Reviews/Commentaries/ADA Statements ADA STATEMENT The Metabolic Syndrome: Time for a Critical Appraisal Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes 1 3 RICHARD KAHN, PHD ELE FERRANNINI, MD seemed clearly related to type 2 diabetes 2 4 JOHN BUSE, MD, PHD MICHAEL STERN, MD (15). This risk factor clustering, and its as- sociation with insulin resistance, led in- vestigators to propose the existence of a unique pathophysiological condition, The term “metabolic syndrome” refers to a clustering of specific cardiovascular disease (CVD) called the “metabolic” (1–3) or “insulin risk factors whose underlying pathophysiology is thought to be related to insulin resistance. resistance” (11) syndrome. This concept Since the term is widely used in research and clinical practice, we undertook an extensive review was unified and extended with the land- of the literature in relation to the syndrome’s definition, underlying pathogenesis, and associa- mark publication of Reaven’s 1988 tion with CVD and to the goals and impact of treatment. While there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been impre- Banting Medal award lecture (16). Reaven cisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable postulated that insulin resistance and its doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically compensatory hyperinsulinemia predis- important information is missing to warrant its designation as a “syndrome.” Until much needed posed patients to hypertension, hyperlip- research is completed, clinicians should evaluate and treat all CVD risk factors without regard to idemia, and diabetes and thus was the whether a patient meets the criteria for diagnosis of the “metabolic syndrome.” underlying cause of much CVD. Although obesity was not included in Reaven’s pri- Diabetes Care 28:2289–2304, 2005 mary list of disorders caused by insulin resistance, he acknowledged that it, too, was correlated with insulin resistance or or most of the 20th century, cardio- was first described, most notably the si- hyperinsulinemia, and that the obvious vascular disease (CVD) was identi- multaneous presence of obesity, type 2 “treatment” for what he termed “syn- F fied as the major cause of morbidity diabetes, hyperlipidemia, and hyperten- drome X” was weight maintenance (or and mortality in the developed world. sion (1–3). Although insulin resistance weight loss) and physical activity. During this period there was considerable (i.e., resistance to insulin-stimulated glu- Reaven’s seminal paper was followed effort to understand the underlying biol- cose uptake) as a feature of type 2 diabetes by many studies documenting the cluster- ogy of the disease and to identify the con- was first described many years earlier (4), ing of CVD risk factors and their relation- tributing risk factors. As risk factors were hyperinsulinemia was also found to be a ship to insulin resistance (17–25). identified, it became apparent that more key feature of type 2 diabetes (5,6), as well Indeed, since Reaven’s publication in than one were often present in the same as hyperlipidemia (7–9), obesity (10– 1988, a recent Medline search for articles individual. Toward the end of the cen- 13), and hypertension (12–14). In addi- using the key words “syndrome X” or “in- tury, the clustering of CVD risk factors tion, a cluster of heart disease risk factors sulin resistance syndrome” or “metabolic ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● syndrome” (conducted 28.01.2005) identified 4,646 citations, with 3,948 From the 1American Diabetes Association, Alexandria, Virginia; the 2Division of Endocrinology and of General Medicine & Clinical Epidemiology, University of North Carolina School of Medicine, Chapel Hill, studies performed on human subjects. North Carolina; the 3Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy; and The term “metabolic syndrome” has the 4Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center now taken hold in the medical literature. at San Antonio, San Antonio, Texas. It has been defined and institutionalized, Address correspondence and reprint requests to Richard Kahn, PhD, American Diabetes Association, 1701 N. Beauregard St., Alexandria, VA 22311. E-mail: [email protected]. principally by the World Health Organi- This statement was reviewed and approved by the Professional Practice Committee of the American zation (WHO) (26) and the Third Report Diabetes Association and by an ad hoc committee of the European Association for the Study of Diabetes of the National Cholesterol Education (members: H. Beck-Nielsen [Odense, Denmark], K. Borch-Johnsen [Gentofte, Denmark], E.A.M. Gale [Bris- Program’s Adult Treatment Panel (ATP tol, U.K.], L. Groop [Malmo¨, Sweden], H.-U. Ha¨ring [Tu¨ bingen, Germany], R.J. Heine [Amsterdam, the III) (27,28), albeit with different defini- Netherlands], and D.R. Matthews [Oxford, U.K.]). Simultaneous publication: This article is being simultaneously published in 2005 in Diabetes Care and tions. In addition, other organizations Diabetologia by the American Diabetes Association and the European Association for the Study of Diabetes. have developed similar, but again not Abbreviations: ATP III, Third Report of the National Cholesterol Education Program’s Adult Treatment identical, definitions (29,30). The fact Panel; CHD, coronary heart disease; CRP, C-reactive protein; CVD, cardiovascular disease; IFG, impaired that a version of the metabolic syndrome fasting glucose; IGT, impaired glucose tolerance; IMT, intimal-medial thickness; WHO, World Health Organization. has its own ICD-9 code (277.7) also sug- © 2005 by the American Diabetes Association, Inc., and Springer-Verlag. Copying with attribution gests that it is well thought out (31,32). allowed for any noncommercial use of the work. In this review we examine the evi- DIABETES CARE, VOLUME 28, NUMBER 9, SEPTEMBER 2005 2289 Critical appraisal of metabolic syndrome dence for its definition and underlying Table 1—Definitions of the metabolic syn- and specificity of the diagnosis and have pathogenesis, as well as analyzing the ev- drome undoubtedly led some physicians to diag- idence for its association with CVD. We ATP III definition (27,28) nose the metabolic syndrome in patients also discuss the evidence for the goals and Any three or more of the following who would not be labeled as such by impact of treatment. We mainly focused criteria: other providers. The impact of a false- our review on papers addressing the met- 1) Waist circumference Ͼ102 cm in men positive or a false-negative diagnosis has abolic syndrome as defined by ATP III, and Ͼ88 cm in women not been reported. the definition that appears to be used 2) Serum triglycerides Ն1.7 mmol/l Second, it is apparent that the defini- most often in the literature. Because the 3) Blood pressure Ն130/85 mmHg tions of the syndrome differ in the criteria ATP III and WHO definitions are some- 4) HDL cholesterol Ͻ1.0 mmol/l in men listed. For example, microalbuminuria is times used almost interchangeably or and Ͻ1.3 mmol/l in women listed in the WHO criteria but not in the compared with one another, we also ex- 5) Serum glucose Ն6.1 mmol/l (Ն5.6 ATP III; insulin resistance (as measured amined the literature that used the WHO mmol/l may be applicable) under hyperinsulinemic-euglycemic con- criteria. WHO definition (26) ditions) is relevant for WHO but not for For two reasons, we did not consider Diabetes, IFG, IGT, or insulin resistance ATP III. And while only an elevated fast- papers whose focus was on the ability of (assessed by clamp studies) and at least ing plasma glucose value is considered the metabolic syndrome to predict diabe- two of the following criteria: important in the ATP III definition, the tes. First, ample data show that the pres- 1) Waist-to-hip ratio Ͼ0.90 in men or WHO criteria recognize any measure ence of the metabolic syndrome is Ͼ0.85 in women whatsoever of insulin resistance. Al- effective in predicting the future risk of 2) Serum triglycerides Ն1.7 mmol/l or though it would promote better under- diabetes. That association, however, is HDL cholesterol Ͻ0.9 mmol/l in men standing of the justification for the criteria probably due to the fact that the definition and Ͻ1.0 mmol/l in women selected, no review of the clinical evi- of the syndrome includes glucose intoler- 3) Blood pressure Ն140/90 mmHg dence for inclusion or exclusion criteria ance, i.e., impaired fasting glucose (IFG) 4) Urinary albumin excretion rate Ͼ20 for either of the two definitions of the syn- or impaired glucose tolerance (IGT), ␮g/min or albumin-to-creatinine ratio drome has been published to date. themselves powerful predictors of future Ն30 mg/g Third and finally, the originally stated diabetes. Second, the practical use of di- rationale for the criteria is that the syn- agnosing metabolic syndrome has not drome components are associated with centered on its power to predict diabetes, 2) Does the treatment of the metabolic insulin resistance (26,27). But, as dis- but rather on its being a multivariate risk syndrome differ from the treatment of its cussed below, there is considerable doubt factor for CVD. individual components? whether all patients with the metabolic This review argues that the metabolic 3) What additional work should be done syndrome are indeed insulin resistant. syndrome is not nearly as well defined to improve our current knowledge of the More recently, a review of the ATP III def- and characterized as often assumed, and metabolic syndrome? inition (28) broadened the etiological ba- that the notion that it is a useful marker of sis for the syndrome from insulin CVD risk above and beyond the risk asso- Clarity of the existing definition resistance alone to include “obesity and ciated with its individual components is Table 1 shows the ATP III and WHO def- disorders of adipose tissue,” as well as a uncertain.