Metabolic Syndrome: The Controversy Continues.

Metabolic Syndrome:

The Controversy Continues.

Prof. Dr. Hesham Salah Eldin MD, FACC, FSCAI

Professor of Cardiology, Faculty of Medicine, Cairo University

In 1988, Reaven introduced the concept of "metabolic"(1-3) or "insulin resistance"(4) syndrome in his landmark publication (5). He postulated that insulin resistance and its compensatory hyperinsulinemia predisposed patients to hypertension, hyperlipidemia, and diabetes and thus was the underlying cause of cardiovascular disease (CVD). Although obesity  was not included in Reaven's seminal paper, he acknowledged that it, too, correlated with insulin resistance or hyperinsulinemia, and that the obvious "treatment" for what he termed "syndrome X" was weight maintenance (or weight loss) and physical activity.

Years after the term metabolic syndrome was first coined, controversy continues over the validity of treating this clustering of certain risk factors as a separate condition. While different organizations use different definitions, metabolic syndrome is generally defined as having any three of the following: increased waist circumference, elevated triglycerides, reduced HDL cholesterol, elevated blood pressure, or elevated fasting glucose, with the World Health Organization (WHO) definition specifying that diabetes/insulin resistance/impaired fasting glucose/impaired glucose tolerance be one of the three (6).

The metabolic syndrome was shown to be associated with an increase in cardiovascular outcomes and, and a new meta-analysis suggests that it increases CVD risk by twofold, and all-cause mortality by 1.5-fold (7).

Individuals who met standard criteria for the metabolic syndrome had at least a 60% increased age- and sex-adjusted risk of new-onset atrial fibrillation (AF) over four and a half years in a prospective community-based study conducted in Japan (8). The study also found that AF risk rose with the number of metabolic-syndrome components a person displayed and that most of the syndrome's components, save raised triglycerides, were individually predictive of AF.

People with the metabolic syndrome were also significantly more likely than others to experience a decline in cognitive function, independent of previous cardiovascular disease, depression, or APOE genotype, in a study of generally healthy adults aged 65 and older who were followed for four years (9). In particular, hypertriglyceridemia and low HDL-cholesterol levels were associated with declines in global cognitive function, and diabetes was associated with deteriorating memory.

Some investigators compared the predictive value of the metabolic syndrome with that of the Framingham risk prediction model. A recent post hoc analysis of the placebo-treated groups in the 4S (Scandinavian Simvastatin Survival Study) and AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) trials (10) showed that the increased event rate in subjects with the metabolic syndrome remained significant after adjustment for the Framingham 10-year risk score, suggesting that the syndrome carries risk not captured by Framingham risk scoring. It should be noted, however, that this analysis omitted diabetes (or any other measure of glucose intolerance) from the metabolic syndrome definition, thereby requiring patients to meet three of the remaining four factors to qualify. This modification may have biased their findings. Also, they dichotomized the Framingham score (i.e., >20% risk vs. ≤20%), so a precise determination of the predictive ability of Framingham versus metabolic syndrome could not be determined.

But in spite of this, and for almost as long as the metabolic syndrome has been around, disagreement over its relevance has always surfaced. This came to headings in 2005 when the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) issued a statement discouraging the use of the term metabolic syndrome, and then a few weeks later, the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) released their own statement encouraging use of the metabolic-syndrome concept

Years later, it appears that little has changed, with critics of the concept of metabolic syndrome having the following arguments:

• First, some of the criteria used for defining the syndrome are ambiguous or incomplete (11-12) including the method for measuring waist circumference.

• Second, it is apparent that the definitions of the syndrome differ in the criteria listed. For example, micro albuminuria is listed in the WHO criteria but not in the ATP III; insulin resistance is relevant for WHO but not for ATP III.

• Third, the originally stated rationale for the criteria is that the syndrome components are associated with insulin resistance (11-12). But there is considerable doubt whether all patients with the metabolic syndrome are indeed insulin resistant.

• Fourth, the fact that there are cut off points for the various

risk factors in the definition of metabolic syndrome implies that values above the specified thresholds are associated with excess risk, while lower values are not, which may not be very appropriate when continuous variables are converted to categorical variables which provides support for calls to replace the categorical definition of metabolic syndrome.

• Fifth, the term metabolic syndrome does not tell the physician what the main driver of risk is.

• Six, and importantly, patients with metabolic syndrome may not be at more at risk of future myocardial infarction (MI) than those with diabetes or hypertension alone, as recently suggested (13).

A study analyzed data from the INTERHEART study, a case-control study of incident acute MI that involved 12 297 cases and 14 606 controls from 52 countries. They classified the study participants using the WHO and International Diabetes Federation (IDF) criteria for metabolic syndrome, and their risks for MI were compared with the individual metabolic-syndrome component factors. Results showed that metabolic syndrome was associated with a two- to three-times increased risk of MI, but the same risk was conferred by having either hypertension or diabetes alone.

In an attempt to eliminate some of the confusion regarding how to identify patients with the syndrome a new joint statement from a number of professional organizations has tightened up the definition of the metabolic syndrome, which previously differed from one organization to the next (14).

The statement, published online October 5, 2009, in Circulation, included the participation of the IDF, NHLBI, the AHA, the World Heart Federation, and the International Atherosclerosis Society.

The new metabolic-syndrome definition streamlines previous differences related to abdominal obesity as defined by measurements in waist circumference and now, the criteria for elevated waist circumference are based on population- and country-specific definitions.

All told, therefore, it appears that the question whether metabolic syndrome deserves a special disease category and its exact positioning remain largely unresolved. Further research may lead to a clearer understanding of its etiology, and hence to a definition that has stronger CVD predictive value.

In the meantime, the metabolic syndrome provides the clinician with a useful reminder of the clustering of certain CVD risk factors, and that life style modification and measures to reduce obesity are likely to increase insulin sensitivity with consequent improvements in cardiovascular risk.