Cardiovascular and Metabolic Risk BRIEF REPORT

All Pre- Is Not the Same: Metabolic and Vascular Risks of Impaired Fasting at 100 Versus 110 mg/dl The Screening for Impaired Glucose Tolerance Study 1 (SIGT 1)

1 2 LAWRENCE S. PHILLIPS, MD VIOLA VACCARINO, MD, PHD cose Ͻ140 mg/dl, IGT by 2-h glucose 2 1 WILLIAM S. WEINTRAUB, MD MARY K. RHEE, MD, MS 140–199 mg/dl, diabetes by 2-h glucose 1 1 DAVID C. ZIEMER, MD RAHIM K. BUDHWANI, MPH Ն200 mg/dl, and IFG as described above; 2 1 PAUL KOLM, PHD JANE M. CAUDLE, MLN Ͼ 2 13 subjects with fasting glucose 125 JOVONNE K. FOSTER, MS mg/dl were excluded from analysis be- cause they could not be included in the IFG categories. Plasma glucose and other he dramatic increase in incidence of cans thought to have “pre-diabetes” to 41 biomarkers were measured in the Clinical diabetes (1) has prompted efforts to million (8). Although such individuals are Laboratory at Grady Memorial Hospital T identify individuals who have considered candidates for management using the Beckman LX-20 (Beckman, milder glucose intolerance, because early aimed at decreasing their risk of progress- Brea, CA). Biomarkers were expressed management with lifestyle change and/or ing to diabetes (9), the metabolic and car- relative to the upper quintile (high) of val- medication can delay progression to dia- diovascular risks of individuals with very ues of the 368 subjects with NGT. The betes with its attendant morbidity, mor- modest abnormalities in FPG are not well “” was examined as tality, and cost (2). It has long been understood. In this study, we compared defined by both International Diabetes recognized that impaired glucose toler- measures of risk in individuals with fast- Federation (10) and National Cholesterol ance (IGT) is a diabetes precursor, but ing glucose 100–109 mg/dl (IFG100) Education Program (NCEP) (11) criteria. recognition of IGT requires oral glucose with those with fasting glucose 110–125 Statistical analyses were conducted using tolerance tests (OGTTs), which many mg/dl (IFG110). S-Plus, version 6 (Insightful, Seattle, health care providers are reluctant to or- WA), and Stata, version 7 (Stata, College der (3). As a more convenient alternative, RESEARCH DESIGN AND Station, TX). the American Diabetes Association has METHODS — The study was ap- emphasized screening by measurement of proved by the Emory University Institu- fasting plasma glucose (FPG) and lowered tional Review Board and involved 550 RESULTS — Clinical demographics the cutoff for abnormal FPG progressively adult volunteer subjects who were not were similar in 95 subjects with IFG100 from 140 to 125 to 110 mg/dl. However, known to have diabetes and were in gen- compared with 41 subjects with IFG110, compared with IGT, an impaired fasting eral good health (had not needed to miss respectively: age 50 vs. 51 years, BMI 32.2 glucose (IFG) cutoff of 110 mg/dl pro- work during the previous week). As part vs. 33.8 kg/m2, female 44 vs. 46%, and vided good specificity but reduced sensi- of the Screening for Impaired Glucose black 36 vs. 41% (all P ϭ NS). Relative to tivity for detecting risk of developing Tolerance (SIGT) study, standard 75-g NGT, IFG100 and IFG110 were associ- diabetes (4–6). OGTTs were performed in the morning ated with (“conferred”) significant (Fig. 1) To obtain increased sensitivity, the after an overnight fast, and fasting blood but comparable risk of the metabolic syn- American Diabetes Association recently and urine samples were obtained for mea- drome by International Diabetes Federa- lowered the cutoff for IFG from 110 to surement of biomarkers. Normal glucose tion criteria (odds ratio ([OR] 7.10 [95% 100 mg/dl (7), and application of this cut- tolerance (NGT) was characterized by CI 4.39–11.46] vs. 10.33 [4.87–21.88]), off has increased the number of Ameri- fasting glucose Ͻ100 mg/dl and 2-h glu- but IFG110 conferred greater risk by NCEP criteria (5.86 [3.66–9.37] for ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● IFG100 vs. 17.25 [7.58–39.14] for From the 1Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of IFG110; P ϭ 0.025). There were also only Medicine, Atlanta, Georgia; and the 2Division of Cardiology, Department of Medicine, Emory University minor differences in risk for elevated C- School of Medicine, Atlanta, Georgia. reactive protein (1.27 [0.76–2.12] vs. Address correspondence and reprint requests to Lawrence S. Phillips, MD, General Clinical Research Center, Emory University Hospital, Room GG-23, 1364 Clifton Rd., Atlanta, GA 30322. E-mail: 1.54 [0.77–3.09]) and alanine amino- [email protected]. transferase (4.03 [2.55–6.38] vs. 2.87 Received for publication 30 January 2006 and accepted in revised form 20 February 2006. [1.52–5.41]). However, only IFG110 in- W.S.W. and P.K. are currently affiliated with Christiana Hospital, Newark, Delaware. creased the risk for high urine albumin- Abbreviations: FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tol- erance; NCEP, National Cholesterol Education Program; NGT, normal glucose tolerance; OGTT, oral glu- to-creatinine ratio (0.59 [0.32–1.08] for cose tolerance test. IFG100 vs. 2.05 [1.05–4.02] for IFG A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 110) and LDL cholesterol Ͼ130 mg/dl factors for many substances. (0.99 [0.61–1.58] vs. 2.42 [1.28–4.56]) DOI: 10.2337/dc06-0242 (both P Ͻ 0.03 for IFG100 vs. IFG110). © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby In contrast, there was a more dra- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. matic difference in risk of postchallenge

DIABETES CARE, VOLUME 29, NUMBER 6, JUNE 2006 1405 IFG levels and metabolic and vascular risks

mates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053, 2004 2. Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA, Walker EA, Fowler SE, Nathan DM, Kahn SE: Pre- vention of with troglita- zone in the diabetes prevention program. Diabetes 54:1150–1156, 2005 3. Davidson MB: Counterpoint: the oral glu- cose tolerance test is superfluous (Edito- rial). Diabetes Care 25:1883–1885, 2002 4. Vaccaro O, Ruffa G, Imperatore G, Iovino V, Rivellese AA, Riccardi G: Risk of diabe- tes in the new diagnostic category of im- Figure 1—ORs for metabolic and/or cardiovascular risk abnormalities associated with IFG100 paired fasting glucose: a prospective (FPG 100–109 mg/dl) and IFG110 (FPG 110–125 mg/dl). Biomarker levels expressed relative to analysis. Diabetes Care 22:1490–1493, the upper quintile of values in individuals with NGT (high C-reactive protein [hi CRP], high 1999 alanine aminotransferase [hi ALT], high urine albumin-to-creatinine ratio [hi alb/Cr]), or the 5. Shaw JE, Zimmet PZ, de Courten M, prevalence in individuals with NGT (metabolic syndrome by NCEP criteria [MetS-NCEP], LDL Dowse GK, Chitson P, Gareeboo H, Hem- :P Ͻ 0.005. raj F, Fareed D, Tuomilehto J, Alberti KGءء ,P Ͻ 0.05ء .([cholesterol Ͼ130 mg/dl [hi LDL], IGT, or diabetes [DIAB Impaired fasting glucose or impaired glu- cose tolerance: what best predicts future glucose intolerance (IGT or diabetes). The in the DECODE (Diabetes Epidemiology: diabetes in Mauritius? Diabetes Care 22: risk conferred by IFG100 was 2.53 (1.55– Collaborative Analysis of Diagnostic Cri- 399–402, 1999 4.13), while the risk for IFG110 was teria in Europe) study (14). Although it is 6. Unwin N, Shaw J, Zimmet P, Alberti 11.54 (5.78–23.02) (P ϭ 0.0004). In not yet established in randomized con- KGMM: Impaired glucose tolerance and multivariable analyses adjusting for age, trolled trials that mortality and/or cardio- impaired fasting glycaemia: the current status on definition and intervention. Dia- race, sex, and BMI, the risk of glucose in- vascular events can be decreased in bet Med 19:708–723, 2002 tolerance was OR 3.22 (95% CI 1.84– individuals with such mild hyperglyce- 7. Genuth S, Alberti KG, Bennett P, Buse J, 5.66) for IFG100 vs. 13.14 (6.12–28.23) mia by interventions other than treatment Defronzo R, Kahn R, Kitzmiller J, Knowler for IFG110 (P ϭ 0.001). with acarbose (15), the hypothesis is be- WC, Lebovitz H, Lernmark A, Nathan D, ing tested in ongoing studies with rosigli- Palmer J, Rizza R, Saudek C, Shaw J, Ste- CONCLUSIONS — The present tazone, nateglinide, ramipril, and ffes M, Stern M, Tuomilehto J, Zimmet P, studies demonstrate that although pre- valsartan. Moreover, several different the Expert Committee on the Diagnosis diabetes, characterized as IFG100 and studies have shown that lifestyle change and Classification of Diabetes Mellitus: IFG110, identifies individuals with simi- and/or medication can reduce progres- Follow-up report on the diagnosis of dia- lar demographics, IFG110 carries in- sion from IGT to diabetes (2,16–18), and betes mellitus. Diabetes Care 26:3160– 3167, 2003 creased risk of the metabolic syndrome by such interventions appear to be cost- Ͼ 8. CDC Diabetes Program: National diabetes NCEP criteria, LDL cholesterol 130 mg/ effective (19). Such considerations indi- fact sheet: national estimates on diabetes dl, and high urine albumin-to-creatinine cate that identification of pre-diabetes [article online], 2003. CDC Diabetes Pubs ratio, and IFG110 is much more likely to should be a national priority. Available from www.cdc.gov/diabetes/ confer risk of postchallenge hyperglyce- The present study demonstrates that pubs/factsheet.htm mia. It has previously been reported that it is particularly important to follow rec- 9. Genuth S: Lowering the criterion for im- individuals with progressive elevation in ognition of IFG110 with additional diag- paired fasting glucose is in order (Com- FPG are more likely to have IGT or diabe- nostic and therapeutic strategies. Since mentary). Diabetes Care 26:3331–3332, tes (9). However, we are not aware of pre- IGT and diabetes are associated with in- 2003 vious comparisons of the risks in creased mortality (above), detection of 10. Alberti KG, Zimmet P, Shaw J: The meta- bolic syndrome–a new worldwide defini- individuals added by inclusion under IFG110 should also prompt consider- tion. Lancet 366:1059–1062, 2005 “newer” criteria (IFG100) versus the risks ation of further evaluation by OGTT. 11. Metabolic syndrome [article online], 2006. conferred by the “older” criteria (IFG110). Available from http://americanheart.org/ Recognition of pre-diabetes is impor- presenter.jhtml?identifierϭ4756. Accessed tant to identify individuals who have risks Acknowledgments— This work was sup- 15 January 2006 that can be modified to improve out- ported in part by grants DK07298, 12. Sorkin JD, Muller DC, Fleg JL, Andres R: comes. The Baltimore Longitudinal Study DK062668, RR017643, DK066204, and The relation of fasting and 2-h postchal- of Aging has shown that mortality is in- RR00039. lenge plasma glucose concentrations to Parts of this study will be presented in ab- creased in men by levels of FPG Ͼ110 mortality: data from the Baltimore Longi- stract form at the 66th annual meeting of the tudinal Study of Aging with a critical re- mg/dl and/or 2-h OGTT glucose levels American Diabetes Association, Washington, Ͼ140 mg/dl, even after adjustment for view of the literature. Diabetes Care 28: DC, 9–13 June 2006. 2626–2632, 2005 the presence of other risk factors (12), and 13. Brunner EJ, Shipley MJ, Witte DR, Fuller mortality was also independently in- JH, Marmot MG: Relation between blood creased by the presence of postchallenge References glucose and coronary mortality over 33 in men in the Whitehall 1. Wild S, Roglic G, Green A, Sicree R, King years in the Whitehall Study. Diabetes Study (13) and in both men and women H: Global prevalence of diabetes: esti- Care 29:26–31, 2006

1406 DIABETES CARE, VOLUME 29, NUMBER 6, JUNE 2006 Phillips and Associates

14. The DECODE Study Group, the Euro- Aunola S, Keinanen-Kiukaanniemi S, 544, 1997 pean Diabetes Epidemiology Group: Glu- Laakso M, Valle TT, Ilanne-Parikka P, 18. Buchanan TA, Xiang AH, Peters RK, Kjos cose tolerance and mortality: comparison Louheranta A, Hamalainen H, Rastas M, SL, Marroquin A, Goico J, Ochoa C, Tan of WHO and American Diabetes Associa- Salminen V, Cepaitis Z, Hakumaki M, S, Berkowitz K, Hodis HN, Azen SP: Pres- tion diagnostic criteria: Diabetes Epide- Kaikkonen H, Harkonen P, Sundvall J, ervation of pancreatic ␤-cell function and miology: Collaborative analysis Of Tuomilehto J, Uusitupa M: Physical activ- prevention of type 2 diabetes by pharma- Diagnostic criteria in Europe. Lancet 354: ity in the prevention of type 2 diabetes: cological treatment of resistance in 617–621, 1999 the Finnish diabetes prevention study. Di- high-risk Hispanic women. Diabetes 51: 15. Chiasson J-L, Josse RG, Gomis R, abetes 54:158–165, 2005 2796–2803, 2002 Hanefeld M, Karasik A, Laakso M: Acar- 17. Pan XR, Li GW, Hu YH, Wang JX, Yang 19. Herman WH, Hoerger TJ, Brandle M, bose treatment and the risk of cardiovas- WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao Hicks K, Sorensen S, Zhang P, Hamman cular disease and hypertension in patients HB, Liu PA, Jiang XG, Jiang YY, Wang JP, RF, Ackermann RT, Engelgau MM, Ratner with impaired glucose tolerance: the Zheng H, Zhang H, Bennett PH, Howard RE: The cost-effectiveness of lifestyle STOP-NIDDM trial. JAMA 290:486–494, BV: Effects of diet and exercise in prevent- modification or metformin in preventing 2003 ing NIDDM in people with impaired glu- type 2 diabetes in adults with impaired 16. Laaksonen DE, Lindstrom J, Lakka TA, cose tolerance: the Da Qing IGT and glucose tolerance. Ann Intern Med 142: Eriksson JG, Niskanen L, Wikstrom K, Diabetes Study. Diabetes Care 20:537– 323–332, 2005

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