Cardiovascular and Metabolic Risk BRIEF REPORT Additional Use of Glycated Hemoglobin for Diagnosis of Type 2 Diabetes in People Undergoing Coronary Angiography Reveals a Subgroup at Increased Cardiovascular Risk 1,2 5 GUENTHER SILBERNAGEL, MD BERNHARD R. WINKELMANN, MD diagnosis as per the ADA 2009 definition 1,3 6 MARCUS E. KLEBER, PHD BERNHARD O. BOEHM, MD 4 3,4,7 are at increased risk of death from any cause TANJA B. GRAMMER, MD WINFRIED MÄRZ, MD and from cardiovascular diseases (10,11). RESEARCH DESIGN AND OBJECTIVEdTo study the prognosis of people with newly diagnosed type 2 diabetes as per d fi METHODS LURIC is a cross-sectional the American Diabetes Association (ADA) 2010 de nition but without diabetes as per the ADA and prospective clinical trial that was de- 2009 definition. signed to investigate cardiovascular risk RESEARCH DESIGN AND METHODSdA total of 2,002 participants of the Ludwigshafen factors. A total of 3,316 white subjects Risk and Cardiovascular Health (LURIC) study without a history of diabetes were studied. were recruited between July 1997 and January 2000 at the Ludwigshafen Heart RESULTSdDuring the follow-up of a mean duration 6 SD of 7.7 6 2.0 years, 346 people died fi n Center in southwestern Germany (10,11). (202 cardiovascular deaths). Subjects with type 2 diabetes as per the ADA 2009 de nition ( = All participants underwent coronary angi- 468) had significantly increased all-cause and cardiovascular mortality compared with people without diabetes as per the ADA 2010 definition (both P # 0.003). Subjects with type 2 diabetes ography. The precise inclusion/exclusion as per the ADA 2010 definition but without diabetes as per the ADA 2009 definition (n =150) criteria have been previously described were at significantly increased risk to die of cardiovascular diseases (P =0.029). (10,11). For the present analyses, subjects with known diabetes or incomplete deter- CONCLUSIONSdUse of the ADA 2010 diabetes definition may be instrumental in improv- mination of the glucometabolic pheno- ing cardiovascular risk stratification in people undergoing coronary angiography. type (missing 75-g oral glucose tolerance test despite fasting glucose ,126 mg/dL) were additionally ruled out. Information on the cause of death was missing for ccording to the 2009 guidelines of Of particular interest, recent data from 11 decedents. These people were ex- Athe American Diabetes Association the Atherosclerosis Risk in Communities cluded when data on cardiovascular (ADA), subjects with increased fast- (ARIC) study and the Ludwigshafen Risk mortality were analyzed. The study was ing glucose ($126 mg/dL) and/or post- and Cardiovascular Health (LURIC) approved by the ethics committee at the challenge glucose ($200 mg/dL) are study have shown that glycated hemoglo- Ärztekammer Rheinland-Pfalz and was diagnosed with diabetes (1). Using the bin is a better predictor for all-cause and conducted in accordance with the Declara- ADA 2010 criteria, subjects with isolated cardiovascular mortality than fasting glu- tion of Helsinki. Informed written consent elevation of glycated hemoglobin $6.5% cose (9,10). was obtained from all participants (10). Di- (fasting glucose ,126 mg/dL, postchal- The objective of the present work in abetes was diagnosed according to the lenge glucose ,200 mg/dL) are also con- 2,002 LURIC participants was to analyze 2009 and 2010 criteria of the ADA (1,2). sidered diabetic individuals (2). whether subjects with newly diagnosed The follow-up for all-cause and cardiovas- Glycated hemoglobin has been asso- type 2 diabetes as per the ADA 2010 de- cular mortality had a mean duration 6 SD ciated with macrovascular disease (3–8). finition who would not have received the of 7.7 6 2.0 years. ccccccccccccccccccccccccccccccccccccccccccccccccc Laboratory analyses From the 1Ludwigshafen Risk and Cardiovascular Health Study Nonprofit LLC, Freiburg, Germany; the The laboratory methods have been reported 2Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, De- previously (10,11). Glucose was measured partment of Internal Medicine, Eberhard-Karls-University Tübingen, Tübingen, Germany; the 3Synlab enzymatically on a Hitachi 717 analyzer Center of Laboratory Diagnostics Heidelberg, Heidelberg, Germany; the 4Mannheim Institute of Public (Roche, Mannheim, Germany). Glycated Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, hemoglobinwasmeasuredwithanimmu- Germany; the 5Cardiology Group Frankfurt-Sachsenhausen, Frankfurt, Germany; the 6Division of Endo- crinology, Department of Internal Medicine, Ulm University, Ulm, Germany; and the 7Clinical Institute of noassay (hemoglobin A1c UNIMATE 5; Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. Hoffmann-LaRoche, Grenzach-Whylen, Corresponding author: Winfried März, [email protected]. Germany). Received 2 June 2011 and accepted 15 August 2011. DOI: 10.2337/dc11-1046 Statistical analysis © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ The baseline clinical and biochemical licenses/by-nc-nd/3.0/ for details. characteristics are presented for three care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online September 12, 2011 Diabetes categorization and mortality groups: group A, subjects without diabe- Table 1dBaseline characteristics according to diabetes definition tes as per the ADA 2010 definition (with- out diabetes); group B, subjects with type fi No diabetes 2 diabetes as per the ADA 2010 de nition as per ADA 2010 T2DM ADA T2DM ADA but without diabetes as per the ADA 2009 definition 2010 2009 P value* definition (T2DM ADA 2010); and group C, subjects with type 2 diabetes as per the n 1,384 150 468 d ADA 2009 definition (T2DM ADA 2009). Male sex 1,012 (73.1) 113 (75.3) 342 (73.1) 0.839 Categorical data are expressed as numbers Age (years) 60.6 6 10.8 62.7 6 9.2 64.6 6 9.5 ,0.001 and percentages. In the case of continu- Fasting glucose (mg/dL) 98 6 10 103 6 11 125 6 28 ,0.001 ous variables, we report means with SDs Glucose 2 h (mg/dL)† 125 6 33 137 6 30 233 6 65 ,0.001 or medians with interquartile ranges. Fasting insulin (mU/L) 8 (6–12) 9 (6–12) 12 (8–21) ,0.001‡ 6 6 6 , P values for differences in baseline char- Hemoglobin A1c (%) 5.7 0.4 6.8 0.5 6.5 1.0 0.001 acteristics among the three groups were BMI (kg/m2) 27.1 6 3.8 28.0 6 4.3 28.2 6 4.0 ,0.001 calculated with the x2 test for categorical Waist circumference (cm)x 97 (12) 101 (11) 101 (11) ,0.001 data and with ANOVA for continuous Systemic hypertension 920 (66.5) 112 (74.7) 379 (81.0) ,0.001 variables. Triglycerides and insulin were Blood lipid level (mg/dL) transformed logarithmically before being Total cholesterol 196 6 38 189 6 37 193 (40) 0.073 used in parametric statistical procedures. LDL cholesterol 120 6 35 117 6 31 116 6 34 0.097 The Cox proportional hazards model was HDL cholesterol 40 6 11 38 6 10 37 6 10 ,0.001 used to test the relationships of the three Triglycerides 137 (103–190) 140 (108–187) 158 (120–222) ,0.001‡ groups with all-cause and cardiovascular Glomerular filtration rate mortality. Two predefined models of (mL/min/1.73 m2)846 17 80 6 18 81 6 18 ,0.001 adjustment were used (model 1: univari- Smoking 0.074 ate; model 2: adjusted for sex, age, BMI, Never 501 (36.2) 48 (32.0) 153 (32.7) d hypertension, smoking, glomerular fil- Former smoker 597 (43.1) 64 (42.7) 232 (49.6) d tration rate, triglycerides, LDL choles- Current smoker 286 (20.7) 38 (25.3) 83 (17.7) d terol, and HDL cholesterol). The results Coronary artery disease are presented as hazard ratios with 95% (50% stenosis) 869 (62.8) 102 (68.0) 344 (73.5) ,0.001 CIs. All statistical tests were two-sided Medication use and P , 0.05 was considered significant. b-Blocker 889 (64.2) 88 (58.7) 303 (64.7) 0.369 The SPSS 15.0 statistical package (SPSS ACE inhibitor 667 (48.2) 78 (52.0) 258 (55.1) 0.031 Inc., Chicago, IL) was used. Calcium antagonist 180 (13.0) 19 (12.7) 87 (18.6) 0.010 Diuretic 250 (18.1) 43 (28.7) 166 (35.5) ,0.001 RESULTSdThe clinical and biochemi- Statin 656 (47.4) 75 (50.0) 234 (50.0) 0.561 cal characteristics of the study partici- Acetyl salicylic acid 983 (71.0) 118 (78.7) 322 (68.8) 0.068 pants and data on mortality are shown in Mortality Table 1. A total of 346 (17.3%) deaths All-cause death 194 (14.0) 30 (20.0) 122 (26.3) d occurred during the follow-up. Among Cardiovascular death|| 111 (8.1) 22 (14.8) 69 (14.9) d these, 202 (58.4%) were accounted for Data are n (%) in cases of categorical data and means 6 SDs or medians (25th–75th percentiles) in cases of by cardiovascular diseases. Compared continuous variables. *x2 test and ANOVA for categorical and continuous data, respectively. †n = 1,384/150/ ‡ xn n with subjects without diabetes, people 238. ANOVA of logarithmically transformed values. = 1,363/149/461. || = 1,378/149/464. with T2DM ADA 2009 (hazard ratio 2.02 [95% CI 1.61–2.53]; P , 0.001) and those with T2DM ADA 2010 (1.54 remained significant after multivariate ad- ADA 2009 and those with T2DM ADA [1.05–2.26]; P = 0.028) had increased justment for both subjects with T2DM 2010.