaign. First the company is promoting the drug itself, spreading the word about rimonabant in the medical and financial communities. (The company has drawn criticism by announcing its rimonabant results at industry conferences rather than in academic peer-reviewed journals.) But instead of offering rimonabant as just the latest obesity drug, Sanofi is laying the groundwork for the medical community to recognize metabolic syndrome – a disease that just happens to be treatable with rimonabant. The company’s education program includes sponsoring conferences, funding research, and providing certification courses for physicians. In the exhibit hall at this summer’s American Diabetes Association conference, for instance, Sanofi set up a multimedia display on the endocannabinoid system, complete with polarized glasses and a 3-D movie. There was plenty of literature on cardiometabolic risk and metabolic syndrome on hand, but there was no mention of the drug that might treat it. “Being the first one to come out, the burden of education is on us,” a Sanofi spokesperson says.

Sanofi’s campaign was supposed to culminate this year with the FDA’s approval of rimonabant to treat obesity, and perhaps this new disease, metabolic syndrome. But in February, Sanofi announced that while the FDA had found rimonabant “approvable,” the agency had additional questions and conditions before rimonabant could actually be approved. The company and the FDA won’t comment, but there’s speculation that the drug’s reported depressive side effects might be a concern. In early August, the company told financial analysts it remains “hopeful and confident” that rimonabant will be approved in the US (it went on sale in Europe this summer). But that’s unlikely to happen until 2007.

In the drug industry, finding disorders like metabolic syndrome is known as “developing new disease markets” or “branding a condition.” Industry critics have their own term for it: “disease mongering,” they say, shaking a finger at pharmaceutical firms for devising treatments for normal conditions of life – menopause, anxiety, obesity. But as tempting a villain as the drug industry makes, it’s not so clear that obesity is, in fact, a normal part of life. Blame corn subsidies or videogames or PepsiCo, but obesity has transformed our nation in the past 30 years. Diet and exercise? It’s easy to recommend, and it’s good in theory, but there’s surprisingly little proof that lifestyle intervention actually works as a weight-loss strategy. In the late 1990s, the Centers for Disease Control and Prevention initiated its Diabetes Prevention Program, a $174 million study hoping to prove that behavioral changes can induce weight loss. To make the point, the program went to extremes. The 3,000 participants received gym memberships and personal trainers, had their food provided, and were coached with daily phone calls from nutritionists – all for two years or more. After all that hand-holding, patients lost an average of 7 percent of their body weight.

The CDC hailed the study as proof that diet and exercise work, but it just as readily proves the opposite. After all, how likely is the average American to stick with – let alone be able to afford – such an intensive program? “It’s very easy to point the finger and blame people for not exercising enough,” says Aronne. “But we’re beginning to understand that there are metabolic issues going on.”

“THE FUTURE OF OBESITY IS DRUGS.” So proclaims Richard Atkinson, pathologist at Virginia Commonwealth University and president of the American Obesity Association, a drug industry-supported advocacy group. Atkinson is among the increasing number of scientists and physicians convinced that the body’s propensity to store fat isn’t something mere diet and exercise can correct. “We don’t consider obesity a disease because it’s easy to see,” he says. “But obesity is biochemistry, and drugs change biochemistry.” Obviously, the emphasis on drug therapies is a huge boon to the pharmaceutical industry, which has more than 350 obesity and metabolic drugs in the pipeline, many far along in clinical trials. Pfizer has CP 945598, its own cannabinoid antagonist. Manhattan Pharmaceuticals has a drug known as OE, which induces weight loss and matches up favorably with the components of metabolic syndrome. Eli Lilly has half a dozen drugs in Phase I trials. And so on. “The trouble is, it is extremely expensive and difficult to get an obesity drug to market,” Atkinson says, pointing the finger at the FDA, among others.

That could be about to change. For several years, the drug industry has been lobbying the FDA to make it easier to get obesity drugs to market. In 2003, the agency started to relent, announcing it would revise its Guidance for the Clinical Evaluation of Weight-Control Drugs, the agency’s checklist of standards for developing obesity drugs. First issued in 1996, the guidance has long vexed the drug industry, starting with the title itself (“weight control” implies a lifestyle problem, rather than a public-health issue). When the FDA invited public comments in 2004, 17 companies and two trade groups offered critiques of the guidance. (The American Obesity Association rewrote the entire guidance, line by line.) Almost unanimously, the industry called on the FDA to redefine obesity as a disease. “Obesity is a chronic disease, which may require pharmacotherapy,” Pfizer’s director of global R&D wrote. Others, including Merck and PhRMA, the pharmaceutical industry’s lobby group, went further, urging the FDA to recognize metabolic syndrome as a disease, too. “Given the association of Metabolic Syndrome with obesity, and the clear link with increased cardiovascular morbidity and mortality,” Merck’s vice president of global regulatory policy wrote, the company “proposes that FDA consider an indication for this syndrome.” The FDA has yet to issue its new guidance, saying only that it’s still under review.

Getting an indication is key, because it would further establish metabolic syndrome as a bona fide disease. So goes the domino effect of recognition: First the National Institutes of Health and the American Heart Association identify metabolic syndrome as a disease, then the FDA creates an indication, and then the HMOs – which have largely refused to reimburse patients for obesity treatments – agree to pick up the tab for metabolic syndrome prescriptions, thus making physicians more likely to prescribe them for their patients. The only drawback is that the market could be too big: If the HMOs see a diagnosis that fits 75 million Americans and a potential bill for $18 billion, they might simply refuse to pay it.

That, of course, is the demographic ripple effect of diseases like metabolic syndrome. As the medical establishment reaches further down the causal chain to identify more risk factors and spot them earlier, and as it assigns names, definitions, and treatments to these diagnoses, more and more people are swept into the disease net. Add in our genetic biomarkers and it’s clear that disease won’t be something we can avoid anymore. It will be something we simply have, just as we have freckles or wear glasses. We will all carry our disease portfolios and will be identified through our ailments – or more precisely, our inclinations toward certain ailments. Metabolic syndrome is just the latest step on this path.

On one level, this is the inevitable progress of medicine. But on another, it makes the idea of disease – or of health, for that matter – a meaningless abstraction. “We all already have a disease,” Kahn says. “Life – it’s a terminal disease, you know.”
Deputy editor Thomas Goetz (thomas@wiredmag.com) wrote about computer models of epidemics in issue 14.01.