What is a disease?

FOR PATIENTS, disease puts a name to an affliction. It answers that question we all face at one time or another: What's the matter with me? If there is a clear and precise explanation for what's wrong, then surely there is an equally clear way to get better.

At 228 pounds, Karen Cunningham knew she wasn't in great health. The owner of a small transcribing business in Louisville, Kentucky, Cunningham had gained 60 pounds during pregnancy in 1991 and just couldn't shake the weight. She always felt fatigued, and her hands and feet were often swollen. Doctors blamed it on her weight. "They said I just needed to lose the excess and I'd be fine," she recalls. Eventually, various specialists (rheumatologists, endocrinologists, internists) offered various diagnoses (high blood pressure, hypothyroidism, osteoarthritis) and prescribed various medications (Synthroid, Celebrex). But nothing worked. "I was really at the end of my rope, really thought whatever I had was going to kill me," she says. "And it would have, had I not found out what the problem was. You can't fight an enemy when you don't know who he is."

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The breakthrough came last December when her new endocrinologist diagnosed her with something called metabolic syndrome. She'd never heard of it. As she Googled to learn more, her chronic ailments – the weight, the high blood pressure, the lack of energy – started to make sense. They even seemed treatable. She's now on Glucophage and Avandia (which both regulate blood sugar) and has lost 20 pounds by cutting out carbohydrates. "Getting a diagnosis was a relief," Cunningham says. "I have hope now, whereas I didn't have any before."

Cunningham is among the first wave of Americans to be diagnosed with metabolic syndrome, a condition that, though only concretely defined five years ago, is now said to afflict as many as 75 million Americans – whether they know it or not. We sit, indeed, amid an epidemic of metabolic syndrome, a fact all the more remarkable because so few people are familiar with it. For this is no virus on the loose, no plague that has spread unchecked. Rather, metabolic syndrome is just a new way to think about a cluster of well-known and increasingly prevalent conditions. Metabolic syndrome is characterized by five risk factors: high blood pressure, high blood sugar, high triglycerides (fatty acids in the bloodstream), low HDL ("good") cholesterol, and obesity. Of the five, obesity – which is itself often referred to as an epidemic – is the most important, because the rise of the morbidly overweight is directly driving the rise in the syndrome. Metabolic syndrome is, in fact, almost indistinguishable from obesity – at least 85 percent of those who have the syndrome are obese or overweight.

The tidiness of that correlation makes it tempting to view metabolic syndrome not as an emerging fact of medicine, but as a fiction, wholly devised and disseminated by the pharmaceutical industry. After all, drug companies have long eyed obesity as the ultimate growth market – and they just happen to have an arsenal of pills poised to target it. Such cynicism isn't misplaced. The drug industry is among the most profitable in the world; pharma's knack for generating money makes oil companies look like lemonade stands. Drug firms owe their prodigious success to doing one thing exceptionally well. R&D? No – marketing. And as perfect an opportunity as obesity might be, it's also a legitimate health crisis that's only getting bigger. The one snag is that most people don't consider being fat a disease, they see it as a lifestyle problem. Which explains the appeal of metabolic syndrome. It's a simple, compelling concept that reframes the issue in scientific terms.

But is it real? In some ways, no. You can't see metabolic syndrome through a microscope, or detect it through a single blood test. Since it's a checklist of risk factors rather than symptoms, it stretches the way we think of disease. It's very much a human invention, a "syndrome" – that term researchers assign to things they don't quite understand. But in other ways, it's absolutely real. Though championed by drug companies, it's been defined and recognized by legitimate health organizations. And it's definitely unhealthy. You can't die of metabolic syndrome, but you can die of what it leads to: diabetes and heart disease.

And even if metabolic syndrome is just another term for obesity, it wouldn't be the first condition of daily life to become a disease. Alcoholism, clinical depression, and gastritis were all once considered personal problems that are now recognized as legitimate medical disorders, with all the trimmings of diagnosis, treatment, and pharmaceuticals. Many of these new illnesses, like osteoporosis, are widely accepted. Others, like fibromyalgia and female sexual dysfunction, remain fuzzy quasi diseases with shaky standing in the medical community.

The question now is whether metabolic syndrome will become accepted – or whether it will be dismissed as bad medicine, the product of an overeager illness industry. Proponents of the concept, including the American Heart Association and the World Health Organization, say the disease illustrates the cutting edge of diagnostics. It exists because we're only now recognizing that some very bad conditions can cluster and compound one another. Certainly metabolic syndrome is compelling to researchers: In the past five years, it has been the subject of no fewer than 15,000 studies, a number that puts it among the most researched conditions in medicine.

But some wonder if metabolic syndrome really identifies anything new. Skeptics, which include the American Diabetes Association, suggest that researchers, physicians, and pharmaceutical companies have been so hasty to embrace the disease (each for their own reasons), they've overlooked evidence that the science behind the diagnosis is flimsy and conjectural. These critics say that so-called metabolic syndrome lumps together risks we already recognize and monitor – or worse, that it's just a fancy way to describe obesity. By accepting it, we medicalize a lifestyle condition that we already know how to treat: with diet and exercise.

The debate is hardly academic. The pharmaceutical industry has spent millions of dollars developing dozens of drugs aimed at obesity generally and metabolic syndrome in particular. Many of those drugs are now or will soon be submitted to the Food and Drug Administration for approval. At the same time, the industry is lobbying the FDA to recognize the syndrome as a disease and to reconsider its approach to obesity drugs, a shift that would accelerate demand for new drugs.

Metabolic syndrome, in other words, could be the great disease of our age. Or it could be a sign of how diseased our age is, a demonstration of how certain we are that there is always a scientific explanation, a diagnosis, and perhaps a pill for what ails us. Either way, metabolic syndrome is a disease whose time has come.

What is a disease?

FOR DOCTORS, disease identifies why people are sick and suggests a course of treatment. For researchers, disease fixes an area of investigation, a mystery to be studied in the hopes of finding a cause or, perhaps, a cure.

Scott Grundy is the Billy Graham of metabolic syndrome. A longtime cardiologist and researcher, and director of the Center for Human Nutrition at the University of Texas Southwestern Medical Center in Dallas, Grundy is often found these days on the dais, spreading the good word. Over the last six months, he's discussed the syndrome at the Metabolic Diseases Drug Discovery and Development World Summit, the Obesity, Lifestyle, and Cardiovascular Disease Symposium, the Targeting Metabolic Syndrome conference, and other events worldwide. He's been evangelizing like this since 2001, when he chaired a National Institutes of Health panel on cholesterol education. The project was created to draw the public's attention to the dangers of high cholesterol. In its discussion of the risks for heart disease, the panel's report (known as the ATP III) called out a metabolic syndrome, a condition that, as Grundy put it at the time, "is as strong a contributor to early heart disease as cigarette smoking" – a remarkable statement, considering how established the risk from cigarettes was and how few in the medical community had even heard of metabolic syndrome.

Grundy was already a recognized pioneer in heart disease and cholesterol research when the ATP III report came out. In the early 1990s, he spearheaded the research proving that statin drugs lower cholesterol levels (statins, which include medications like Lipitor and Crestor, now generate $25 billion annually in sales). Now he's back in the vanguard, having written or cowritten about 90 papers on obesity and metabolic syndrome in the past five years.

The NIH first sounded the alarm on obesity rates in 1977, when the proportion of overweight or obese people in the US stood at about 40 percent. Today, two out of three Americans fall into that category, a statistic that makes obesity the most pressing public health issue of our day, Grundy says. "Have you ever been to the Orlando airport? Taken a look at the size of those people? This isn't going away." And, he adds, we have a good idea of their fate: They're more likely to develop diabetes (the number of diabetics in the US has almost doubled in the past decade, nearly all due to obesity) and more likely to die of heart disease than those who are not overweight. Boosting awareness of the syndrome, Grundy believes, may be our best chance to defuse this time bomb. By inserting a new disease into the causal chain, at a point before obesity turns into diabetes or heart disease, millions of at-risk people can be identified and treated. For many, a diagnosis of metabolic syndrome can get them off the couch in a way that a doctor tut-tutting about their extra pounds cannot.

It was 1988 when Gerald Reaven, an endocrinologist at Stanford, saw a cluster of symptoms that seemed to arise out of insulin resistance and dubbed it "syndrome X." Over the next decade, researchers began using terms like "insulin resistance syndrome" and "metabolic syndrome X." In 1998, the World Health Organization, noting the same cluster of risks, offered physicians a checklist of conditions that make up "the metabolic syndrome." The ATP III followed in 2001, identifying five factors – low HDL, high blood pressure, high triglyceride levels, high blood-sugar levels, and abdominal obesity – as the defining criteria for the syndrome. Meet any three of the five criteria and you have a diagnosis. (Though the multiple-choice route seems kludgy, it's not without precedent: Rheumatic fever and systemic lupus are likewise diagnosed through a mix-and-match of criteria.)

The ATP III codified what might have seemed like common sense into a new and suddenly dangerous ailment. With a bit of math, it became clear that metabolic syndrome was ubiquitous: As many as 50 million Americans fit under the umbrella (as the definition's cutoff points were tweaked, the number would climb to 75 million). People with the syndrome are twice as likely to die from – and three times as likely to have – a heart attack or stroke compared to people without it, according to the International Diabetes Federation (which offered its own definition of the condition last year). It's a disease more prevalent than arthritis and asthma combined.

In short order, the metabolic syndrome industry was thriving. The WHO assigned it an International Classification of Disease code – a crucial step that let physicians diagnose and refer to it in insurance documents. Conferences, research, and drug development followed. "A few things came together," Grundy says. "One, metabolic syndrome was becoming very common; with the rise in obesity, we've seen a rise in all these risk factors. Two, the drug companies saw an opportunity for new drug development, to see if they could target several things at once. So obesity is driving the syndrome, and also driving interest in the syndrome." Indeed, by last year, many pharma insiders were betting that FDA recognition of the disease as a legitimate drug target was imminent.

NOT EVERYONE IN THE MEDICAL COMMUNITY jumped on the bandwagon. In 2003, Richard Kahn, chief scientific and medical officer for the American Diabetes Association, began looking into the syndrome. He reviewed five years of research – some 10,000 papers in all – in order to assess whether the diagnosis had any clinical value. Was the syndrome, he wondered, a better indicator of long-term risk than any of the individual risks? In other words, was the sum greater than its parts?

Kahn's results, published in September 2005 as a joint statement of the ADA and the European Association for the Study of Diabetes, stunned the medical establishment: He found no proof that a diagnosis of metabolic syndrome better predicted long-term cardiovascular disease. "We found that the metabolic syndrome has been imprecisely defined," Kahn and his coauthors wrote. "There is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a cardiovascular disease risk marker." The statement continued: "Our analysis indicates that too much critically important information is missing to warrant its designation as a 'syndrome.' Until much-needed research is completed, clinicians should evaluate and treat all cardiovascular disease risk factors without regard to whether a patient meets the criteria for diagnosis of the 'metabolic syndrome.'"

A skeptic by nature – he's a committed atheist and seems to be always itching for a debate – Kahn is proud of the work. "We irrefutably present the evidence," he says. "As a way of saying you're at risk for something, it's a very poor predictor." He insists he didn't set out to take down Grundy or the American Heart Association, which has championed the concept. And he agrees that the risks underlying the syndrome are real. But Kahn says he grew alarmed that "a research tool" meant to draw attention to the obesity problem was hardening into a diagnostic set of rules. "It became codified into an explicit disease, and then the train left the station. But the definition is arbitrary, it's pulled out of the air."

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."