Colleagues, the following is FYI and does not necessarily reflect my own
opinion. I have no further knowledge of the topic. If you do not wish to
receive these posts, set your email filter to filter out any messages
coming from   @nutritionucanlivewith.com    and the program will remove
anything coming from me.
---------------------------------------------------------
http://www.medscape.com/viewarticle/514211
Access is free, but requires a one-time subscription.

The Metabolic Syndrome: Perhaps an Etiologic Mystery but Far From a Myth 
-- Where Does the International Diabetes Federation Stand?

Paul Z. Zimmet, MD; George Alberti, MA, DPhil, BMBCh

Medscape Diabetes & Endocrinology.  2005;7(2) ©2005 Medscape
Posted 10/11/2005

Setting the Scene: The American Diabetes Association/European 
Association for the Study of Diabetes Shot Across the Bow of the 
Metabolic Syndrome

Although the underlying cause of the metabolic syndrome remains 
controversial, the ultimate importance of the syndrome is that it helps 
identify individuals at high risk for cardiovascular disease (CVD) and 
type 2 diabetes.[1] This is clearly a major benefit of its widespread 
recognition and acceptance. Nevertheless, a recent position paper 
jointly sponsored by the American Diabetes Association (ADA) and the 
European Association for the Study of Diabetes (EASD)[2,3] has 
questioned the existence and utility of the metabolic syndrome. Kahn and 
colleagues,[2,3] on behalf of these organizations, have suggested that 
the time has come for a critical appraisal of the metabolic syndrome. 
They claim that there is confusion about the syndrome. If this is so, 
then they have further added to this confusion with a long and tortuous 
exposé of its supposed problems. Their article, we believe, indicates a 
number of misconceptions and inconsistencies that we would like to 
address. Many of the issues that they raise have been covered in the 
recent International Diabetes Federation (IDF) Consensus,[4] which they 
barely quote.

We recognize the importance of debate; however, the appearance of this 
initiative on behalf of 2 of the world's leading regional diabetes 
organizations raises questions of motive and timing. Are the criticisms 
part of a "turf protection" scenario[5] or do they have a valid 
scientific basis?

In recent years, there has been increasing interest in the metabolic 
syndrome by the American Heart Association, the American College of 
Cardiology, the International Atherosclerosis Society, and other 
specialist groups in diabetes, insulin resistance, hypertension, and 
cardiology worldwide, effectively removing it from the province of pure 
diabetes. Thus, far from the metabolic syndrome being an offshoot of 
type 2 diabetes, one could consider that type 2 diabetes is but one of 
several manifestations of the metabolic syndrome.[1]

The ADA/EASD position paper[2,3] was released in a burst of publicity, 
and the issue received considerable media exposure. The authors of the 
ADA/EASD statement direct their main criticisms at earlier definitions, 
namely, those of the World Health Organization (WHO)[6] and the National 
Cholesterol Education Program Adult Treatment Panel III (ATP III).[7] 
Some investigators in the diabetes field, after embracing the concept 
wholeheartedly for about 15 years, are having "second thoughts" about 
the metabolic syndrome, not unreasonable in a rapidly changing field, 
providing that there are cogent arguments to do so. Several of the 
authors of the statement have been vigorous proponents of the metabolic 
syndrome. As recently as 2 years ago, Zachary Bloomgarden, MD,[8] 
reported on a presentation by Professor Ferrannini, one of the ADA/EASD 
paper authors, at the Endocrine Society's 85th Annual Meeting:

     Glycemic abnormality predicts hypertension and increased blood 
pressure predicts glycemic abnormality, with hyperinsulinemia an 
important additional predictive factor, Ferrannini noted, further 
suggesting the usefulness of the concept of metabolic syndrome. He 
concluded that 'the syndrome itself is atherogenic,' but suggested that 
insulin resistance causes atherosclerosis via the 'intermediate 
phenotypes' of increased blood pressure, dyslipidemia, and abnormal 
glycemia, suggesting that therapy not be primarily directed at insulin 
resistance. The metabolic syndrome exists, and he asserted, 'It predicts 
itself so it's not just an innocent cluster.' Whether it is directly 
atherogenic is not clearly established, and whether it can be prevented 
is an important therapeutic question.

Unfortunately, the joint ADA/EASD statement[2,3] was published before 
the detailed report of the IDF Consensus report on the metabolic 
syndrome appeared in print.[9] Nevertheless, the key features of the IDF 
report were available and summarized on the IDF Web site. It is 
noteworthy that 2 of the main authors of the ADA/EASD statement were on 
or represented on the IDF group and signed up to their conclusions.[4] 
In this commentary, we respond to the ADA/EASD statement in the light of 
deliberations of the IDF panel.
The Metabolic Syndrome: Setting the Scene

As co-chairmen of the recent IDF Consensus publication on a new global 
definition of the metabolic syndrome,[4] we welcome the debate 
engendered by the ADA and EASD. However, one must view the situation in 
terms of the world health challenge. A cluster of key cardiovascular 
risk factors, namely, abdominal obesity, dyslipidemia, hyperglycemia, 
and hypertension, are now one of the major public health challenges 
worldwide.[1] Although the association of several of these risk factors 
has been known for more than 80 years, the clustering received only 
limited attention until 1988, when Dr. Gerald Reaven[10] described 
syndrome X: insulin resistance, hyperglycemia, hypertension, low 
high-density lipoprotein (HDL) cholesterol, and raised very low-density 
lipoprotein (VLDL) triglycerides. Reaven[10] actually omitted obesity 
from the cluster, but it is now recognized as an essential component -- 
especially abdominal (visceral) obesity.[1,4] The syndrome is now widely 
recognized in cardiovascular, diabetes, and renal circles.
The Metabolic Syndrome -- Development of Concept and Definition

In the past few years, there has been a growing interest in the 
phenomenon of risk-factor clustering that increases the "global risk" 
for atherosclerotic CVD. One pattern of this clustering is exemplified 
by the metabolic syndrome, labeled as such because the CVD risk factors 
that make up this pattern appear to be of metabolic origin. This 
clustering of metabolic risk factors has perhaps been best articulated 
by several distinguished diabetes investigators,[9-15] who noted that 
most people who exhibit this risk pattern also have insulin resistance. 
This constellation of CVD risk factors has been given a number of names, 
such as deadly quartet, syndrome X, and insulin resistance syndrome.[16]

Just as the metabolic syndrome has borne a variety of names, numerous 
definitions have surfaced since the first attempt to standardize 
criteria by WHO in 1998. WHO proposed a more descriptive "definition" 
(or clinical criteria) for the metabolic syndrome.[7] Its purpose was to 
give utility in clinical practice to what was increasingly recognized by 
the scientific community as a multidimensional risk factor for both CVD 
and type 2 diabetes. We agree with Kahn and colleagues[2,3] on the 
ambiguity of the various definitions, but they result from the healthy 
process of evolution in relation to clinical utility. Therefore, 
criticism of the WHO and ATP III definitions as being inconsistent 
ignores the fact that ATP III was developed to improve on the earlier 
WHO definition and to make it more clinically useful.[8] This is, of 
course, part of the normal pattern of development in any rapidly 
evolving field.

With obesity prevalence rising worldwide,[17] it has become evident that 
a particular pattern of risk factors is common in overweight and obese 
individuals, particularly those with central adiposity. The latter may 
be a major driving force behind the metabolic syndrome.[1] This view has 
led to some controversy as to whether insulin resistance or visceral 
obesity is the major cause of the metabolic syndrome.[1] The fact that 
obesity is probably the major cause of insulin resistance in the general 
population complicates this debate. Regardless of the precise metabolic 
pathways involved, both central obesity and insulin resistance are 
common risk conditions underlying the metabolic syndrome.[1,13]
The Metabolic Syndrome: The Cardiovascular Interests

The concept of the metabolic syndrome has attracted much interest in the 
cardiovascular field. Cardiologists have recognized that the clustering 
of metabolic risk factors (metabolic syndrome) is a pattern of risk 
increasingly observed in persons exhibiting CVD. Although the metabolic 
syndrome does not encompass all CVD risk factors, it nonetheless appears 
to be a dominant picture of risk in a large portion of the population 
with CVD. For this reason, the National Cholesterol Education Program 
ATP III introduced the metabolic syndrome as a coequal partner of 
elevated low-density lipoprotein (LDL) as a risk factor for CVD.[8] 
Underlying this initiative was the recognition of the need for 
clinicians to identify and deal with the risk factors emerging from the 
dramatic rise in the prevalence of obesity in the United States.

ATP III further simplified the clinical criteria developed by WHO in 
order to make the concept of the metabolic syndrome "user-friendly" for 
clinicians. This move saw enhanced worldwide interest in the metabolic 
syndrome by providing both clinicians and epidemiologists with simple 
measures that can be used in both research and clinical settings. 
Moreover, cardiologists have been particularly receptive to 
incorporating the syndrome into their prevention strategies. In the 
United States, the American Heart Association has joined the National 
Heart, Lung, and Blood Institute to better delineate considerations of 
diagnosis and clinical management of the syndrome in their educational 
programs.[14,15]

Contemporaneously, there has been a strong movement among cardiovascular 
investigators to emphasize global risk that includes a summation of the 
CVD risk factors, including type 2 diabetes. The Framingham Heart Study 
took the lead in developing algorithms that incorporate all of the risk 
factors for the assessment of absolute risk, ie, the likelihood of 
developing cardiovascular events over a defined period of time (eg, 
10-year risk).[16] Other investigators[17,18] have proposed modified 
risk-assessment tools that use similar risk-factor sets, but which are 
not necessarily identical to those of Framingham.
The Pharmaceutical Industry: Innocent Bystanders?

In the debate on the relevance of the metabolic syndrome, there have 
been claims that the pharmaceutical industry invented the syndrome to 
boost their own profits.[19] The editorial accompanying the ADA/EASD 
statement on its publication in Diabetologia noted the recommendation in 
the IDF report that the thiazolidinediones be used, highlighting only 
one of a number of agents suggested, which included metformin, acarbose, 
orlistat, and new compounds, such as incretin mimetics, dipeptidyl 
peptidase IV inhibitors, protein tyrosine phosphatase 1B inhibitors, and 
the endocannabinoid receptor blocking agents. The history of development 
of knowledge about the syndrome discussed here and elsewhere[1] does not 
provide any support for that claim. Certainly, one result of the 
interest generated in the metabolic syndrome in cardiovascular and 
diabetes circles is that the pharmaceutical industry is responding with 
research initiatives to develop drugs that target several or all of the 
components of the metabolic syndrome. These drugs are in an early stage 
of development, but some promising leads have been forthcoming.[20] 
Indeed, IDF, like many others, strongly recommends the use of lifestyle 
modification as the first line of treatment. Should appropriate drugs be 
developed, then of course they should be used if they benefit people by 
preventing or delaying the development of CVD and diabetes.
The 2005 IDF Global Definition of the Metabolic Syndrome

In 2005, the IDF set forth modified clinical criteria for the metabolic 
syndrome.[4,9] These are designed for global application in clinical 
practice and represent modifications of the WHO and ATP III definitions. 
The IDF definition has a greater emphasis on abdominal (visceral) 
obesity as the core feature of the syndrome, making it an essential 
requirement for diagnosis. The other variables employed by ATP III are 
unmodified. The other simple clinical measures employed by ATP III are 
modified only slightly; and when they are present in persons with 
abdominal obesity, the syndrome is defined. The IDF took an important 
step forward by defining abdominal obesity for different ethnic 
populations defined by waist circumference measurements based on 
epidemiologic data from various ethnic populations.[21,22] This 
extension adds universality and worldwide applicability to the concept 
of the metabolic syndrome. The claim by Kahn and colleagues[2,3] that 
there is no basis for these ethnic-specific cutoffs displays an alarming 
lack of awareness of the literature -- and of the outside world!
Addressing the Issues Raised by the Joint ADA/EASD Statement

The authors of the ADA/EASD statement have raised a number of specific 
questions[2,3] that we address:

     * The clarity of the existing definition and whether it is 
justifiable to employ the term "syndrome" to the clustering of metabolic 
risk factors;

     * Whether the metabolic syndrome is a valid indicator of 
cardiovascular risk;

     * Whether there is enough known about the pathogenesis of the 
syndrome to justify including it in clinical practice;

     * Whether the WHO and ATP III criteria are the best ways to 
identify the syndrome in clinical practice; and

     * Whether cardiovascular prevention requires anything more than 
treatment of the individual risk factors.

1. The Clarity of the Existing Definition and Whether It Is Justifiable 
to Employ the Term Syndrome to the Clustering of Metabolic Risk Factors

Nomenclature. The ADA/EASD group seems confused about the definition of 
a syndrome. A well-accepted definition is: "The group or recognizable 
pattern of symptoms or abnormalities that indicate a particular trait or 
disease.[23]" The clustering of metabolic abnormalities that have 
provoked this debate appear to be fundamentally related to obesity and 
insulin resistance, but, because no firm underlying cause has been 
identified, clearly it fits the accepted definition of a syndrome and 
not a disease state.

We admit freely that the clustering of metabolic risk factors has posed 
a problem in nomenclature. A variety of terms have been suggested, as 
described above. More recently, dysmetabolic syndrome,[24] 
hypertriglyceridemic waist,[13] cardiometabolic syndrome,[25] or simply 
cardiometabolic risk have been added to the burgeoning variations of 
nomenclature. It is likely that the competition and disagreements about 
naming will continue! However, Kahn and colleagues[2,3] ask whether the 
clustering represents a syndrome. If a syndrome represents a clustering 
of disease-related conditions, then certainly the term is appropriate. 
The term syndrome has long been used in the diabetes field (eg, syndrome 
X, insulin resistance syndrome, and the metabolic syndrome),[9, 26-28] 
and is increasingly employed by the cardiovascular field. Therefore, to 
challenge its usage after many years of widespread acceptance appears to 
be a retrograde maneuver to say the least.

Definition. The ADA/EASD group[2,3] states that the metabolic syndrome 
is imprecisely defined. In the manner in which the definition has been 
arrived at, their confusion is again apparent. The IDF first lists 
several features of the syndrome, which include abdominal body fat 
distribution, insulin resistance, atherogenic dyslipidemia (elevated 
triglyceride, low HDL, small LDL particles, and elevated apolipoprotein 
B), elevated blood pressure, a proinflammatory state, and a 
prothrombotic state.[6] There is a general agreement in both the 
cardiovascular and diabetes fields that these are general features of 
the metabolic syndrome.[4,6,7] A simple definition would be "a 
clustering of closely related risk factors for cardiovascular disease 
and diabetes."

But we suspect that when Kahn and colleagues[2,3] state that the 
syndrome is imprecisely defined, they mean that diagnostic criteria are 
not adequately defined to apply them in clinical practice. On that 
basis, would they argue that the definition of diabetes mellitus, as 
defined by the ADA as a fasting blood glucose concentration of 126 mg/dL 
(7.0 mmol/L) or higher, or its random glucose criterion[29] is any more 
precise? Let's see what they say about the ADA's recent definition of 
"prediabetes.[24]" Is this more precise? (See below for further discussion.)

For a condition such as the metabolic syndrome in which there is a 
clustering of risk factors, precise clinical criteria are difficult to 
propose. For this reason, ATP III took 2 steps in its effort to achieve 
clinical utility. First, it restricted the clinical diagnosis to simple 
clinical measures: waist circumference, fasting triglycerides, HDL 
cholesterol, blood pressure, and fasting glucose. This ensured that 
clinicians almost anywhere in the world can readily identify affected 
individuals. In addition, it used thresholds for each of these measures 
that had already been defined by expert panels.[8] The IDF employed the 
same approach by maintaining ATP III thresholds for all measures except 
waist circumference.[4] For this parameter, thresholds were modified 
according to ethnic population, which similarly had been established for 
these populations by expert panels based on published data.[21,22]

Thresholds by necessity are arbitrary, but in the ATP III[7] and IDF 
clinical definitions,[4] their use has the virtue of simplicity. By 
analogy, because cholesterol, blood pressure, glucose, and other risk 
factors are continuously related to CVD and diabetes risk, there is no 
compelling reason to identify specific thresholds for any of these other 
than for utility. This is exemplified by the actions of the ADA itself, 
in that expert panels of the ADA periodically modify their thresholds 
for the definition of diabetes.[29] The same reasoning can be applied to 
the definition of the metabolic syndrome. Therefore, as the current 
thresholds employed for clinical diagnosis are based on contemporary 
recommendations of accepted expert panels, Kahn and colleagues[2,3] are 
stretching credibility with the claim that the current clinical 
definition of the metabolic syndrome is imprecise.

Indeed, it is ironic that the ADA/EASD experts[2,3] question the 
definition of the metabolic syndrome, considering the recent stance of 
the ADA on prediabetes. Despite the ADA's attraction to this term, 
prediabetes is not a new term. It was introduced in the context of 
classification in the 1965 WHO Report on Diabetes Mellitus.[30] The WHO 
report stated,[30] "This is a term that can be used retrospectively when 
reviewing a case," and that the term should be used for the period of 
time from conception to the diagnosis of an episode of diabetes. 
"However," the report continued, "prediabetes should exclude impairment 
of glucose tolerance by definition."

The WHO statement is mutually exclusive of the recommended ADA usage. 
Yet, according to the ADA, prediabetes is a simplifying diagnosis that 
can be applied to people who have either impaired glucose tolerance or 
impaired fasting glucose. By labeling people with prediabetes, the ADA 
implies that they will eventually develop diabetes, but, in reality, 
progression to diabetes is by no means certain. So it is inappropriate 
to use the term when there is only a 50% chance of developing diabetes 
in the next 10 years. It also excludes others with as great a risk of 
developing diabetes, eg, those with a first-degree family history of the 
disorder. Moreover, it could be argued that using the term prediabetes 
in clinical practice creates a medical condition out of a risk factor 
for diabetes -- with all the accompanying psychosocial stress that this 
implies.

Surely, this is the same argument that they use to demolish the 
metabolic syndrome! The ADA justification is that warning individuals 
that they have prediabetes is a wake-up call for the need for lifestyle 
changes. ADA panelists decided that adding the term prediabetes to the 
medical vocabulary is justified for preventive purposes even though it 
increases the number of persons with a "medical condition" by millions. 
Now, can anyone explain to us how this ADA stance is different from the 
rationale for identifying persons with the metabolic syndrome who are at 
increased risk for CVD and type 2 diabetes in the years ahead?
2. Is There Enough Known About Pathogenesis of the Syndrome to Justify 
Including It in Clinical Practice?

Several underlying factors appear to contribute to the development of 
the metabolic syndrome.[1] The ADA/EASD statement acknowledges that the 
clustering of these CVD risk factors may imply a common underlying 
etiology. This in itself may be a good justification for using the 
concept of a syndrome. There are, however, more disputes about how they 
interact than about what they are. These factors interact in complex 
ways that are not entirely understood and are reviewed in detail 
elsewhere.[1] Kahn and colleagues[2,3] nonetheless asked whether the 
metabolic syndrome should be elevated to a medical condition when the 
causation is incompletely understood. Do they have knowledge that we do 
not have about the precise etiology of type 1 and/or type 2 diabetes? 
Although the same thing could be said of many other medical conditions, 
the IDF report has outlined in some detail the factors contributing to 
the development of the metabolic syndrome.[4] These can be briefly reviewed.

The primary underlying causes of the metabolic syndrome were identified 
as central obesity and insulin resistance. Central obesity almost 
certainly is a major cause of insulin resistance.[1] Because of the 
strong connection between central obesity and the risk factors of the 
metabolic syndrome, the IDF Consensus identified an increase in waist 
circumference as a necessary component of the clinical diagnosis of the 
metabolic syndrome.[4] Some individuals or ethnic groups may be 
unusually insulin-resistant and develop the metabolic syndrome despite 
levels of abdominal obesity below diagnostic thresholds, but such 
persons are relatively uncommon, less than 5% in the recent Australian 
national survey (Shaw J, et al., unpublished).

In recent years, much has been learned about how excess body fat 
contributes to the metabolic syndrome. The role of excess circulating 
free fatty acids derived from adipose tissue in the causation of insulin 
resistance in muscle and the liver has been known for many years.[1] 
More recent research has documented the production of a large number of 
other adipokines that seemingly promote the risk factors of the 
metabolic syndrome.[31-33] These include inflammatory cytokines (eg, 
tumor necrosis factor-alpha and interleukin [IL]-6), plasminogen 
activator inhibitor-1, leptin, adiponectin, and angiotensinogen, among 
others. The release of the "protective" adiponectin by adipose tissue is 
reduced in obese persons. It seems clear that adipose tissue metabolism 
is central to the development of the metabolic syndrome.[1] Nonetheless, 
there are several modifying factors that affect the expression of the 
syndrome. Some of these include advancing age with loss of muscle mass, 
physical inactivity, endocrine dysfunction, and genetic factors that 
modify the response to underlying risk factors. Regardless, the 
complexity of the pathogenesis of the metabolic syndrome does not 
justify eliminating it as a higher risk condition for CVD and type 2 
diabetes, just as the lack of knowledge on the pathogenesis of type 2 
diabetes does not rule it out as a disease state!
3. Is the Metabolic Syndrome a Valid Indicator of Cardiovascular Risk?

Predicting Risk for Cardiovascular Disease. The 2 major clinical 
outcomes of the metabolic syndrome are CVD and type 2 diabetes.[1] The 
relative risk for CVD varies somewhat among different reports. However, 
as a general rule, the risk from the metabolic syndrome for major CVD 
events is approximately twice as high as for those without the 
syndrome.[1] For type 2 diabetes, the metabolic syndrome confers an 
approximate 5-fold greater risk.[1] Finally, type 2 diabetes itself is 
accompanied by increased risk for CVD, and most of this increased risk 
is conferred by the concomitant risk factors of the metabolic syndrome. 
In other words, type 2 diabetes alone, independent of the metabolic 
syndrome, carries much less risk for CVD than when the metabolic 
syndrome is concomitantly present.[34]

It cannot be overemphasized that the metabolic syndrome is not an 
absolute risk predictor. This misconception has seemingly led the 
ADA/EASD experts to question whether the metabolic syndrome has clinical 
utility as a risk predictor. To predict absolute risk for individuals, 
sometimes called global risk, it is necessary to include all of the risk 
factors related to the outcome. For CVD, these include age, sex, total 
cholesterol, HDL cholesterol, triglyceride, blood pressure, body mass 
index, glucose status, tobacco usage, and family history, depending on 
the risk-assessment algorithm employed.[35-37] The metabolic syndrome is 
an incomplete predictor of absolute risk, and to question it for this 
reason represents a significant misunderstanding of its use in clinical 
practice.

The prime purpose of absolute risk prediction is to identify persons 
whose 10-year risk for CVD is high enough to justify introducing drug 
therapy for risk reduction. The most important drugs for this purpose 
currently are cholesterol-lowering drugs and low-dose aspirin. The 
metabolic syndrome does not serve as a tool to define absolute risk for 
decisions about preventive drug therapy. The clinical utility of the 
syndrome for risk assessment lies in its ability to readily identify 
individuals who are at a relatively high, long-term risk for both CVD 
and diabetes. All such individuals should undergo absolute risk 
assessment to determine whether they are candidates for preventive drug 
therapies. But once found to have the metabolic syndrome, they deserve 
more intensive intervention with lifestyle approaches. This distinction 
between different forms of risk and their significance is blurred by the 
authors of the ADA/EASD statement.[2,3]

Is the Risk the Sum of the Parts? Kahn and colleagues[2,3] are not alone 
in asking whether the risk accompanying the metabolic syndrome is 
"greater than the sum of its parts." There are 3 answers to this question.

First, statistical epidemiologists differ as to whether multiple 
risk-factor conditions best fit an additive model or a multiplicative 
(synergistic) model. If the latter holds, then the risk that is 
associated with multiple risk factors is greater than the sum of the 
individual risk factors. If the former is true, the risk equates to the 
sum of that conveyed by the individual risk factors. A sizable body of 
experts favors the multiplicative model. Included among these are the 
Framingham Heart Study investigators.[38] If this model holds, then the 
risk accompanying the metabolic syndrome is indeed greater than the sum 
of its parts.

Second, the metabolic syndrome contains risk factors that are not 
commonly identified in clinical practice, eg, prothrombotic state and 
proinflammatory states.[1] Even if the appropriate model is an additive 
one, the risk is greater than its readily identifiable parts.

Finally, some of the so-called "independent" risk factors, eg, blood 
pressure and HDL cholesterol, subsume some of the risk contained in the 
"hidden" risk factors of the metabolic syndrome. Thus, it cannot be 
assumed that all of the risk accompanying the metabolic syndrome can be 
reversed by lowering blood pressure and raising HDL levels, the 
so-called independent risk factors associated with the syndrome.

Kahn and colleagues[2,3] suggest that C-reactive protein could be a 
"valuable" addition to the definition of the syndrome. This requires the 
research that both they and the IDF call for. However, the more 
"sophisticated" the definition becomes, the more it loses the primary 
objective of supplying a simple clinical tool to define those at 
greatest risk, particularly in poor developing nations where the 
metabolic syndrome is on an exponential rise.
4. Does Cardiovascular Prevention Require Anything More Than Treatment 
of the Individual Risk Factors?

Clinical trials reveal that blood pressure-lowering drugs reduce risk 
less than predicted from epidemiologic studies, and to date, there are 
no robust clinical trials to document that HDL-raising therapies will 
significantly reduce the risk for CVD. Thus, the prescription of Kahn 
and colleagues[2,3] to just treat the independent risk factors of the 
metabolic syndrome does not ensure the degree of risk reduction that is 
implied. In addition, their arguments neglect the fact that the 
summation of the individual CVD risk factors account for only 50% of 
cardiovascular risk, and current therapies reduce risk by only 50%. This 
means that there is a 50% "residual risk" that cannot be explained by 
the risk factors. If we are to cut into the additional CVD risk, we need 
to affect other factors. The metabolic syndrome is one of the components 
of residual risk, and is the best additional target to the standard risk 
factors. The big question for the future is whether pharmacologic 
therapy will be found to target the metabolic syndrome specifically. In 
the meantime, however, we know that lifestyle modification will improve 
the many components of the syndrome.
5. Are the WHO and ATP III Criteria for the Syndrome the Best Way to 
Identify the Syndrome in Clinical Practice?

Kahn and colleagues,[2,3] on behalf of the ADA and EASD, question 
whether the metabolic syndrome is clinically useful. Without doubt, 
because of the increased prevalence of the underlying causes of the 
metabolic syndrome (eg, obesity and sedentary lifestyles), the 
clustering of risk factors portends an enormous increase in CVD and type 
2 diabetes worldwide.[1] The fact that diabetes itself, when combined 
with the metabolic syndrome, is associated with greater CVD risk 
represents a great challenge for the management of patients with 
diabetes. At the same time, it also has significant public health 
implications for the prevention of CVD and type 2 diabetes. It is likely 
to provide a useful practical tool that reminds healthcare professionals 
of the metabolic consequences of obesity, and identifies individuals at 
risk for CVD and diabetes who are likely to benefit from (lifestyle) 
interventions. The clustering of CVD risk factors is a call to action 
for preventive medicine, as it is clearly not satisfactory just to treat 
the major risk factors once they have reached categorically increased 
levels. This would be a prescription for widespread use of drug therapy 
in primary prevention and would be a huge burden on economically 
developed societies, and an even greater burden on developing nations.

Few would disagree that it is better and more economical to detect the 
clustering at an earlier stage of development and to introduce lifestyle 
interventions to prevent progression to a more advanced risk. This is a 
task for both public health and clinical sectors of the healthcare 
system. An additional benefit of the new IDF criteria is that the 
initial screening test is simple and low-cost, ie, measurement of waist 
size.
Summary

The IDF, and clearly many other international groups, regard the 
metabolic syndrome as a viable and useful concept in clinical medicine. 
Debate is always welcomed as a stimulus to new understanding, but 
criticism should have a valid platform, something that is not always 
apparent in the ADA/EASD statement[2,3] and the supporting editorial in 
Diabetologia.[19] The IDF report does raise a series of questions that 
need more research.

The IDF's new clinically oriented definition of the metabolic 
syndrome[4] is an important new approach that health professionals can 
employ to facilitate detection and intervention for risk reduction in 
one common pattern of multifactorial risk for both CVD and type 2 
diabetes. Most important is the need to promote lifestyle interventions 
to reduce long-term risk. But at the same time, absolute risk assessment 
is required to assist clinicians in making decisions about drug 
therapies for prevention in higher risk patients. It is important to 
note that the American Heart Association and National Heart, Lung, and 
Blood Institute have just published a scientific statement on the 
metabolic syndrome that contains an updated ATP III classification.[39] 
In the updated ATP III classification, increased waist circumference is 
not deemed a necessity if the 3 other risk-factor criteria are present. 
The ATP III definition also allows for the lower waist circumference 
risk thresholds, particularly for Asian Americans. This updated ATP III 
version and the new IDF criteria[9] identify essentially the same 
individuals as having the metabolic syndrome.[39] Thus, not only are ATP 
III and the IDF criteria virtually identical; their recommendations for 
clinical management are also identical.

The ADA/EASD attempt to disregard the metabolic syndrome will only 
confuse health professionals at all levels. The utility of the syndrome 
as a public health initiative has been put at risk by a statement that 
has come "out of the blue" and does not reflect the past intellectual 
and constructive contributions of some of its individual authors! Debate 
is always welcomed, but misconstrued criticism can only harm the 
initiatives of others in the CVD, diabetes, and other related fields who 
were making progress in raising awareness of patients toward risk-factor 
clustering. The ADA/EASD stance may also hinder research and 
fund-raising, baffle the public, and weaken its confidence in clinical 
scientists as well as delay treatment advances. This reflects a total 
lack of foresight and vision.

Perhaps the last words should be with Richard N. Fogoros, MD,[5] writing 
as "Dr Rich" on a Web site:

     Dr Rich suspects that what the ADA/EASD are doing here is engaging 
in turf protection. The concept of the metabolic syndrome has 
non-specialists paying a lot more attention to conditions related to 
diabetes (specifically, to insulin-resistance and related conditions) 
than they ever have in the past. Indeed, in recent years, 
non-diabetes-specialists are engaging numerous active clinical trials 
aimed at insulin-resistance conditions (i.e., metabolic syndrome.) One 
suspects that the relatively small ADA, viewing the recent efforts of 
the American Heart Association and American College of Cardiology in 
this regard, is beginning to feel like Netscape did in the mid-1990s 
when Microsoft decided to enter the browser business. This, of course, 
is pure speculation, but something must explain the otherwise nearly 
inexplicable effort to quash the metabolic syndrome.

Related Links

The Metabolic Syndrome: Time for a Critical Appraisal

Author Response to "The Metabolic Syndrome: Perhaps an Etiologic Mystery 
but Far From a Myth -- Where Does the International Diabetes Federation 
Stand?"
References

    1. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 
2005:365:1415-1428. Abstract
    2. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: 
time for a critical appraisal: joint statement from the American 
Diabetes Association and the European Association for the Study of 
Diabetes. Diabetologia. 2005;48:1684-1699. and Diabetes Care. 
2005.28:2289-2304.
    3. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: 
time for a critical appraisal: joint statement from the American 
Diabetes Association and the European Association for the Study of 
Diabetes. Diabetes Care. 2005;28:2289-2304. Abstract
    4. International Diabetes Federation. The IDF consensus worldwide 
definition of the metabolic syndrome. Available at: 
http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf Accessed 
October 4, 2005.
    5. Fogoros RN. Does metabolic syndrome exist? About.com. Available 
at: 
http://heartdisease.about.com/od/diabetesmetabolicsynd/a/metsynyn.htm 
Accessed October 4, 2005.
    6. Alberti KG, Zimmet PZ. Definition, diagnosis and classification 
of diabetes mellitus and its complications. Part 1: diagnosis and 
classification of diabetes mellitus provisional report of a WHO 
consultation. Diabet Med. 1998;15:539-553. Abstract
    7. Executive Summary of The Third Report of The National Cholesterol 
Education Program (NCEP) Expert Panel on Detection, Evaluation, And 
Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel 
III). JAMA. 2001;285:2486-2497. Abstract
    8. Bloomgarden ZT. The Endocrine Society meeting: topics in insulin 
sensitivity and hypertension. Diabetes Care. 2003;26:2679-2688. Abstract
    9. Alberti KGMM, Zimmet P, Shaw J. The metabolic syndrome -- a new 
worldwide definition. Lancet. 2005;366:1059-1062. Abstract
   10. Reaven GM. Banting lecture 1988. Role of insulin resistance in 
human disease. Diabetes. 1988;37:1595-1607. Abstract
   11. Zimmet PZ, Alberti KG, Shaw JE. Mainstreaming the metabolic 
syndrome: a definitive definition. This new definition should assist 
both researchers and clinicians. Med J Aust. 2005;183:175-176. Abstract
   12. Zimmet P, Alberti KG, Shaw J. Global and societal implications of 
the diabetes epidemic. Nature. 2001;414:782-787. Abstract
   13. Lemieux I, Pascot A, Couillard C, et al. Hypertriglyceridemic 
waist: a marker of the atherogenic metabolic triad (hyperinsulinemia; 
hyperapolipoprotein B; small, dense LDL) in men? Circulation. 
2000;102:179-184.
   14. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. 
National Heart, Lung, and Blood Institute; American Heart Association. 
Definition of metabolic syndrome: report of the National Heart, Lung, 
and Blood Institute/American Heart Association conference on scientific 
issues related to definition. Arterioscler Thromb Vasc Biol. 
2004;24:e13-18. Abstract
   15. Grundy SM, Hansen B, Smith SC Jr, Cleeman JI, Kahn RA; American 
Heart Association; National Heart, Lung, and Blood Institute; American 
Diabetes Association. Clinical management of metabolic syndrome: report 
of the American Heart Association/National Heart, Lung, and Blood 
Institute/American Diabetes Association conference on scientific issues 
related to management. Circulation. 2004;109:551-556. Abstract
   16. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, 
Kannel WB. Prediction of coronary heart disease using risk factor 
categories. Circulation. 1998;97:1837-1847. Abstract
   17. Assmann G, Cullen P, Schulte H. Simple scoring scheme for 
calculating the risk of acute coronary events based on the 10-year 
follow-up of the prospective cardiovascular Munster (PROCAM) study. 
Circulation. 2002;105:310-315. Abstract
   18. Voss R, Cullen P, Schulte H, Assmann G. Prediction of risk of 
coronary events in middle-aged men in the Prospective Cardiovascular 
Munster Study (PROCAM) using neural networks. Int J Epidemiol. 
2002;31:1253-1262. Abstract
   19. Gale EAM. Editorial: the myth of the metabolic syndrome. 
Diabetologia. 2005;10:1873-1875.
   20. Van Gaal LF, Rissanen AM, Scheen AJ; RIO-Europe Study Group. 
Effects of the cannabinoid-1 receptor blocker rimonabant on weight 
reduction and cardiovascular risk factors in overweight patients: 1-year 
experience from the RIO-Europe study. Lancet. 2005;365:1389-1397. Abstract
   21. WHO Expert Consultation. Appropriate body-mass index for Asian 
populations and its implications for policy and intervention strategies. 
Lancet. 2004;363:157-163. Abstract
   22. Snehalatha C, Viswanathan V, Ramachandran A. Cutoff values for 
normal anthropometric variables in Asian Indian adults. Diabetes Care. 
2003;26:1380-1384. Abstract
   23. Doegenomes.org. Genome glossary. Available at: 
http://www.ornl.gov/sci/techresources/Human_Genome/glossary Accessed 
October 4, 2005.
   24. Zimmet P, Shaw J, Alberti KG. Preventing type 2 diabetes and the 
dysmetabolic syndrome in the real world: a realistic view. Diabet Med. 
2003;20:693-702. Abstract
   25. Castro JP, El-Atat FA, McFarlane SI, Aneja A, Sowers JR. 
Cardiometabolic syndrome: pathophysiology and treatment. Curr Hypertens 
Rep. 2003;5:393-401. Abstract
   26. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. 
Cardiovascular risk factors in confirmed prediabetic individuals. Does 
the clock for coronary heart disease start ticking before the onset of 
clinical diabetes? JAMA. 1990;263:2893-2898.
   27. Ferrannini E, Haffner SM, Mitchell BD, Stern MP. 
Hyperinsulinemia: the key feature of a cardiovascular and metabolic 
syndrome. Diabetologia. 1991;34:416-422. Abstract
   28. Ferrannini E, Balkau B. Insulin: in search of a syndrome. Diabet 
Med. 2002;19:724-729. Abstract
   29. Genuth S, Alberti KG, Bennett P, et al; Expert Committee on the 
Diagnosis and Classification of Diabetes Mellitus. Follow-up report on 
the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160-3167. 
Abstract
   30. World Health Organization. Technical Report Series No. 310. 
Diabetes Mellitus. Report of a WHO Expert Committee: WHO Geneva; 1965.
   31. Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines: 
molecular links between obesity and atherosclerosis. Am J Physiol Heart 
Circ Physiol. 2005;288:H203.1-41.
   32. Matsuzawa Y. Adipocytokines and metabolic syndrome. Semin Vasc 
Med. 2005;5:34-39. Abstract
   33. Trayhurn P. Endocrine and signalling role of adipose tissue: new 
perspectives on fat. Acta Physiol Scand. 2005;184:285-293. Abstract
   34. Alexander CM, Landsman PB, Teutsch SM, Haffner SM; Third National 
Health and Nutrition Examination Survey (NHANES III); National 
Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, 
diabetes, and prevalence of coronary heart disease among NHANES III 
participants age 50 years and older. Diabetes. 2003;52:1210-1214. Abstract
   35. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, 
Kannel WB. Prediction of coronary heart disease using risk factor 
categories. Circulation. 1998;97:1837-1847. Abstract
   36. Assmann G, Cullen P, Schulte H. Simple scoring scheme for 
calculating the risk of acute coronary events based on the 10-year 
follow-up of the prospective cardiovascular Munster (PROCAM) study. 
Circulation. 2002;105:310-315. Abstract
   37. Voss R, Cullen P, Schulte H, Assmann G. Prediction of risk of 
coronary events in middle-aged men in the Prospective Cardiovascular 
Munster Study (PROCAM) using neural networks. Int J Epidemiol. 
2002;31:1253-1262. Abstract
   38. Kannel WB, Larson M. Long-term epidemiologic prediction of 
coronary disease. The Framingham experience. Cardiology. 
1993;82:137-152. Abstract
   39. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and 
Management of the Metabolic Syndrome. An American Heart 
Association/National Heart, Lung, and Blood Institute Scientific 
Statement. Executive Summary. Circulation. 2005; [Epub ahead of print].


Paul Z. Zimmet, MD, PhD, Professor, International Diabetes Institute, 
Caulfield, Victoria, Australia; Co-Chairman, International Diabetes 
Federation Consensus Report: "Metabolic Syndrome -- a New World-Wide 
Definition"

George Alberti, MA, DPhil, BMBCh, Professor of Medicine, University of 
Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom; Past President 
of the International Diabetes Federation; Co-Chairman, International 
Diabetes Federation Consensus Report: "Metabolic Syndrome -- a New 
World-Wide Definition"

Disclosure: Paul Z. Zimmet, MD, PhD, has disclosed that he has received 
grants for educational activities from AstraZeneca, Sanofi-Aventis, and 
Bristol-Myers Squibb. Dr. Zimmet has also disclosed that he serves as an 
advisor or consultant to Novartis and Bristol-Myers Squibb.

Disclosure: George Alberti, MA, DPhil, BMBCh, has disclosed that he has 
received grants for educational activities from AstraZeneca and 
Sanofi-Aventis. Dr. Alberti has also disclosed that he has served an 
advisor or consultant to AstraZeneca.
-- 
Kathrynne Holden, MS, RD < [log in to unmask] >
"Ask the Parkinson Dietitian"  http://www.parkinson.org/
"Eat well, stay well with Parkinson's disease"
"Parkinson's disease: Guidelines for Medical Nutrition Therapy"
http://www.nutritionucanlivewith.com/

----------------------------------------------------------------
This message was sent through the Ageing in Europe
mailing list.
Please visit the homepage of the ESA Research Network
on Ageing in Europe at http://www.ageing-in-europe.de
----------------------------------------------------------------