ORIGINAL ARTICLE

doi: 10.1111/j.1463-1326.2007.00724.x

National Cholesterol Education Program and International Diabetes Federation definitions of metabolic syndrome in the prediction of diabetes. Results from the FIrenze-Bagno A Ripoli study
E. Mannucci,1 M. Monami,1 B. Cresci,2 L. Pala,2 G. Bardini,2 M. G. Petracca,2 I. Dicembrini,2 A. Pasqua,3 E. Buiatti3 and C. M. Rotella2
1 2

Diabetes Section, Geriatric Unit, Department of Critical Care, University of Florence, Florence, Italy Endocrine Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy 3 Epidemiology Unit, Local Health Unit 10, Florence, Italy

Background: The International Diabetes Federation (IDF) proposed to modify the diagnostic criteria for metabolic syndrome (MS) previously issued by the National Cholesterol Education Program (NCEP). Aim of the present investigation is to compare the predictive value for diabetes of NCEP and IDF definitions of MS in a large sample of predominantly Caucasian subjects. Methods: A prospective observational study was performed on a cohort study (n ¼ 3096) enrolled in a diabetesscreening programme, the FIrenze-Bagno A Ripoli study. All subjects with fasting glucose >126 mg/dl and/or post-load glucose !200 mg/dl (5.7%) were excluded from the present analysis. Follow-up of each subject was continued until diagnosis of diabetes, death or until 31 December 2005. Mean follow-up was 27.7 Æ 11.3 months. Results: Among subjects enrolled, 13.7 and 25.2% were affected by MS using NCEP and IDF criteria respectively. During follow-up, 38 new cases of diabetes were diagnosed, with a yearly incidence rate of 0.5%. The relative risk for diabetes in subjects with MS was 10.10 [5.13; 20.00] and 7.87 [3.70; 16.7] using NCEP and IDF definitions respectively. After adjustment for age, sex, fasting glucose and waist circumference, NCEP-defined MS, but not IDF-, was significantly associated with incident diabetes (hazard ratio, 95% CI: 2.41 [1.01; 5.95] and 2.05 [0.80; 5.29] respectively). Conclusions: Although the reasons for the proposed changes in diagnostic criteria for MS are easily understandable, the newer IDF definition, while increasing estimates of prevalence of the syndrome, reduces the effectiveness of MS in identifying subjects at risk for diabetes. Further research is needed before the previous NCEP criteria are abandoned.
Keywords: diabetes, metabolic syndrome, obesity Received 2 December 2006; returned for revision 2 February 2007; revised version accepted 7 February 2007

Background and Aims
The International Diabetes Federation (IDF) proposed to modify the diagnostic criteria for metabolic syndrome

(MS) previously issued by the Adult Treatment Panel III of the National Cholesterol Education Program (NCEP) [1,2]. The threshold for fasting glucose and waist circumference was lowered, and abdominal adiposity was

Correspondence: Carlo Maria Rotella, MD, Section of Endocrinology, Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. E-mail: c.rotella@dfc.unifi.it

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Diabetes, Obesity and Metabolism, 10, 2008, 430–435

# 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd

metabolic syndrome. and each participant provided informed written consent. Brea.001 <0.1 100 100 p (95% CI) ns <0.e. 430–435 j 431 . or prevalence (%).9 47. female) Age (years) BMI (kg/m2) Total cholesterol (mg/dl) Impaired glucose tolerance (%) MS (%.5 12.05 <0. Plasma glucose was measured by a glucose oxidase method. Register of patients with diabetes in Florence Local Unit of the National Health Service. NCEP. was assessed in order to elucidate the specific effect of modification of criteria of waist circumference on the risk of diabetes.6 68. IDF) Hypertension (%) Hypertriglyceridaemia (%) Low HDL cholesterol (%) High waist (%. total and HDL cholesterol and triglycerides were determined by an automated enzymatic method (Beckman. laboratory tests. IDF) High fasting PG (%. Venous blood samples for lipid profile and plasma glucose were collected in the morning after overnight fast (>8 h).01 ns <0. etc.001 <0. Newly diagnosed cases of diabetes. Briefly. AHA/NHLBI criteria were also considered [3].). The local ethical committee approved the study. All patients with diabetes are encouraged to register to obtain full reimbursement for diabetes-related drugs.5 25. Aim of the present investigation is to compare the predictive value for diabetes of NCEP and IDF definitions of NCEP in a large sample of predominantly Caucasian subjects.01 <0.6 54. National Cholesterol Education Program.6]. African American. An alternative definition proposed by the American Heart Association and the National Heart. CA.E.001 <0.8 92. except for a lower threshold (100 mg/dl) of fasting glucose [3]. Obesity and Metabolism. NCEP) High fasting PG (%. public conferences and letters from family doctors. In order to obtain registra- Research Design and Methods A prospective observational study was performed on a cohort study enrolled in a diabetes-screening programme.7%) were excluded from the present analysis. All subjects underwent a standard oral glucose tolerance test (75 g in 50% water solution. without highlighting significant differences. 2008. All subjects with fasting glucose >126 mg/dl and/or post-load glucose !200 mg/dl (n ¼ 175. A detailed personal and medical history was collected. Hispanic and non-Hispanic White subjects [10].1 9.6 Æ 7.01 Baseline variable Gender (%.0 24. NCEP) High waist (%.01 <0.7 31. medical devices (i. with lower waist thresholds and with abdominal adiposity as a necessary condition).8 52. plasma glucose. 10.5 19. Laboratory determinations were performed in the Central Laboratory of Careggi Hospital in # Table 1 Characteristics of the sample Diabetes status at follow-up Non-diabetic (n 5 2883) 57. 31 December 2004.4 63.5 44.01 <0.0 13. diabetes mellitus. the mean of three measurements of systolic and diastolic blood pressure was considered for analysis [13].7 Æ 11. PG. International Diabetes Federation. The characteristics of the sample enrolled (n ¼ 2921) are summarized in table 1. height and waist circumference were measured following World Health Organization recommendations [12]. Furthermore. with measurement of plasma glucose after 120 min).e. Florence. including current and previous relevant medical conditions and any current pharmacological treatment. not significant. Details of this investigation are reported in greater detail elsewhere [11]. 5. but with a higher (110 mg/dl) threshold for fasting glucose. diagnostic procedures and medical visits. Lung.3 DM (n 5 38) 47. ns. were identified from three different sources: 1. all subjects living in Florence and in the nearby town of Bagno a Ripoli aged 40–75 years without known diabetes were invited to participate through newspaper and TV advertising.01 <0. however.001 <0.4 36. IDF) DM. IDF criteria have been shown to be either equivalent [7] or inferior [8] to NCEP criteria for MS in the prediction of cardiovascular disease and all-cause mortality in different populations. MS. MS and diabetes j OA rendered a necessary condition for diagnosis.8 211. The category of MS is intended to identify subjects at high risk for diabetes [4] and cardiovascular disease [5.9 28. Data are expressed as mean Æ s. USA). MS was diagnosed according to NCEP [1] and IDF criteria [2].5 Æ 4.001 <0. the small size of the samples enrolled could have prevented the detection of minor differences. and Blood Institute (AHA/NHLBI) is similar to that of NCEP.8 65.6 Æ 37.3 Æ 36. Two studies have compared the predictive value for diabetes of IDF and NCEP definitions of MS in samples of Chinese [9]. IDF.8 Æ 4. the FIrenze-Bagno A Ripoli study. the predictive value of a definition of MS similar to that of IDF (i. glucose self-monitoring equipment. insulin syringes.4 78. NCEP) MS (%.d. 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes. Blood pressure was measured in sitting position.5 61. Mannucci et al. weight.1 207.9 78.8 29.5 10. after a 5-min rest using a mercury sphygmomanometer with a cuff of appropriate size.

but not NCEP. as defined by NCEP criteria. 38 new cases of diabetes were diagnosed. when normally distributed and as median (quartiles) when their distribution was not normal. 2.00 (B) 1. 1 Cumulative incidence of diabetes mellitus among individuals with and without metabolic syndrome (MS).80 0 10 20 30 40 50 Time (months) Time (months) Fig. Hospital admissions with diabetes (International Classification of Disease code 250) included among diagnoses at discharge.87 [3.70. During follow-up.13. sex and fasting glucose but not when waist circumference was added to the model. grey line: MS absent. Mannucci et al. 16.OA j MS and diabetes E. Conversely.85 0.7%) and 736 (25. statistical significance was retained when fasting glucose and waist circumference at enrolment were added to the model as covariates (table 2). with a yearly incidence rate of 0. criteria.5%. 2008. (A) NCEP defined. Chisquare test was used for between-group comparisons of categorical variables. For comparisons between groups. 21 could be categorized as affected by MS when using IDF. Obesity and Metabolism. 432 j Diabetes.2%) were affected by MS using NCEP and IDF criteria respectively.7 Æ 11. Kaplan–Meier analysis was carried out in order to assess differences in incidence of diabetes between groups. and a stepwise Cox regression was performed for multivariate analysis. 20. IDF. patients need a certification by their family doctor or by an endocrinologist or a diabetes specialist.1.10 [5. Results Among subjects enrolled.or AHA/NHLBI-defined MS was significantly associated with incident diabetes after adjustment for age. 430–435 # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd . Reimbursement for use of oral hypoglycaemic drugs and/or insulin. unpaired two-tailed Student’s t-tests and Mann–Whitney U tests were applied to normally and non-normally distributed parameters respectively. Mean follow-up was 27.3 months.90]. Follow-up of each subject was continued until diagnosis of diabetes.85 0. Individuals with MS. Cases were identified through the Tuscany Regional Hospital Discharge System database.80 0 10 20 30 40 50 0.90 0.00 0. tion.90 0.001].30. (A) 1. death or until 31 December 2005.95 Cumulative incidence of diabetes (%) Cumulative incidence of diabetes (%) 0. definition and 379 individuals fulfilled both definitions. Black line: MS present. Three-hundred and fifty-seven subjects fulfilled NCEP. 3.00] and 7. showed a significantly higher incidence of diabetes after adjustment for age and sex.d. Relative risk of diabetes (with 95% CI) was calculated in different groups. p < 0. Both NCEPand IDF-defined MS were associated with a significantly increased risk of diabetes (figure 1).7] using NCEP and IDF definitions respectively.53 [4. 10. The relative risk of diabetes in subjects with MS was 10.95 0. 400 (13. Statistical analysis was performed on SPSS 12. Data were expressed as mean Æ s. (B) IDF defined. Those fulfilling AHA/NHLBI criteria (n ¼ 557) also had a significantly increased risk of diabetes [relative risk (RR) 8. 16.0. but not IDF.

therefore.72.30].82]. Furthermore.78. In fact.01 1.56 5.47 [14. 75.29 <0.466 0. AHA/NHLBI [3] suggested that the threshold for fasting glucose should be lowered to 100 mg/dl. their risk of diabetes was not significantly different from those fulfilling both sets of criteria.01).15]. However. 23. Uncertainties over definitions of the syndrome suggest caution in the use of this category in routine clinical practice [14]. was established as a necessary condition for diagnosis.90 6.9]) but a significantly lower risk than those fulfilling both IDF and NCEP criteria (p < 0. Those fulfilling NCEP. abdominal adiposity.049 0. the parameters chosen for the identification of the syndrome [14. subjects with MS (n ¼ 240) showed a higher risk for diabetes (RR 40. IDF. Discussion The diagnostic criteria for MS have been the object of many controversies over the years.001).00 12.05 4.07 [3.88 3.51 1. In fact. 430–435 j 433 .41 1.28 3.50 17. American Heart Association and National Heart.83 [18. NCEP.137 Using IDF diagnostic criteria.93 [4. sex.05.01). following recommendations issued by the American Diabetes Association. sex and fasting plasma glucose.20 8. The main purpose of diagnosing MS is the identification of a population of subjects with metabolic frailty. 10. Lung. # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes. 7 p < 0. respectively.001) when fasting glucose. are controversial. but with the same threshold for fasting glucose as NCEP (110 mg/dl).00 3. p < 0. MS and diabetes j OA Table 2 Cox regression analysis for incident diabetes 95% CI HR Model 1 NCEP AHA/NHLBI IDF Model 2 NCEP AHA/NHLBI IDF Model 3 NCEP AHA/NHLBI IDF Lower Upper p 9.58 1. the difference between subjects fulfilling only IDF and those satisfying only NCEP criteria did not reach statistical significance.04] and 9. Model 1: adjusted for age and sex. 89. hazard ratio. Several studies have compared the predictive value of NCEP and IDF definitions of MS for cardiovascular disease and all-cause mortality. The IDF provided a new definition of MS.53. p < 0. in fact.01 p = ns 0 IDF NCEP + – – + + + Fig.001 <0. At the same time.003 0. showed a significant increase of diabetes incidence (RR 12.E.02 0. the diagnostic threshold for fasting glucose was also lowered. for the two models). in particular ethnic differences and diabetes status. and Blood Institute.4]. fasting plasma glucose and waist circumference.09 5.95 3.12 7. AHA/NHLBI. National Cholesterol Education Program.01 p = ns Yearly rate for incident diabetes (× 1000) 6 5 4 3 2 1 – – p < 0. 2 Yearly incidence of diabetes mellitus among individuals with and without metabolic syndrome following NCEP and IDF definitions (p < 0. which has a central pathogenetic role in MS. Differences in the results of individual studies reflect marked heterogeneity in the characteristics of the samples enrolled.05).69 5. who are at higher risk for diabetes and cardiovascular disease.41 2.6 [1.84.044 0. Obesity and Metabolism. or both fasting glucose and waist circumference. p < 0. even when adjusted for age and sex (OR 33. Individuals fulfilling IDF criteria only did not show a significantly higher incidence of diabetes when compared to those without MS (RR 2. HR. which was designed to adhere more closely to the pathophysiology of the syndrome [2]. IDF lowered diagnostic thresholds for elevated waist circumference. NCEP criteria for MS [1] have been widely used in epidemiological research for some years. IDF criteria have been reported to be either equivalent [7] or inferior [8] to NCEP criteria.00 2. was added to the model (OR 10.80 20.07 3. This difference retained statistical significance (p < 0.40 2. International Diabetes Federation. Mannucci et al.001 0.001 <0.41. providing specific references for different ethnic groups. Model 3: adjusted for age. but not IDF criteria. most of the available data on this syndrome were collected and analysed using this definition of MS.86 7. NCEP criteria only or both sets of criteria for MS is reported in figure 2.5.24 1.08]. 2008. 8. the proposed diagnostic thresholds [14. p < 0.7 [0.15] and even the number of criteria needed for diagnosis [16]. such changes should be sufficiently motivated. Incidence of diabetes in subjects fulfilling IDF criteria only. Any modification of diagnostic criteria for a disease makes previously published data more difficult to interpret. 104. 27. Model 2: adjusted for age.015 0. in accordance with more recent definitions of fasting hyperglycaemia issued by the American Diabetes Association.001).02 1.

Elisaf M. Almgren P. these data suggest that the use of lower thresholds for waist circumference. Our data show that the adoption of the diagnostic criteria proposed by IDF could reduce the predictive value of MS. Italy. Mannucci E. confirming previous reports [8]. References 1 Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection. Mikhailidis DP. reduces the effectiveness of MS in identifying subjects at risk for diabetes. Cleeman JI. Acknowledgements This work was supported by grants from Menarini Diagnostics International. the reduction of thresholds for fasting glucose. but with a higher threshold for fasting glucose (110 mg/dl). Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart. Williams K et al. In fact. Two previous studies [9. some individuals fulfil NCEP criteria only and some others IDF criteria only. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. Lakka TA et al. When IDF criteria are used. Mannucci et al. one of the studies involved a predominantly Asian population with a much lower BMI [9]. Remarkably. Lancet 2005. 2 Alberti KG. this latter population is composed of subjects with a relatively low risk of diabetes. Shaw J. and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Williams K. 430–435 . could improve the identification of people at very high risk for diabetes. the predictive value for diabetes of AHA/NHBLI is not superior to that of IDF definition of MS. 5 Isomaa B. Diabetes Obes Metab 2006 (in press). Okoloise M. in comparison with previous NCEP criteria. Furthermore. and from the Italian Ministry of University and Scientific Research (PRIN Projects). Circulation 2005. Taken together. 6 Lakka HM. 366: 1059– 1062. The metabolic syndrome – a new worldwide definition. on the other hand. as recently proposed by AHA/NHLBI and IDF. 285: 2486–2497. Obesity and Metabolism. The prevalence of the metabolic syndrome using the National Cholesterol Educational Program and International Diabetes Federation definitions. 21: 1157–1159. Karter AJ. JAMA 2001. It has been observed that the category of MS could be much more useful to predict diabetes rather than cardiovascular disease [17]. 10. Laaksonen DE. Cardiovascular morbidity and mortality associated with the metabolic syndrome. while the other enrolled subjects with a higher degree of obesity and a higher incidence of diabetes. Furthermore. Curr Med Res Opin 2005. Prediction of type 2 diabetes mellitus with alternative definitions # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd 434 j Diabetes. 288: 2709– 2716. In conclusion. although the pathophysiological reasons for the proposed changes in diagnostic criteria for MS are easily understandable. 7 Monami M. Ganotakis ES.10] had failed to detect any difference between NCEP and IDF definitions of MS for the prediction of diabetes. in those with NCEP-defined MS. Stern MP. a definition of MS based on IDF criteria. Haffner SM. there seems to be no reason to prefer AHA/NHBLI definition of MS over IDF definition for the assessment of risk of incident diabetes.OA j MS and diabetes E. Li HB. Conversely. This means that AHA/NHBLI criteria identify a lower number of subjects with a similar risk for diabetes in comparison with IDF. and Blood Institute scientific statement. Tuomi T et al. 3 Grundy SM. These data show that NCEP criteria are more effective than IDF criteria in the identification of people at risk for diabetes. Lung. evaluation. 9 Wang JJ. 2008. applies to an even lower number of subjects than those fulfilling NCEP definition of MS. 4 Lorenzo C. even in individuals without [10]. Masotti G. 10 Hanley AJ. 26: 3153–3159. Diabetes Care 2001. 8 Athyros VG. while increasing estimates of prevalence of the syndrome. Further research is needed before the previous NCEP criteria are abandoned. despite this fact. Florence. the newer IDF definition. The present investigation was performed in a larger sample than previous studies and therefore has a greater statistical power to detect differences. together with the consideration of abdominal adiposity as a necessary condition for diagnosis. 24: 683–689. Marchionni N. Daniels SR et al. Diabetes Care 2003. seems to be detrimental for the prediction of diabetes. AHA/NHBLI criteria produce a lower prevalence of MS than those of IDF. Kinnunen L et al. the characteristics of previously described samples were rather different from the one presently described. a higher prevalence of MS is obtained. but with a considerably greater predictive value for diabetes. IDF and ATP-III definitions of metabolic syndrome in the prediction of all-cause mortality in type 2 diabetic patients. The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study. On the basis of these data. JAMA 2002. the two definitions of MS identify different populations of subjects. the diagnosis of MS with IDF criteria does not add to the prediction of diabetes. Zimmet P. 112: 2735–2752. How well does the metabolic syndrome defined by five definitions predict incident diabetes and incident coronary heart disease in a Chinese population? Atherosclerosis 2006 (Epub ahead of print).

Buse J. Diabetes Care 2005. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. 10. 51: 931–938. Report of a WHO consultation. Circulation 2005. Risks for all-cause mortality. Ungar A et al. Diabetes Care 2005. 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. 15 Reaven GM. 16 Monami M. 28: 1769–1778.E. 894: 1–253. 14 Kahn R. 28: 2289–2304. Stern M. 29: 2515–2517. 2008. 11 Mannucci E. Fasting plasma glucose and glycated haemoglobin in the screening of diabetes and impaired glucose tolerance. 13 Chalmers J. MS and diabetes j OA of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study. Mancia G et al. Obesity and Metabolism. 40: 181–186. World Health Organ Tech Rep Ser 2000. cardiovascular disease. Acta Diabetol 2003. MacMahon S. Lambertucci L. Mannucci et al. The metabolic syndrome: requiescat in pace. Is the third component of metabolic syndrome really predictive of outcome in type 2 diabetic patients? Diabetes Care 2006. 430–435 j 435 . 21: 1009–1060. 12 Obesity: preventing and managing the global epidemic. Ferrannini E. Clin Chem 2005. and diabetes associated with the metabolic syndrome: a summary of the evidence. Guidelines sub-committee of the World Health Organization. Ognibene A. Sposato I et al. # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes. Clin Exp Hypertens 1999. 17 Ford ES. 112: 3713– 3721.