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Metabolic syndrome: flawed science or clinical tool?

As experts debate the validity of a label, clinicians weigh in on using it in practice

From the December ACP Observer, copyright 2005 by the American College of Physicians.

By Janet Colwell

Metabolic syndrome—the condition characterized by clustering risk factors for heart disease and diabetes—has been described as a modern epidemic, defined by national medical organizations and even assigned its own disease code. Yet physicians are receiving conflicting guidance about what is gained—or lost—by diagnosing it.

From a clinical perspective, the differences come down to several key questions. Is giving patients a diagnosis of metabolic syndrome more useful than diagnosing and treating its single components, such as hypertension, obesity and glucose intolerance? And does diagnosing the syndrome make it easier to identify those at risk for heart disease or diabetes?

Two recent papers come to different conclusions. On the one hand, the American Heart Association (AHA) and the National Heart Lung and Blood Institute (NHLBI) published a scientific statement in the September 2005 issue of the journal Circulation providing new guidance on how to diagnosis and treat the syndrome. According to that statement, the metabolic syndrome deserves its label because it is characterized by the clustering of a particular set of risk factors for cardiovascular disease.

The report indicated that physicians who see the cluster of cardiovascular risk factors as a syndrome will think differently about how to treat it. The statement emphasized that diagnosis of the metabolic syndrome is first and foremost about the need for weight reduction and increased physical activity, which will reduce all of these risk factors at once. A report from the International Diabetes Federation published in the April 16, 2005, issue of The Lancet largely agreed with the positions taken in the September AHA/NHLBI statement.

In clinical practice, Sarah G. Thompson, ACP Member, said she diagnoses metabolic syndrome almost daily.

"When patients have that constellation of risk factors, I tend to treat them more aggressively than if they had just one," said Dr. Thompson, a general internist with the seven-physician Penn Medicine at Radnor in Radnor, Pa.

Plus, she pointed out, using the label helps when counseling patients. "I tell them that they have metabolic syndrome and that patients with this are at increased risk for cardiovascular complications," she said, "so it's even more important that they lose weight or get their blood pressure down."

On the other hand, however, the American Diabetes Association (ADA) came out with its own statement in September calling a diagnosis of metabolic syndrome misleading. Such a diagnosis, the statement said, wrongly suggests a clear pathophysiology and may draw attention away from other serious problems.

"[Diagnosing metabolic syndrome] diminishes the importance of the components," said Richard Kahn, PhD, ADA's chief scientific and medical officer and lead author of the strongly worded "critical appraisal" of the syndrome in the September 2005 issue of Diabetes Care. "For many people who have cardiovascular disease risk factors, such as a previous heart event or high cholesterol or smoking, diagnosing the metabolic syndrome has been documented to add nothing—and may detract from—the seriousness of the patients' problems and the attention these other risk factors deserve."

The syndrome's evolution

The term "metabolic syndrome" has become widely accepted since it was first described in the late 1980s by Gerald M. Reaven, MD.

At the time, Dr. Reaven theorized that insulin resistance was the underlying cause of cardiovascular disease because it made patients more susceptible to hypertension, hyperlipidemia and diabetes. Dr. Reaven, who called the condition "syndrome x," recognized that obesity was also associated with insulin resistance and recommended weight loss as primary therapy.

His work inspired further research into the relationship between cardiovascular disease and insulin resistance, and led to current definitions of what is now known as metabolic syndrome. ("Dysmetabolic syndrome x" now carries its own ICD-9 code: 277.7.)

The syndrome's most commonly cited definition comes from the National Cholesterol Education Program's Adult Treatment Panel III (ATP III), published in 2001. The panel stated that a metabolic syndrome diagnosis requires the presence of at least three out of five risk factors: abdominal obesity, elevated triglycerides, low HDL cholesterol, hypertension and type 2 diabetes. Obesity, it said, is not required for diagnosis but is a key underlying risk factor.

This year's AHA/NHLBI statement reaffirmed the ATP III criteria for diagnosis and identified abdominal obesity as a central characteristic. It also maintained that even though the syndrome is not a distinct disease with a single cause, diagnosing it helps physicians identify people at higher risk for heart disease and encourages them to intervene early.

Around the same time, however, the ADA and the European Association for the Study of Diabetes published their appraisal of the metabolic syndrome—and reached a different conclusion.

While it acknowledged that the syndrome has been "a useful paradigm," drawing attention to cardiovascular risk factors that tend to cluster, the paper cautioned physicians to wait for more research before labeling patients with metabolic syndrome, which has been estimated to affect 25% of the U.S. adult population. The syndrome is not well defined, the paper said, and there is considerable doubt about whether it helps predict who is at greater risk for heart disease.

Moreover, weight reduction and exercise—first-line treatments for metabolic syndrome—are also the recommended therapies for treating the individual risk factors associated with the syndrome. What advantage is there, then, the paper's authors asked, to diagnosing metabolic syndrome, when the risk delineated by it is no greater than the sum of individual risk factors?

According to the ADA paper, "Clinicians … should neither rely on nor require a diagnosis of metabolic syndrome to prescribe and encourage what is now a fundamental tenet of medicine—weight maintenance (or reduction), exercise, and a healthy meal plan."

Why make the diagnosis?

"If the answer is that we're trying to predict diabetes, why would we try to predict it with metabolic syndrome when we can predict it equally well if not better with a glucose test?" asked the ADA's Dr. Kahn. Similarly, "how does [metabolic syndrome] predict cardiovascular disease any better than the other tools we have?"

Dr. Kahn dismissed the idea that diagnosing the syndrome helps physicians counsel patients about lifestyle changes. "It's like saying that if we give people a scary term they will be more likely to act, but there's no data to suggest that," he said. "It's startling to think that physicians need to diagnose the metabolic syndrome before they can recommend weight loss and exercise to overweight or at-risk patients."

Building a syndrome around insulin resistance doesn't make sense, he added, because it's not clear to what extent insulin resistance contributes to heart disease. Insulin resistance may be just another factor, not the core of the problem, and there's no scientific basis for linking it to other factors that may lead to heart disease.

But some physicians contend the ADA critique is out of step with clinical practice. "The purpose of the metabolic syndrome construct is to identify a population of individuals who will really benefit from more intensive lifestyle modification," said Christie M. Ballantyne, FACP, director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine and Methodist DeBakey Heart Center in Houston. "ATP III is very clear about that."

According to Dr. Ballantyne, it's just easier and faster for physicians to assess whether someone has three of the five metabolic syndrome criteria rather than using the more accurate but more time-consuming Framingham risk equation.

Dr. Ballantyne, who has adopted the ATP III method in his own practice, said he goes through a five- to seven-minute discussion with patients explaining how their body processes proteins, carbohydrates and fats. He then emphasizes how diet and exercise can cut down or eliminate all their risk factors associated with the metabolic syndrome and reduce their chance of developing diabetes. People are often motivated to make changes, he said, once they understand that they have a problem with energy metabolism and that their excess weight is tied to their health problems.

And using the metabolic syndrome also encourages physicians to look for other risk factors when a patient presents with an increased waist circumference (see "Metabolic syndrome: criteria and concerns"), he said. That encourages physicians to think about lifestyle changes before prescribing drugs for hypertension, high cholesterol and other risk factors. "When someone like that walks in, I say, 'Here's someone who may be at increased risk for heart disease or diabetes, and there are some simple things [he] can do.' "

Dr. Thompson, in Radnor, Pa., said recognizing syndrome symptoms prompts her to check patients for associated conditions, such as polycystic ovarian syndrome in women and fatty liver disease.

And William B. Kannel, FACP, professor of medicine and public health at Boston University School of Medicine in Boston and director of the Framingham Heart Study from 1966-79, likewise acknowledged the usefulness of the syndrome in practice—even though he said metabolic syndrome adds little to existing methods of assessing cardiovascular disease risk.

"The basic researchers get concerned with the validity of the metabolic construct in which this is proposed," Dr. Kannel said. "But physicians are interested in user-friendly, clinically useful guidelines and this is something useful that you can do in your office."

While the syndrome does not improve existing methods of predicting heart disease, he said, it may be the best tool physicians have for predicting type 2 diabetes in time for preventive steps.

"At Framingham we've found that people who have this syndrome as defined by ATP III have about a fivefold increase of developing overt diabetes, so it's a very strong predisposing condition," said Dr. Kannel. "There are many diabetics who go years before their diabetes is diagnosed and meanwhile they have an accelerated atherogenic process taking place. That's another reason for detecting this early."

A work in progress

At the same time, Harold E. Bays, FACP, an endocrinologist, said that while diagnosing metabolic syndrome may encourage physicians to look at the "whole patient," he has reservations about the scientific inadequacies of the term.

"The way we've approached this is, 'Here's this cluster of stuff that all goes together that we see all the time in the office and we know that it increases risk for atherosclerosis, so we've got to call it something,' " said Dr. Bays, who is medical director of the Louisville Metabolic and Atherosclerosis Research Center in Louisville, Ky. But there are issues to resolve, he said, such as the fact that the term "metabolic syndrome" makes no attempt to identify any unified pathophysiological process.

Dr. Bays said he would like to see more research on what has been known since the 1970's: how weight gain causes fat cell dysfunction (adiposopathy) in susceptible patients, which in turn, contributes to metabolic diseases such as diabetes, hypertension, and high cholesterol.

"Once it is better accepted that improvement in adiposopathy improves metabolic disease," he said, "research efforts can better be directed toward developing therapies and drugs that treat a unified pathophysiologic process—'sick fat'—rather than the problematic 'metabolic syndrome.' "

According to Dr. Kannel, metabolic syndrome is a scientific "work in progress." As researchers further define the syndrome, he added, new components may emerge, such as increased fibrinogen, small dense LDL cholesterol or increased blood viscosity—all of which have been linked to insulin resistance.

The information included herein should never be used as a substitute of clinical judgment and does not represent an official position of ACP.

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