Clinical Use of the Metabolic Syndrome: Why the Confusion
http://www.100md.com
《临床糖尿病学》
Abstract
IN BRIEF
The term "metabolic syndrome" refers to a cluster of risk factors for cardiovascular disease and type 2 diabetes that occurs as a result of obesity and insulin resistance. Considerable confusion surrounding the precise use of this term in the clinical setting has led to difficulty in assessing the utility of this concept. This article provides a simple framework for understanding the disparate approaches to this syndrome. This understanding will facilitate decision-making regarding the role of the metabolic syndrome in everyday clinical practice.
Introduction
Stated generally, the metabolic syndrome is a multiplex risk factor for cardiovascular disease (CVD) and type 2 diabetes that reflects the clustering of individual risk factors resulting from obesity and insulin resistance. Currently, this multiplex is thought to be composed of the following broadly stated metabolic risk conditions: atherogenic dyslipidemia, hypertension, glucose intolerance, proinflammatory state, and a prothrombotic state. Atherogenic dyslipidemia is itself an aggregate term encompassing elevated triglycerides and apolipoprotein B, increased small LDL particles, and reduced HDL.
Although the metabolic syndrome is a relatively new concept, research into the clustering of individual cardiovascular risk factors is an old enterprise. In the 1920s, investigators were reporting the occurrence of hyperglycemia, hypertension, and hyperuricema in certain groups of individuals.1 In the 1960s, obesity and hyperlipidemia were added to this cluster.2 Then in 1988, Gerald Reaven systematized the concept of a risk factor syndrome and suggested that insulin resistance and resultant compensatory hyperinsulinemia could mechanistically explain most of this clustering phenomenon.3 At that time, the treatment for what he called "syndrome X" was thought to be lifestyle modification. Since 1988, there has been a flurry of research corroborating the idea of a risk factor cluster mediated by insulin resistance,4-7 describing it using factor analysis,8-13 and linking it with CVD.13-16
A new thread in the story of the metabolic syndrome emerged at the turn of the millennium. Several groups, including the World Health Organization (WHO)17 and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII),18 published clinical definitions of the metabolic syndrome intended for use in assigning clinical diagnoses to patients. This was followed by creation of an International Classification of Diseases diagnostic code (277.7) for metabolic syndrome. 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 current confusion about whether the term "metabolic syndrome" refers to pathophysiological observation or clinical diagnosis stems from this abrupt change in focus.
Confusion has led to a climate of skepticism about the future of the metabolic syndrome. Is it an artificial, mathematical concept that simply recasts old known risk factors into a new disease entity19 Or does the clustering indeed reflect a single pathophysiology that can be a target for therapeutic decisions20,21 Can the metabolic syndrome offer advantages over existing models for the prediction of cardiovascular events22 Or, given the confusion and the lingering doubts about its potential role in clinical practice, should the metabolic syndrome simply be declared dead23 Although these are all defensible concerns, the current conflict over the metabolic syndrome is still largely about differences in its intended function. The trouble remains ambiguity about what the metabolic syndrome is, how it should be defined, and what the purpose is for its existence.
Given the confusion over the metabolic syndrome, we sought to make explicit the present usage of the term in the literature and to suggest a framework for organizing its many descriptions.
Methods
We searched the National Library of Medicine's Medline database for human studies published since 1988, using combinations of the following text words in their titles or abstracts: "metabolic syndrome," "definition," "insulin resistance syndrome," "dysmetabolic syndrome," and "syndrome X." The search was augmented by scanning selected journals through March 2006. Bibliographies of all retrieved articles served as a check of the completeness of the electronic search.
After screening the titles of the 4,544 identified articles, we examined abstracts of 1,620 articles available in English for pertinence to the study objective. Full text was examined of 442 articles incorporating explicit use of the metabolic syndrome as either a study exposure or an outcome. Studies referring to a different metabolic syndrome (e.g., microvascular angina syndromes) and studies lacking a clear definition of the metabolic syndrome were excluded.
The descriptions of the metabolic syndrome used in the selected studies were abstracted, and the articles were grouped by their approach to defining the syndrome.
Pathophysiological Perspective
The pathophysiological perspective seeks to demonstrate how a single defect, insulin resistance, leads to a variety of pathological changes (Table 1), resulting in increased risk for a constellation of clinical conditions (Table 2).24 It should be noted that CVD is just one of these important clinical conditions. Whereas the outdated term "syndrome X" focused only on CVD, we now understand that insulin resistance is mechanistically implicated in the development of polycystic ovarian syndrome (PCOS), nonalcoholic fatty liver disease (NAFLD), breast cancer, and other conditions. In this way, the intent of the metabolic syndrome is to provide a conceptual framework for understanding why clinical conditions cluster in individual patients. In short, it explains to practitioners why an obese, insulin-resistant individual is likely to have elevated liver transaminases (NAFLD), irregular menstrual cycles (PCOS), and a proinflammatory state manifested by elevated C-reactive protein and be at risk for developing several types of cancer.
From the pathophysiological perspective, the blame for the syndrome rests squarely on insulin resistance and the resultant hyperinsulinemia. This view is supported by evidence from the basic science and clinical research laboratories from the past 30 years.3,24 Obesity is thought to exacerbate insulin resistance and thus increase the likelihood of an associated adverse clinical condition, but it is not considered a fundamental component of the syndrome because it need not be present. Proponents defend this decision with data showing that insulin resistance is indeed not a cause of obesity24 and that the clustering of risk factors can occur in insulin-resistant individuals of normal weight.25 Most of those approaching the metabolic syndrome from this perspective, particularly basic scientists and endocrinologists, prefer the term "insulin resistance syndrome" to stress the underlying pathophysiology.
The primary goal of the metabolic syndrome from the pathophysiological perspective is to alert physicians to an increased likelihood of multiple adverse conditions in insulin-resistant patients. Making a clinical diagnosis of metabolic syndrome based on strict criteria is not the focus, nor is using the syndrome as a cardiovascular risk calculator. From this perspective, the prevalence of metabolic syndrome can simply be defined by the distribution of insulin sensitivity in the population. Approximately one-third of the apparently healthy population is sufficiently insulin resistant to be at increased risk for the abnormalities shown in Table 2.26 The current treatment for these individuals is considered to be lifestyle modification for the improvement of insulin sensitivity.
Clinical Epidemiological Perspective
The clinical epidemiological perspective seeks to assemble a group of related metabolic risk factors and to use this grouping for the prediction of future cardiovascular events. Decisions about which risk factors comprise the metabolic syndrome and their threshold values are based largely on their predictive values, with less emphasis on a unifying pathophysiological entity. Thus, from this perspective, obesity is considered a core component of the metabolic syndrome rather than a modulator of the effects of insulin resistance.27
The primary clinical goals of this approach are to make a diagnosis of metabolic syndrome and to use this diagnosis for risk stratification of patients according to their long-term likelihood (> 10-30 years) for atherosclerotic CVD.28,29 The metabolic syndrome is not designed to be a competitor to the Framingham risk score, which calculates short-term risk over the course of 10 years.30 Rather, it is formulated to aid the global assessment of lifetime risk. Generally speaking, advocates of this approach to the metabolic syndrome include lipid specialists and cardiologists. First-line treatment for metabolic syndrome is once again lifestyle intervention, with particular attention to dyslipidemia.18,29
Advocates of this approach support their formulations of the metabolic syndrome with data from population-based epidemiological studies.13,16,31-40 Frequently, these are post hoc analyses of large prospective cohort studies or clinical trials. In general, these studies support the idea that a cluster of metabolic risk factors can predict cardiovascular outcomes better than the sum of its component risk variables considered individually.41 For example, Isomaa et al.16 found a threefold increased risk of coronary heart disease and stroke with the metabolic syndrome in the Botnia study, and Lakka et al.13 reported a relative risk of 4.2 for death from coronary heart disease after adjusting for known risk factors in the Kuopio Ischaemic Heart Disease Risk Factor Study. However, few cohorts have been assembled with the primary intent of studying the metabolic syndrome.
Differences in the Perspectives
These two approaches to the metabolic syndrome are fundamentally different. (Table 3.) The pathophysiological perspective begins with a single defect, insulin resistance, and explores its consequences. CVD is just one of these consequences. The clinical epidemiological perspective is concerned primarily with CVD and the construction of a set of risk factors that best predict cardiovascular outcomes. From this perspective, insulin resistance may or may not explain the clustering phenomenon relating the risk factors; the pathophysiological mechanism is less immediate.
These two approaches can perhaps be better understood with a simple analogy. In many ways, the difference between the goals of the pathophysiological and clinical epidemiological perspectives is analogous to the differences between an exploratory prospective study and a retrospective case-control study (Figure 1). In a prospective study, a single exposure is defined, with the goal of measuring a set of outcomes that might be associated with that exposure. In a similar way, the pathophysiological perspective seeks to begin with a single exposure, insulin resistance, and explain how it leads to variety of clinical conditions (PCOS, NAFLD, and CVD, for example). In a case-control study, a single outcome is defined, and the goal of the study is to construct a set of risk factors for that outcome. In a similar way, the clinical epidemiological perspective begins with a single outcome, CVD, and attempts to describe a set of correlated risk factors for the prediction of CVD.
There are several implications of this difference in approach. Foremost is the impact on our understanding of the role of obesity in the metabolic syndrome. From the clinical epidemiological perspective, obesity is thought to play the central role because it best explains the occurrence of the other syndrome components, and in many studies it is the individual component most predictive of CVD.42-44 From this perspective, the metabolic syndrome epidemic has resulted from an obesity epidemic, and reducing patient weight is therefore viewed as a goal of therapy. From the pathophysiological perspective, obesity plays a peripheral role in the metabolic syndrome. Adiposity is considered a modest contributor to the metabolic syndrome, explaining about as much of the variation in the syndrome as physical fitness ( 25%), considerably less than that contributed by genetic predispositions to insulin resistance.45 Proponents argue that it is insulin-resistant obese people, not insulin-sensitive ones, who suffer from increased rates of the diseases associated with the metabolic syndrome.46 To quote Gerald Reaven, "All obese people are not created equal—insulin resistance is the major determinant of cardiovascular disease in over-weight/obese individuals."46 Obesity is considered simply a modulator of the underlying disease.
Second is the issue of other diseases related to insulin resistance. Are they are a part of the metabolic syndrome From the pathophysiological perspective, conditions such as PCOS and NAFLD are a crucial part of the clinical picture of the insulin-resistant patient. However, they currently have little role in the clinical epidemiological perspective and thus in most current clinical definitions because they are not well-studied risk factors for CVD.
Finally, the difference in approach has implications for the inclusion of new components in clinical metabolic syndrome definitions. For example, some have criticized the predictive power of the metabolic syndrome relative to the Framingham risk equation and suggested the inclusion of age, sex, or smoking in the syndrome.22 Although these risk factors would certainly improve the syndrome's predictive power, they certainly are not consequences of insulin resistance.24 Proponents of the pathophysiological perspective would thus reject their inclusion. However, these same scientists may argue for the inclusion of adiponectin, which is highly correlated with insulin resistance, yet is not as well studied as a predictor of cardiovascular events.47,48 On the other hand, a risk factor such as C-reactive protein appears both to offer improved predictive power and to be a consequence of insulin resistance and thus is championed by scientists from both perspectives.49
Current Definitions
The WHO "working definition" published in 1998 and revised in 1999 was the first available clinical definition.17 This definition recognized CVD as the primary outcome of the syndrome and suggested that whereas "each component of the cluster conveys [cardiovascular] risk... as a combination they become much more powerful."17 This document recommended "vigorous early management of the syndrome"17 for the prevention of adverse cardiovascular events. Emphasis was placed on detection of insulin resistance, requiring either a direct or indirect measure of insulin sensitivity for diagnosis. The remaining criteria, two of which must be present, include elevated blood pressure, elevated triglycerides, reduced HDL, and central obesity.
The NCEP ATPIII proposed a simpler, easier-to-use definition in 200118 and revised it in 2005.29 The purpose of this definition was "to identify people at higher long-term risk for atherosclerotic cardiovascular disease" and target them for "clinical management of obesity and its metabolic complications."29 At least three of five well-known cardiovascular risk factors must be present for diagnosis. Emphasis is placed on abdominal obesity as measured by waist circumference rather than an explicit requirement for insulin resistance. In general, the NCEP ATPIII definition requires less abnormality in the risk variables than the WHO definition. The NCEP ATPIII noted that, with regard to etiology, "no single pathogenesis has been elucidated, nor may one exist."29
In 2003, the American Academy of Clinical Endocrinologists (AACE) proposed criteria for an "insulin resistance syndrome."50 AACE chose this term to refocus the discussion on the underlying pathogenesis of insulin resistance and resultant hyperinsulinemia. This definition, drawing largely from the pathophysiological perspective, is much broader and includes noncardiovascular consequences of insulin resistance, such as NAFLD and PCOS. A family history of type 2 diabetes is also considered a risk factor for the syndrome. Most strikingly, there is no set number of criteria necessary for diagnosis; AACE considers this a matter to be determined by physicians. Thus, the purpose of the AACE definition is to alert physicians to the underlying metabolic state of patients, rather than to indicate a particular level of cardiovascular risk. A comparison of these definitions is shown in Table 4.
The International Diabetes Federation (IDF) definition, proposed in 2005, is the most recent entry into the competition to define the metabolic syndrome.44 It nearly reiterates the NCEP ATPIII definition, yet it takes the emphasis on central obesity even further by requiring an enlarged waist circumference for diagnosis.
Remaining Questions
Which perspective best represents the metabolic syndrome Should the focus be on the pathophysiology of insulin resistance and its consequences Or should the focus be on the use of risk factor clusters to predict cardiovascular events Answers to these questions will determine how we assess the utility of the syndrome in our clinical practices and how we approach proposed clinical definitions such as those of the WHO and the NCEP ATPIII.
From the pathophysiological perspective, clinicians should critically evaluate the following questions:
Do insulin resistance and the resultant compensatory hyperinsulinemia adequately explain the risk factor clustering
Do current clinical definitions adequately identify individuals who are insulin resistant
Can insulin resistance be treated
Can the complications of insulin resistance/hyperinsulinemia be prevented
From the clinical epidemiological perspective, we must ask:
Does the metabolic syndrome predict cardiovascular events better than its component risk factors
Why are certain risk factors for CVD included in the definition, whereas others are not (e.g., C-reactive protein)51
Why dichotomize risk variables with a binary metabolic syndrome definition when a risk equation with continuous measures would better express overall risk
Are all patients with metabolic syndrome at similar risk, or is it in fact a more heterogeneous group
Does the treatment for metabolic syndrome differ from the common treatment of its individual component risk factors
These questions have been reviewed in detail elsewhere.21 By organizing them according to perspective (pathophysiological versus clinical epidemiological), we hope to help clinicians focus their evaluation of metabolic syndrome based on explicit expectations of the concept in their own clinical practices.
Clinical Utility
During the past year, both the American Diabetes Association (ADA)21 and the American Heart Association (AHA)28 have published position statements on the metabolic syndrome. The ADA, leaning toward the pathophysiological perspective, cites imprecise definition of the syndrome, lack of certainty over its pathogenesis, and doubt about its use as a single CVD risk marker in its decision to not support clinical use of the metabolic syndrome. At the very least, the ADA prefers that patients with type 2 diabetes not be eligible for diagnosis. The ADA appears frustrated with the present trajectory of the metabolic syndrome, stating that the supporters of the syndrome "focus on the syndrome and don't concentrate on the disease."21
In sharp contrast, the AHA stands behind the NCEP ATPIII definition of the metabolic syndrome. While admitting its imperfections, the AHA argues that the diagnostic criteria are in evolution and that the syndrome represents a significant step forward in the holistic treatment of the commonly overlooked cardiovascular risk factors seen in obese patients. This organization is less troubled by a unifying pathogenesis, stating that the syndrome probably has more than one cause. "Regardless of cause," the AHA statement notes, "the syndrome identifies individuals at elevated risk for atherosclerotic cardiovascular disease."28
Scott Grundy, a lipidologist and champion of the NCEP ATPIII definition, has recently published an article titled "Metabolic Syndrome: Connecting and Reconciling Cardiovascular and Diabetes Worlds."41 Indeed, a growing number of clinicians are noticing the divergence between the diabetes and cardiology communities. Others simply conclude that, given the seemingly arbitrary clinical definitions and the uncertain clinical utility, the metabolic syndrome should be declared dead.23 Who is right The answer depends, as usual, on your perspective.
Perspectives are rarely changed by another review article. Events, not words, change perspectives. The most likely event that would bridge these differences, if not render them moot, would be the development of new products that either target an underlying unifying pathophysiological process or a system that modulates that process. Several possibilities, ranging from the thiazolidinedione-like class peroxisome proliferator-activated receptor-, agonists targeting insulin resistance52,53 to newer agents selectively targeting the endocannabinoid system,54,55 may bring some resolution to this debate. They may, that is, if they prove safe and effective in treating individuals with an agreed-upon cluster of findings.
In the meantime, physicians must be clear what they mean by "metabolic syndrome." With more precise usage of this term, we might make focused criticisms of the current clinical definitions of the syndrome and make informed decisions about the usefulness of the metabolic syndrome concept in our own clinical practices.
Michael Blaha, MD, is a medical house officer at Johns Hopkins School of Medicine in Baltimore Md. Tom A. Elasy, MD, MPH, is medical director of the Vanderbilt Eskind Diabetes Clinic and the Ann and Roscoe R. Robinson Associate Professor of Medicine at Vanderbilt University Medical Center in Nashville, Tenn.
REFERENCES
1 Kylin E: Studien hypertonie-hyperglykamiehyperurikamie syndrome. Zentralblatt fur innere. Medizin 44:105 -127, 1923
2 Avogaro P, Crepaldi G, Enzi G, Tiengo A: Associazione di iperlipidemia, diabete mellito e obesita di medio grado. Acto Diabetol Lat 4 : 36-41,1967
3 Reaven G: Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes 37:1595 -1607, 1988
4 Zavaroni I, Bonora E, Pagliara M, Dall'Aglio E, Luchetti L, Buonanno G, Bonati PA, Bergonzani M, Gnudi L, Passeri M: Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 320:702 -706, 1989
5 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 263:2893 -2898, 1990
6 Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP: Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes41 : 717-722,1992
7 Schmidt MI, Duncan BB, Watson RL, Sharrett AR, Brancati FL, Heiss G: A metabolic syndrome in whites and African-Americans: the Atherosclerosis Risk in Communities baseline study. Diabetes Care 19:414 -418, 1996
8 Meigs JB, D'Agostino RB Sr, Wilson PW, Cupples LA, Nathan DM, Singer DE: Risk variable clustering in the insulin resistance syndrome: the Framingham Offspring Study. Diabetes 46:1594 -1600, 1997
9 Meigs JB: Invited Commentary: Insulin resistance syndrome Syndrome X Multiple metabolic syndrome A syndrome at all Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 152 : 908-911,2000
10 Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP: Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 152:897 -907, 2000
11 Hanley AJ, Karter AJ, Festa A, D'Agostino R Jr, Wagenknecht LE, Savage P, Tracy RP, Saad MF, Haffner S: Factor analysis of metabolic syndrome using directly measured insulin sensitivity: the Insulin Resistance Atherosclerosis Study. Diabetes 51:2642 -2647, 2002
12 Shen BJ, Todaro JF, Niaura R, McCaffery JM, Zhang J, Spiro A 3rd, Ward KD: Are metabolic risk factors one unified syndrome Modeling the structure of the metabolic syndrome X. Am J Epidemiol 157:701 -711, 2003
13 Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709 -2716, 2002
14 Wilson PW, Kannel WB, Silbershatz H, D'Agostino RB: Clustering of metabolic factors and coronary heart disease. Arch Intern Med159 : 1104-1109,1999
15 Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K: Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year followup results of the Helsinki Policemen Study. Arterioscler Thromb Vasc Biol20 : 538-544,2000
16 Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L: Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683 -689, 2001
17 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 Med15 : 539-553,1998
18 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) final report. Circulation 106: 3143-3421,2002
19 Mitka M: Metabolic syndrome recasts old cardiac, diabetes risk factors as a "new" entity. JAMA 291:2062 -2063, 2004
20 Hill JO, Bessesen D: What to do about the metabolic syndrome Arch Intern Med 163: 395-397,2003
21 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 Care28 : 2289-2304,2005
22 Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM: Does the metabolic syndrome improve identification of individuals at risk for type 2 diabetes and/or cardiovascular disease Diabetes Care27 : 2676-2681,2004
23 Reaven GM: The metabolic syndrome: requiescat in pace. Clin Chem51 : 931-938,2005
24 Reaven G: The metabolic syndrome or the insulin resistance syndrome Different names, different concepts, and different goals. Endocrinol Metab Clinics North Am 33:283 -303, 2004
25 McLaughlin T, Allison G, Abbasi F, Lamendola C, Reaven G: Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals. Metab Clin Exp53 : 495-499,2994
26 Reaven GM: Insulin resistance, cardiovascular disease, and the metabolic syndrome: how well do the emperor's clothes fit Diabetes Care27 : 1011-1012,2004
27 Grundy SM: What is the contribution of obesity to the metabolic syndrome Endocrinol Metab Clinics North Am 33:267 -282, 2004
28 Grundy SM: Metabolic syndrome scientific statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Arterioscler Thromb Vasc Biol 25:2243 -2244, 2005
29 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F; American Heart Association; National Heart, Lung, and Blood Institute: Diagnosis and management of the metabolic syndrome. Circulation 112:2735 -2752, 2005
30 Grundy SM: Point: the metabolic syndrome still lives. Clin Chem51 : 1352-1354,2005
31 Alexander CM, Landsman PB, Teutsch SM, Haffner SM: NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes52 : 1210-1214,2003
32 Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K: Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 164: 1066-1076,2004
33 Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP: National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 110:1251 -1257, 2004
34 Athyros VG, Mikhailidis DP, Papageorgiou AA, Didangelos TP, Ganotakis ES, Symeonidis AN, Daskalopoulou SS, Kakafika AI, Elisaf M; METS-GREECE Collaborative Group: Prevalence of atherosclerotic vascular disease among subjects with the metabolic syndrome with or without diabetes mellitus: the METS-GREECE Multicentre Study. Curr Med Res Opin 20 : 1691-1701,2004
35 Girman CJ, Rhodes T, Mercuri M, Pyorala K, Kjekshus J, Pedersen TR, Beere PA, Gotto AM, Clearfield M; 4S Group and the AFCAPS/TexCAPS Research Group: The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol93 : 136-141,2004
36 Rutter MK, Meigs JB, Sullivan LM, D'Agostino RB Sr, Wilson PW: C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation110 : 380-385,2004
37 McNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE, Ballantyne CM, Heiss G: The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care 28: 385-390,2005
38 Scuteri A, Najjar SS, Morrell CH, Lakatta EG: The metabolic syndrome in older individuals: prevalence and prediction of cardiovascular events: the Cardiovascular Health Study. Diabetes Care 28:882 -887, 2005
39 Wannamethee SG, Shaper AG, Lennon L, Morris RW: Metabolic syndrome vs. Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 165:2644 -2650, 2005
40 Sattar N, Gaw A, Scherbakova O, Ford I, O'Reilly DS, Haffner SM, Isles C, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J: Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 108:414 -419, 2003
41 Grundy SM: Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol 47:1093 -1100, 2006
42 Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, Shofer JB, Fish BE, Knopp RH, Kahn SE: Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. Diabetes53 : 2087-2094,2004
43 Laakso M, Kovanen P: Metabolic syndrome: to be or not to be Ann Med38 : 32-33,2006
44 Alberti KG, Zimmet P, Shaw J, Group IDFETFC: The metabolic syndrome—a new worldwide definition. Lancet 366:1059 -1062, 2005
45 Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven G: Relationship between degree of obesity and in vivo insulin action in man. Am J Physiol 248:E286 -E291, 1985
46 Reaven G: All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diabetes Vasc Dis Res 2:105 -112, 2005
47 Chandran M, Phillips SA, Ciaraldi T, Henry RR: Adiponectin: more than just another fat cell hormone Diabetes Care 26:2442 -2450, 2003
48 Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB: Plasma adiponectin levels and risk of myocardial infarction in men. JAMA291 : 1730-1737,2004
49 Ridker PM, Wilson PWF, Grundy SM: Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk Circulation 109:2818 -2825, 2004
50 Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, Hellman R, Jellinger PS, Kendall D, Krauss RM, Neufeld ND, Petak SM, Rodbard HW, Seibel JA, Smith DA, Wilson PW: American College of Endocrinology position statement on the insulin resistance syndrome. Endocrine Pract9 : 237-252,2003
51 Grundy SM: The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol 97:3A -11A, 2006
52 Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation106 : 679-684,2002
53 Barish G, Narkar V, Evans R: PPARdelta: a dagger in the heart of the metabolic syndrome. J Clin Invest 116:590 -597, 2006
54 Despres J, Golay A, Sjostrom L; Group RiO-LS: Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med353 : 2121-2134,2005
55 Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J; Group RI-NAS: Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients. RIO-North America: a randomized controlled trial. JAMA 295:761 -775, 2006(Michael Blaha, MD and Tom)
IN BRIEF
The term "metabolic syndrome" refers to a cluster of risk factors for cardiovascular disease and type 2 diabetes that occurs as a result of obesity and insulin resistance. Considerable confusion surrounding the precise use of this term in the clinical setting has led to difficulty in assessing the utility of this concept. This article provides a simple framework for understanding the disparate approaches to this syndrome. This understanding will facilitate decision-making regarding the role of the metabolic syndrome in everyday clinical practice.
Introduction
Stated generally, the metabolic syndrome is a multiplex risk factor for cardiovascular disease (CVD) and type 2 diabetes that reflects the clustering of individual risk factors resulting from obesity and insulin resistance. Currently, this multiplex is thought to be composed of the following broadly stated metabolic risk conditions: atherogenic dyslipidemia, hypertension, glucose intolerance, proinflammatory state, and a prothrombotic state. Atherogenic dyslipidemia is itself an aggregate term encompassing elevated triglycerides and apolipoprotein B, increased small LDL particles, and reduced HDL.
Although the metabolic syndrome is a relatively new concept, research into the clustering of individual cardiovascular risk factors is an old enterprise. In the 1920s, investigators were reporting the occurrence of hyperglycemia, hypertension, and hyperuricema in certain groups of individuals.1 In the 1960s, obesity and hyperlipidemia were added to this cluster.2 Then in 1988, Gerald Reaven systematized the concept of a risk factor syndrome and suggested that insulin resistance and resultant compensatory hyperinsulinemia could mechanistically explain most of this clustering phenomenon.3 At that time, the treatment for what he called "syndrome X" was thought to be lifestyle modification. Since 1988, there has been a flurry of research corroborating the idea of a risk factor cluster mediated by insulin resistance,4-7 describing it using factor analysis,8-13 and linking it with CVD.13-16
A new thread in the story of the metabolic syndrome emerged at the turn of the millennium. Several groups, including the World Health Organization (WHO)17 and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII),18 published clinical definitions of the metabolic syndrome intended for use in assigning clinical diagnoses to patients. This was followed by creation of an International Classification of Diseases diagnostic code (277.7) for metabolic syndrome. 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 current confusion about whether the term "metabolic syndrome" refers to pathophysiological observation or clinical diagnosis stems from this abrupt change in focus.
Confusion has led to a climate of skepticism about the future of the metabolic syndrome. Is it an artificial, mathematical concept that simply recasts old known risk factors into a new disease entity19 Or does the clustering indeed reflect a single pathophysiology that can be a target for therapeutic decisions20,21 Can the metabolic syndrome offer advantages over existing models for the prediction of cardiovascular events22 Or, given the confusion and the lingering doubts about its potential role in clinical practice, should the metabolic syndrome simply be declared dead23 Although these are all defensible concerns, the current conflict over the metabolic syndrome is still largely about differences in its intended function. The trouble remains ambiguity about what the metabolic syndrome is, how it should be defined, and what the purpose is for its existence.
Given the confusion over the metabolic syndrome, we sought to make explicit the present usage of the term in the literature and to suggest a framework for organizing its many descriptions.
Methods
We searched the National Library of Medicine's Medline database for human studies published since 1988, using combinations of the following text words in their titles or abstracts: "metabolic syndrome," "definition," "insulin resistance syndrome," "dysmetabolic syndrome," and "syndrome X." The search was augmented by scanning selected journals through March 2006. Bibliographies of all retrieved articles served as a check of the completeness of the electronic search.
After screening the titles of the 4,544 identified articles, we examined abstracts of 1,620 articles available in English for pertinence to the study objective. Full text was examined of 442 articles incorporating explicit use of the metabolic syndrome as either a study exposure or an outcome. Studies referring to a different metabolic syndrome (e.g., microvascular angina syndromes) and studies lacking a clear definition of the metabolic syndrome were excluded.
The descriptions of the metabolic syndrome used in the selected studies were abstracted, and the articles were grouped by their approach to defining the syndrome.
Pathophysiological Perspective
The pathophysiological perspective seeks to demonstrate how a single defect, insulin resistance, leads to a variety of pathological changes (Table 1), resulting in increased risk for a constellation of clinical conditions (Table 2).24 It should be noted that CVD is just one of these important clinical conditions. Whereas the outdated term "syndrome X" focused only on CVD, we now understand that insulin resistance is mechanistically implicated in the development of polycystic ovarian syndrome (PCOS), nonalcoholic fatty liver disease (NAFLD), breast cancer, and other conditions. In this way, the intent of the metabolic syndrome is to provide a conceptual framework for understanding why clinical conditions cluster in individual patients. In short, it explains to practitioners why an obese, insulin-resistant individual is likely to have elevated liver transaminases (NAFLD), irregular menstrual cycles (PCOS), and a proinflammatory state manifested by elevated C-reactive protein and be at risk for developing several types of cancer.
From the pathophysiological perspective, the blame for the syndrome rests squarely on insulin resistance and the resultant hyperinsulinemia. This view is supported by evidence from the basic science and clinical research laboratories from the past 30 years.3,24 Obesity is thought to exacerbate insulin resistance and thus increase the likelihood of an associated adverse clinical condition, but it is not considered a fundamental component of the syndrome because it need not be present. Proponents defend this decision with data showing that insulin resistance is indeed not a cause of obesity24 and that the clustering of risk factors can occur in insulin-resistant individuals of normal weight.25 Most of those approaching the metabolic syndrome from this perspective, particularly basic scientists and endocrinologists, prefer the term "insulin resistance syndrome" to stress the underlying pathophysiology.
The primary goal of the metabolic syndrome from the pathophysiological perspective is to alert physicians to an increased likelihood of multiple adverse conditions in insulin-resistant patients. Making a clinical diagnosis of metabolic syndrome based on strict criteria is not the focus, nor is using the syndrome as a cardiovascular risk calculator. From this perspective, the prevalence of metabolic syndrome can simply be defined by the distribution of insulin sensitivity in the population. Approximately one-third of the apparently healthy population is sufficiently insulin resistant to be at increased risk for the abnormalities shown in Table 2.26 The current treatment for these individuals is considered to be lifestyle modification for the improvement of insulin sensitivity.
Clinical Epidemiological Perspective
The clinical epidemiological perspective seeks to assemble a group of related metabolic risk factors and to use this grouping for the prediction of future cardiovascular events. Decisions about which risk factors comprise the metabolic syndrome and their threshold values are based largely on their predictive values, with less emphasis on a unifying pathophysiological entity. Thus, from this perspective, obesity is considered a core component of the metabolic syndrome rather than a modulator of the effects of insulin resistance.27
The primary clinical goals of this approach are to make a diagnosis of metabolic syndrome and to use this diagnosis for risk stratification of patients according to their long-term likelihood (> 10-30 years) for atherosclerotic CVD.28,29 The metabolic syndrome is not designed to be a competitor to the Framingham risk score, which calculates short-term risk over the course of 10 years.30 Rather, it is formulated to aid the global assessment of lifetime risk. Generally speaking, advocates of this approach to the metabolic syndrome include lipid specialists and cardiologists. First-line treatment for metabolic syndrome is once again lifestyle intervention, with particular attention to dyslipidemia.18,29
Advocates of this approach support their formulations of the metabolic syndrome with data from population-based epidemiological studies.13,16,31-40 Frequently, these are post hoc analyses of large prospective cohort studies or clinical trials. In general, these studies support the idea that a cluster of metabolic risk factors can predict cardiovascular outcomes better than the sum of its component risk variables considered individually.41 For example, Isomaa et al.16 found a threefold increased risk of coronary heart disease and stroke with the metabolic syndrome in the Botnia study, and Lakka et al.13 reported a relative risk of 4.2 for death from coronary heart disease after adjusting for known risk factors in the Kuopio Ischaemic Heart Disease Risk Factor Study. However, few cohorts have been assembled with the primary intent of studying the metabolic syndrome.
Differences in the Perspectives
These two approaches to the metabolic syndrome are fundamentally different. (Table 3.) The pathophysiological perspective begins with a single defect, insulin resistance, and explores its consequences. CVD is just one of these consequences. The clinical epidemiological perspective is concerned primarily with CVD and the construction of a set of risk factors that best predict cardiovascular outcomes. From this perspective, insulin resistance may or may not explain the clustering phenomenon relating the risk factors; the pathophysiological mechanism is less immediate.
These two approaches can perhaps be better understood with a simple analogy. In many ways, the difference between the goals of the pathophysiological and clinical epidemiological perspectives is analogous to the differences between an exploratory prospective study and a retrospective case-control study (Figure 1). In a prospective study, a single exposure is defined, with the goal of measuring a set of outcomes that might be associated with that exposure. In a similar way, the pathophysiological perspective seeks to begin with a single exposure, insulin resistance, and explain how it leads to variety of clinical conditions (PCOS, NAFLD, and CVD, for example). In a case-control study, a single outcome is defined, and the goal of the study is to construct a set of risk factors for that outcome. In a similar way, the clinical epidemiological perspective begins with a single outcome, CVD, and attempts to describe a set of correlated risk factors for the prediction of CVD.
There are several implications of this difference in approach. Foremost is the impact on our understanding of the role of obesity in the metabolic syndrome. From the clinical epidemiological perspective, obesity is thought to play the central role because it best explains the occurrence of the other syndrome components, and in many studies it is the individual component most predictive of CVD.42-44 From this perspective, the metabolic syndrome epidemic has resulted from an obesity epidemic, and reducing patient weight is therefore viewed as a goal of therapy. From the pathophysiological perspective, obesity plays a peripheral role in the metabolic syndrome. Adiposity is considered a modest contributor to the metabolic syndrome, explaining about as much of the variation in the syndrome as physical fitness ( 25%), considerably less than that contributed by genetic predispositions to insulin resistance.45 Proponents argue that it is insulin-resistant obese people, not insulin-sensitive ones, who suffer from increased rates of the diseases associated with the metabolic syndrome.46 To quote Gerald Reaven, "All obese people are not created equal—insulin resistance is the major determinant of cardiovascular disease in over-weight/obese individuals."46 Obesity is considered simply a modulator of the underlying disease.
Second is the issue of other diseases related to insulin resistance. Are they are a part of the metabolic syndrome From the pathophysiological perspective, conditions such as PCOS and NAFLD are a crucial part of the clinical picture of the insulin-resistant patient. However, they currently have little role in the clinical epidemiological perspective and thus in most current clinical definitions because they are not well-studied risk factors for CVD.
Finally, the difference in approach has implications for the inclusion of new components in clinical metabolic syndrome definitions. For example, some have criticized the predictive power of the metabolic syndrome relative to the Framingham risk equation and suggested the inclusion of age, sex, or smoking in the syndrome.22 Although these risk factors would certainly improve the syndrome's predictive power, they certainly are not consequences of insulin resistance.24 Proponents of the pathophysiological perspective would thus reject their inclusion. However, these same scientists may argue for the inclusion of adiponectin, which is highly correlated with insulin resistance, yet is not as well studied as a predictor of cardiovascular events.47,48 On the other hand, a risk factor such as C-reactive protein appears both to offer improved predictive power and to be a consequence of insulin resistance and thus is championed by scientists from both perspectives.49
Current Definitions
The WHO "working definition" published in 1998 and revised in 1999 was the first available clinical definition.17 This definition recognized CVD as the primary outcome of the syndrome and suggested that whereas "each component of the cluster conveys [cardiovascular] risk... as a combination they become much more powerful."17 This document recommended "vigorous early management of the syndrome"17 for the prevention of adverse cardiovascular events. Emphasis was placed on detection of insulin resistance, requiring either a direct or indirect measure of insulin sensitivity for diagnosis. The remaining criteria, two of which must be present, include elevated blood pressure, elevated triglycerides, reduced HDL, and central obesity.
The NCEP ATPIII proposed a simpler, easier-to-use definition in 200118 and revised it in 2005.29 The purpose of this definition was "to identify people at higher long-term risk for atherosclerotic cardiovascular disease" and target them for "clinical management of obesity and its metabolic complications."29 At least three of five well-known cardiovascular risk factors must be present for diagnosis. Emphasis is placed on abdominal obesity as measured by waist circumference rather than an explicit requirement for insulin resistance. In general, the NCEP ATPIII definition requires less abnormality in the risk variables than the WHO definition. The NCEP ATPIII noted that, with regard to etiology, "no single pathogenesis has been elucidated, nor may one exist."29
In 2003, the American Academy of Clinical Endocrinologists (AACE) proposed criteria for an "insulin resistance syndrome."50 AACE chose this term to refocus the discussion on the underlying pathogenesis of insulin resistance and resultant hyperinsulinemia. This definition, drawing largely from the pathophysiological perspective, is much broader and includes noncardiovascular consequences of insulin resistance, such as NAFLD and PCOS. A family history of type 2 diabetes is also considered a risk factor for the syndrome. Most strikingly, there is no set number of criteria necessary for diagnosis; AACE considers this a matter to be determined by physicians. Thus, the purpose of the AACE definition is to alert physicians to the underlying metabolic state of patients, rather than to indicate a particular level of cardiovascular risk. A comparison of these definitions is shown in Table 4.
The International Diabetes Federation (IDF) definition, proposed in 2005, is the most recent entry into the competition to define the metabolic syndrome.44 It nearly reiterates the NCEP ATPIII definition, yet it takes the emphasis on central obesity even further by requiring an enlarged waist circumference for diagnosis.
Remaining Questions
Which perspective best represents the metabolic syndrome Should the focus be on the pathophysiology of insulin resistance and its consequences Or should the focus be on the use of risk factor clusters to predict cardiovascular events Answers to these questions will determine how we assess the utility of the syndrome in our clinical practices and how we approach proposed clinical definitions such as those of the WHO and the NCEP ATPIII.
From the pathophysiological perspective, clinicians should critically evaluate the following questions:
Do insulin resistance and the resultant compensatory hyperinsulinemia adequately explain the risk factor clustering
Do current clinical definitions adequately identify individuals who are insulin resistant
Can insulin resistance be treated
Can the complications of insulin resistance/hyperinsulinemia be prevented
From the clinical epidemiological perspective, we must ask:
Does the metabolic syndrome predict cardiovascular events better than its component risk factors
Why are certain risk factors for CVD included in the definition, whereas others are not (e.g., C-reactive protein)51
Why dichotomize risk variables with a binary metabolic syndrome definition when a risk equation with continuous measures would better express overall risk
Are all patients with metabolic syndrome at similar risk, or is it in fact a more heterogeneous group
Does the treatment for metabolic syndrome differ from the common treatment of its individual component risk factors
These questions have been reviewed in detail elsewhere.21 By organizing them according to perspective (pathophysiological versus clinical epidemiological), we hope to help clinicians focus their evaluation of metabolic syndrome based on explicit expectations of the concept in their own clinical practices.
Clinical Utility
During the past year, both the American Diabetes Association (ADA)21 and the American Heart Association (AHA)28 have published position statements on the metabolic syndrome. The ADA, leaning toward the pathophysiological perspective, cites imprecise definition of the syndrome, lack of certainty over its pathogenesis, and doubt about its use as a single CVD risk marker in its decision to not support clinical use of the metabolic syndrome. At the very least, the ADA prefers that patients with type 2 diabetes not be eligible for diagnosis. The ADA appears frustrated with the present trajectory of the metabolic syndrome, stating that the supporters of the syndrome "focus on the syndrome and don't concentrate on the disease."21
In sharp contrast, the AHA stands behind the NCEP ATPIII definition of the metabolic syndrome. While admitting its imperfections, the AHA argues that the diagnostic criteria are in evolution and that the syndrome represents a significant step forward in the holistic treatment of the commonly overlooked cardiovascular risk factors seen in obese patients. This organization is less troubled by a unifying pathogenesis, stating that the syndrome probably has more than one cause. "Regardless of cause," the AHA statement notes, "the syndrome identifies individuals at elevated risk for atherosclerotic cardiovascular disease."28
Scott Grundy, a lipidologist and champion of the NCEP ATPIII definition, has recently published an article titled "Metabolic Syndrome: Connecting and Reconciling Cardiovascular and Diabetes Worlds."41 Indeed, a growing number of clinicians are noticing the divergence between the diabetes and cardiology communities. Others simply conclude that, given the seemingly arbitrary clinical definitions and the uncertain clinical utility, the metabolic syndrome should be declared dead.23 Who is right The answer depends, as usual, on your perspective.
Perspectives are rarely changed by another review article. Events, not words, change perspectives. The most likely event that would bridge these differences, if not render them moot, would be the development of new products that either target an underlying unifying pathophysiological process or a system that modulates that process. Several possibilities, ranging from the thiazolidinedione-like class peroxisome proliferator-activated receptor-, agonists targeting insulin resistance52,53 to newer agents selectively targeting the endocannabinoid system,54,55 may bring some resolution to this debate. They may, that is, if they prove safe and effective in treating individuals with an agreed-upon cluster of findings.
In the meantime, physicians must be clear what they mean by "metabolic syndrome." With more precise usage of this term, we might make focused criticisms of the current clinical definitions of the syndrome and make informed decisions about the usefulness of the metabolic syndrome concept in our own clinical practices.
Michael Blaha, MD, is a medical house officer at Johns Hopkins School of Medicine in Baltimore Md. Tom A. Elasy, MD, MPH, is medical director of the Vanderbilt Eskind Diabetes Clinic and the Ann and Roscoe R. Robinson Associate Professor of Medicine at Vanderbilt University Medical Center in Nashville, Tenn.
REFERENCES
1 Kylin E: Studien hypertonie-hyperglykamiehyperurikamie syndrome. Zentralblatt fur innere. Medizin 44:105 -127, 1923
2 Avogaro P, Crepaldi G, Enzi G, Tiengo A: Associazione di iperlipidemia, diabete mellito e obesita di medio grado. Acto Diabetol Lat 4 : 36-41,1967
3 Reaven G: Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes 37:1595 -1607, 1988
4 Zavaroni I, Bonora E, Pagliara M, Dall'Aglio E, Luchetti L, Buonanno G, Bonati PA, Bergonzani M, Gnudi L, Passeri M: Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 320:702 -706, 1989
5 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 263:2893 -2898, 1990
6 Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP: Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes41 : 717-722,1992
7 Schmidt MI, Duncan BB, Watson RL, Sharrett AR, Brancati FL, Heiss G: A metabolic syndrome in whites and African-Americans: the Atherosclerosis Risk in Communities baseline study. Diabetes Care 19:414 -418, 1996
8 Meigs JB, D'Agostino RB Sr, Wilson PW, Cupples LA, Nathan DM, Singer DE: Risk variable clustering in the insulin resistance syndrome: the Framingham Offspring Study. Diabetes 46:1594 -1600, 1997
9 Meigs JB: Invited Commentary: Insulin resistance syndrome Syndrome X Multiple metabolic syndrome A syndrome at all Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 152 : 908-911,2000
10 Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP: Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 152:897 -907, 2000
11 Hanley AJ, Karter AJ, Festa A, D'Agostino R Jr, Wagenknecht LE, Savage P, Tracy RP, Saad MF, Haffner S: Factor analysis of metabolic syndrome using directly measured insulin sensitivity: the Insulin Resistance Atherosclerosis Study. Diabetes 51:2642 -2647, 2002
12 Shen BJ, Todaro JF, Niaura R, McCaffery JM, Zhang J, Spiro A 3rd, Ward KD: Are metabolic risk factors one unified syndrome Modeling the structure of the metabolic syndrome X. Am J Epidemiol 157:701 -711, 2003
13 Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709 -2716, 2002
14 Wilson PW, Kannel WB, Silbershatz H, D'Agostino RB: Clustering of metabolic factors and coronary heart disease. Arch Intern Med159 : 1104-1109,1999
15 Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K: Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year followup results of the Helsinki Policemen Study. Arterioscler Thromb Vasc Biol20 : 538-544,2000
16 Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L: Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683 -689, 2001
17 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 Med15 : 539-553,1998
18 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) final report. Circulation 106: 3143-3421,2002
19 Mitka M: Metabolic syndrome recasts old cardiac, diabetes risk factors as a "new" entity. JAMA 291:2062 -2063, 2004
20 Hill JO, Bessesen D: What to do about the metabolic syndrome Arch Intern Med 163: 395-397,2003
21 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 Care28 : 2289-2304,2005
22 Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM: Does the metabolic syndrome improve identification of individuals at risk for type 2 diabetes and/or cardiovascular disease Diabetes Care27 : 2676-2681,2004
23 Reaven GM: The metabolic syndrome: requiescat in pace. Clin Chem51 : 931-938,2005
24 Reaven G: The metabolic syndrome or the insulin resistance syndrome Different names, different concepts, and different goals. Endocrinol Metab Clinics North Am 33:283 -303, 2004
25 McLaughlin T, Allison G, Abbasi F, Lamendola C, Reaven G: Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals. Metab Clin Exp53 : 495-499,2994
26 Reaven GM: Insulin resistance, cardiovascular disease, and the metabolic syndrome: how well do the emperor's clothes fit Diabetes Care27 : 1011-1012,2004
27 Grundy SM: What is the contribution of obesity to the metabolic syndrome Endocrinol Metab Clinics North Am 33:267 -282, 2004
28 Grundy SM: Metabolic syndrome scientific statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Arterioscler Thromb Vasc Biol 25:2243 -2244, 2005
29 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F; American Heart Association; National Heart, Lung, and Blood Institute: Diagnosis and management of the metabolic syndrome. Circulation 112:2735 -2752, 2005
30 Grundy SM: Point: the metabolic syndrome still lives. Clin Chem51 : 1352-1354,2005
31 Alexander CM, Landsman PB, Teutsch SM, Haffner SM: NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes52 : 1210-1214,2003
32 Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K: Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 164: 1066-1076,2004
33 Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP: National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 110:1251 -1257, 2004
34 Athyros VG, Mikhailidis DP, Papageorgiou AA, Didangelos TP, Ganotakis ES, Symeonidis AN, Daskalopoulou SS, Kakafika AI, Elisaf M; METS-GREECE Collaborative Group: Prevalence of atherosclerotic vascular disease among subjects with the metabolic syndrome with or without diabetes mellitus: the METS-GREECE Multicentre Study. Curr Med Res Opin 20 : 1691-1701,2004
35 Girman CJ, Rhodes T, Mercuri M, Pyorala K, Kjekshus J, Pedersen TR, Beere PA, Gotto AM, Clearfield M; 4S Group and the AFCAPS/TexCAPS Research Group: The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol93 : 136-141,2004
36 Rutter MK, Meigs JB, Sullivan LM, D'Agostino RB Sr, Wilson PW: C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation110 : 380-385,2004
37 McNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE, Ballantyne CM, Heiss G: The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care 28: 385-390,2005
38 Scuteri A, Najjar SS, Morrell CH, Lakatta EG: The metabolic syndrome in older individuals: prevalence and prediction of cardiovascular events: the Cardiovascular Health Study. Diabetes Care 28:882 -887, 2005
39 Wannamethee SG, Shaper AG, Lennon L, Morris RW: Metabolic syndrome vs. Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 165:2644 -2650, 2005
40 Sattar N, Gaw A, Scherbakova O, Ford I, O'Reilly DS, Haffner SM, Isles C, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J: Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 108:414 -419, 2003
41 Grundy SM: Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol 47:1093 -1100, 2006
42 Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, Shofer JB, Fish BE, Knopp RH, Kahn SE: Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. Diabetes53 : 2087-2094,2004
43 Laakso M, Kovanen P: Metabolic syndrome: to be or not to be Ann Med38 : 32-33,2006
44 Alberti KG, Zimmet P, Shaw J, Group IDFETFC: The metabolic syndrome—a new worldwide definition. Lancet 366:1059 -1062, 2005
45 Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven G: Relationship between degree of obesity and in vivo insulin action in man. Am J Physiol 248:E286 -E291, 1985
46 Reaven G: All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diabetes Vasc Dis Res 2:105 -112, 2005
47 Chandran M, Phillips SA, Ciaraldi T, Henry RR: Adiponectin: more than just another fat cell hormone Diabetes Care 26:2442 -2450, 2003
48 Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB: Plasma adiponectin levels and risk of myocardial infarction in men. JAMA291 : 1730-1737,2004
49 Ridker PM, Wilson PWF, Grundy SM: Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk Circulation 109:2818 -2825, 2004
50 Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, Hellman R, Jellinger PS, Kendall D, Krauss RM, Neufeld ND, Petak SM, Rodbard HW, Seibel JA, Smith DA, Wilson PW: American College of Endocrinology position statement on the insulin resistance syndrome. Endocrine Pract9 : 237-252,2003
51 Grundy SM: The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol 97:3A -11A, 2006
52 Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation106 : 679-684,2002
53 Barish G, Narkar V, Evans R: PPARdelta: a dagger in the heart of the metabolic syndrome. J Clin Invest 116:590 -597, 2006
54 Despres J, Golay A, Sjostrom L; Group RiO-LS: Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med353 : 2121-2134,2005
55 Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J; Group RI-NAS: Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients. RIO-North America: a randomized controlled trial. JAMA 295:761 -775, 2006(Michael Blaha, MD and Tom)