Requiescat in Pace —

Like the impish dufmanno, I’ve had troubling keeping up with my writing. As some of you may know, I’ve had a touch of the Reaven’s syndrome and I haven’t quite felt myself lately.

Reaven’s syndrome is better known as metabolic syndrome, a constellation of risk factors for heart disease with insulin resistance as the proposed underlying cause.

Reaven was the guy who brought metabolic syndrome to the forefront of the American medical consciousness, and you know you’ve done something major with your life when they name a disease after you.

In 1988, diabetes researcher Dr. Gerald Reaven gave the 1988 Banting lecture, which is an annual series organized by the American Diabetes Association on the latest and greatest in diabetes research. His speech would change everything we know about obesity and health by reintroducing syndrome X ,or metabolic syndrome, to the medical community.

First discovered in 1923, the theory posited that insulin resistance can cause a “clustering of hypertension, hyperglycemia, and gout,” which can then be treated therapeutically. (PDF) Reaven introduced hyperlipidemia (high triglycerides and low HDL, the “good” fat) and abdominal fat as additional risk factors for insulin resistance, and turned attention to metabolic syndrome’s role in cardiovascular disease (CVD).

The usefulness of a metabolic syndrome diagnosis is to institute lifestyle changes to prevent long-term cardiovascular damage. Research has mostly substantiated his theory and the global medical community immediately set out to conquer this new understanding of an old health threat. According to this study from the July 2006 issue of Clinical Diabetes, the World Health Organization and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) “published clinical definitions of the metabolic syndrome intended for use in assigning clinical diagnoses to patients.”

Although these definitions provided some uniformity to research efforts over the past 5 years, they also changed the focus of the metabolic syndrome to the clinical setting.

The definition of metabolic syndrome varies by the institution defining it, but the 2001 ATP III definition is the one most frequently used in diagnosing metabolic syndrome. Patients with three out of five of the following criteria are diagnosed with metabolic syndrome:

• Central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 36 inches(female)
• Dyslipidemia: TG ≥ 1.7 mmol/L (150 mg/dl)
• Dyslipidemia: HDL-C < 40 mg/dL (male), < 50 mg/dL (female)
• Blood pressure ≥ 130/85 mmHg
• Fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dl)

A 2004 revision (PDF) by the American Heart Association (AHA) reduced the waist circumference of women by one inch and the elevated fasting glucose to 100 mg/dL.

Despite all of the diagnostic certainty, the usefulness of metabolic syndrome as a diagnosis is remarkably controversial. And according to this 2005 scientific statement from the AHA and National Heart, Lung, and Blood Institute:

Although the metabolic syndrome is often referred to as a discrete entity, it is important to recognize, as noted earlier, that it is a syndrome and not a defined uniform entity. No single pathogenesis has been elucidated, nor may one exist. Thus, the syndrome could range from a cluster of unrelated risk factors to a constellation of risk factors linked through a common underlying mechanism.

Among the most outspoken critics of metabolic syndrome is Gerald Reaven. In a 2005 review in Clinical Chemistry, Reaven questioned the usefulness of metabolic syndrome as a clinical diagnosis:

[I]t appears that making the diagnosis of the metabolic syndrome does not bring with it much in the way of pathophysiologic understanding or clinical utility, and deciding that individuals do not have it because they fail to satisfy three of five arbitrarily chosen criteria may withhold relevant therapeutic intervention.

Remember that glorious day in March 2005 when the media announced to the world that the Father of Metabolic Syndrome announced that his theoretical baby was DOA?

But why the change of heart? How did the man responsible for such a seismic shift in medical attention go from sounding the alarm on metabolic syndrome to recommending its abandonment?

Reaven goes into greater detail, addressing beginning with the arbitrary nature of the cutoff points for the five indicators:

Perhaps the most crucial issue is that the diagnostic criteria for the metabolic syndrome did not result from a prospective study and do not represent the outcome of an evidence-based process, but are a reflection of the best estimates of a panel of “experts”.

The cutoffs chosen aren’t based on research, but on estimates, which already puts the metrics on shaky ground. But even more importantly, the ATP III definition gives equal weight to each of the risk factors (the “3 out of 5″ model means that any single risk factor is just as important as the other four), despite zero evidence supporting this stance:

Furthermore, not only are the cut points for the five chosen criteria arbitrary, there is no reason to believe that the individual elements of the metabolic syndrome are equally reflective of either the presumed basic defect or the risk of CVD.

He then goes on to question the usefulness of the “3 out of 5″ model.

Indeed, it is not clear what led to the decision to select five criteria (why not four or six?), nor why satisfying any three of five arbitrary criteria has more clinical utility than any two others.

For those three simple reasons alone, Reaven calls the usefulness of metabolic syndrome into question:

In light of the above considerations, there is ample reason to question the clinical utility of making a positive (or negative) diagnosis of the metabolic syndrome.

But that is not all.

Reaven then cracks open the five criteria and examines each on critically, beginning with waist circumference. According to Reaven, the apple shape is simply a risk factor for insulin resistance, which is, in turn, a risk factor for CVD.

Unfortunately, misinformed physicians like Dr. Rob Huizenga of The Biggest Loser, completely ignore the fact that even though 75% of those with insulin resistance are obese, over 75% of obese people will never get diabetes.

And as Dr. Reaven points out, central obesity isn’t an isolated risk factor:

Instead, obesity is a lifestyle variable that, along with physical inactivity, has an adverse effect on insulin-mediated glucose disposal.

Sedentary obesity influences the risk factor more than obesity alone, so simply measuring waist circumference is not informative on its own. Dr. Reaven then goes on to comment on the inefficiency of obesity “treatment”:

[A]lthough being overweight/obese increases the chances of an individual being significantly insulin resistant, by no means are all overweight/obese individuals insulin resistant, and, of greater clinical relevance, weight loss in overweight/obese individuals who are not insulin resistant does not lead to substantial clinical benefit. [emphasis mine]

Reaven concludes emphatically that recommending weight loss to non-insulin resistant has no clinical benefit, yet isn’t that the entire focus of our public health campaign about making all fatties thin? Isn’t our public health campaign about preventing disease in the fatties?

Yet, Dr. Reaven, the man who popularized metabolic syndrome, warns that putting metabolically healthy fat people on diets has no clinical significance for metabolic syndrome.

And then, he drops a bombshell.

You see, the medical community has been emphasizing waist circumference as a superior indicator of CVD risk over BMI. The argument goes that BMI doesn’t take lean muscle into account, so waist circumference can separate out the body builders from the fatties, since fatties will have a higher waist-to-hip ratio.

Therefore, when people point out that BMI sucks as a health metric, they simply say, “Yeah, but waist circumference is the real measure of health.”

Not so much, says Reaven:

At the simplest level, the values of the two variables were highly correlated in a recent analysis of data from ~20 000 participants in the National Health and Nutrition Survey (NHANES) from 1988–1994 and 1999–2000. More specifically, the r values were >0.9 in every subgroup analyzed and were essentially identical irrespective of differences in sex, age, or ethnicity.

Translation: BMI and waist circumference are essentially the same. Waist circumference and BMI tell almost the exact same story, and a shift in attention will do nothing to improve our diagnostic prognostications.

And as if that weren’t enough, Reaven goes on to point out that the WHO has expressed concern that waist circumference is also influenced by ethnicity and, therefore, an ethnicity-specific chart would be required to tease out an individual’s risk factor.

Obviously, that isn’t going to happen, since we no longer even distinguish between gender differences in BMI. And considering the “melting pot” of the United States, it would be nearly impossible to use such stratified values in clinical practice.

Finally, Reaven emphasizes the role body size should play in our diagnostic toolbox:

[I]t seems most sensible to simply measure height and weight, assess BMI, and know that having a BMI >25.0 kg/m2 increases the chances that an individual will be insulin resistant in the same way as, for example, having a family history of type 2 diabetes, essential hypertension, or CVD; being of non-European ancestry; or having acanthosis nigricans. It should alert one to look for the manifestations of insulin resistance – no more, no less.

Obesity is not some Vague Future Health Threat, but one of many indicators that should alert physicians to the possibility of insulin resistance. Period.

Pretty exciting stuff, eh?

But wait, there’s more!

The second criteria, known as impaired fasting glucose (IFG), has even more issues. To be diagnosed with diabetes, one must have a fasting glucose of over 126, but the newly christened “prediabetes” category includes those with a fasting glucose of 110 to 125, which is the range for IFG. Reaven questions whether prediabetes, or IFG, has any relevant predictive value:

Although there is substantial epidemiologic evidence that the higher the plasma glucose concentration, the more likely an individual is to develop type 2 diabetes, it is not as clear that the use of IFG provides a particularly effective way to identify either the presence of insulin resistance or to predict CVD risk.

He then goes on to reference a study which applied this definition of “clinically significant insulin resistance” and found that out of 490 apparently healthy individuals, just 27 had IFG. Of those 27, just 17 had insulin resistance. Reaven concludes that reliance on IFG creates “a test with great specificity (327 of 337, or ~97%), but low sensitivity (17 of 163, or ~10%).”

The predictive value for insulin resistance can be improved threefold by using impaired glucose tolerance (IGT) of 140-199. But even with this improvement, glucose levels failed to predict accurately in ~25% of the most insulin-resistant people.

The result, Reaven says, is that the IFG cutoff “occurs too infrequently to be very useful in the diagnosis of either insulin resistance or the metabolic syndrome.” And that was before the lowered the cutoff to from 110 to 100! The only consequence of this revision is that the prevalence of IFG has increased from 9.5% to 32.3%.

Compounding the problem, Reaven observed, is that IFG levels may be creating a problem where one does not exist:

Finally, the authors of both publications expressed great concern that adoption of the newly proposed ADA definition of IFG would have adverse public health consequences, with Borch-Johnsen et al. warning that use of the proposed new definition of IFG would create “a pandemic of prediabetes.” [emphasis mine]

Reaven concludes that the entire blood glucose category is essentially useless in identifying insulin resistance:

In the absence of obtaining this information, neither cut point for identifying patients with the metabolic syndrome proposed by the ATP III seems to be particularly useful.

Reaven compares how IFG accounts for 5-15% variation in insulin resistance, while high triglycerides can account for ~36% of the variability, making it a superior metric. Along with low HDL, dyslipidemia serves as the best “independent” risk factor for CVD, as well as suggestive of insulin resistance.

Hypertension is a mixed bag. High blood pressure alone does little to predict CVD risk, but hypertension in conjunction with dyslipidemia can be a recipe for disaster. Rather than treating all high blood pressure as a risk factor, Reaven recommends looking at the whole picture:

[I]t may be more important from a clinical standpoint to focus on whether an increase in blood pressure is associated with the dyslipidemic manifestations of insulin resistance, rather than questioning if the patient in question meets the diagnostic criteria for the metabolic syndrome.

Reaven concludes his paper by emphasizing that insulin resistance is not a disease, but a “physiologic state that greatly increases the chances of an individual developing several closely related abnormalities and associated clinical syndromes.”

Reaven then gives an incisive example of why the 3 out of 5 model may be doing more harm than good:

[I]magine two men, both of whom have blood pressures and plasma TG concentrations high enough to satisfy the ATP III criteria to merit the diagnosis of the metabolic syndrome, but neither had a large enough waist or a high enough fasting plasma glucose to qualify for that diagnosis. In fact, the only apparent difference between them was that the HDL-C concentration was 38 mg/dL in one of them, whereas the other one had a value of 42 mg/dL. By definition, one man has the metabolic syndrome; the other does not. Are these individuals fundamentally different? Would the treatment options differ in any substantive way? Does knowing that a patient has an increased blood pressure, as well as a high plasma TG concentration, not merit appropriate clinical intervention? Does it matter that the patient does not have the metabolic syndrome, because his WC, fasting plasma glucose concentration, and HDL-C concentration do not meet the arbitrary criteria established by the ATP III?

In the end, Reaven cites two large studies that applied the WHO and ATP III definitions of metabolic syndrome, both of which concluded that metabolic syndrome is useless at predicting a person’s risk for type 2 diabetes or CVD. And if metabolic syndrome can’t predict the outcomes which it was created to predict, then why are we still focusing so intently on it?

In March 2005, Dr. Gerald Reaven published the obituary for metabolic syndrome. Yet like the living dead, it walks among us, infecting millions of innocent people with fear and concern over a pseudo-disease with absolutely no clinical utility.

I think it’s high time we honor Dr. Reaven’s contribution to our understanding of obesity and health, and finally put this zombie “disease” to rest.