Additional Use of Glycated Hemoglobin for Diagnosis of Type 2 Diabetes in People Undergoing Coronary Angiography Reveals a Subgroup at Increased Cardiovascular Risk

LURIC is a cross-sectional and prospective clinical trial that was designed to investigate cardiovascular risk factors. A total of 3,316 white subjects were recruited between July 1997 and January 2000 at the Ludwigshafen Heart Center in southwestern Germany (10,11). All participants underwent coronary angiography. The precise inclusion/exclusion criteria have been previously described (10,11). For the present analyses, subjects with known diabetes or incomplete determination of the glucometabolic phenotype (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 11 decedents. These people were excluded when data on cardiovascular mortality were analyzed. The study was approved by the ethics committee at the Ärztekammer Rheinland-Pfalz and was conducted in accordance with the Declaration of Helsinki. Informed written consent was obtained from all participants (10). Diabetes was diagnosed according to the 2009 and 2010 criteria of the ADA (1,2). The follow-up for all-cause and cardiovascular mortality had a mean duration ± SD of 7.7 ± 2.0 years.

The laboratory methods have been reported previously (10,11). Glucose was measured enzymatically on a Hitachi 717 analyzer (Roche, Mannheim, Germany). Glycated hemoglobin was measured with an immunoassay (hemoglobin A_1c UNIMATE 5; Hoffmann-LaRoche, Grenzach-Whylen, Germany).

The baseline clinical and biochemical characteristics are presented for three groups: group A, subjects without diabetes as per the ADA 2010 definition (without diabetes); group B, subjects with type 2 diabetes as per the ADA 2010 definition but without diabetes as per the ADA 2009 definition (T2DM ADA 2010); and group C, subjects with type 2 diabetes as per the ADA 2009 definition (T2DM ADA 2009). Categorical data are expressed as numbers and percentages. In the case of continuous variables, we report means with SDs or medians with interquartile ranges. P values for differences in baseline characteristics among the three groups were calculated with the χ² test for categorical data and with ANOVA for continuous variables. Triglycerides and insulin were transformed logarithmically before being used in parametric statistical procedures. The Cox proportional hazards model was used to test the relationships of the three groups with all-cause and cardiovascular mortality. Two predefined models of adjustment were used (model 1: univariate; model 2: adjusted for sex, age, BMI, hypertension, smoking, glomerular filtration rate, triglycerides, LDL cholesterol, and HDL cholesterol). The results are presented as hazard ratios with 95% CIs. All statistical tests were two-sided and P < 0.05 was considered significant. The SPSS 15.0 statistical package (SPSS Inc., Chicago, IL) was used.

The clinical and biochemical characteristics of the study participants and data on mortality are shown in Table 1. A total of 346 (17.3%) deaths occurred during the follow-up. Among these, 202 (58.4%) were accounted for by cardiovascular diseases. Compared with subjects without diabetes, people 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 [1.05–2.26]; P = 0.028) had increased all-cause mortality. After multivariate adjustment, this association remained significant for individuals with T2DM ADA 2009 (1.62 [1.28–2.04]; P < 0.001) but turned insignificant for those with T2DM ADA 2010 (1.34 [0.91–1.97]; P = 0.141). There was no significant difference in all-cause mortality between subjects with T2DM ADA 2009 and people with T2DM ADA 2010 (P = 0.360, model 2). Compared with subjects without diabetes, subjects with T2DM ADA 2009 (1.99 [1.48–2.69]; P < 0.001) and those with T2DM ADA 2010 (1.98 [1.25–3.13]; P = 0.003) more frequently died of cardiovascular diseases. These associations remained significant after multivariate adjustment for both subjects with T2DM ADA 2009 (1.62 [1.18–2.21]; P = 0.003) and subjects with T2DM ADA 2010 (1.67 [1.05–2.65]; P = 0.029). There was no significant difference in cardiovascular mortality between subjects with T2DM ADA 2009 and subjects with T2DM ADA 2010 (P = 0.894, model 2).

The current study shows that LURIC participants with newly diagnosed T2DM ADA 2010 have increased cardiovascular mortality compared with those without diabetes. Of importance, there were no differences in mortality rates for cardiovascular disease between LURIC participants with T2DM ADA 2009 and those with T2DM ADA 2010. In agreement, subjects with T2DM ADA 2009 and people with T2DM ADA 2010 had a similar cardiovascular risk factor profile.

There is broad evidence that type 2 diabetes will increase the risk of cardiovascular death (12–14). Thus far, only subjects with elevated fasting or postchallenge glucose were diagnosed with diabetes (1). However, fasting and postchallenge glucose have high intraindividual variability (15). Hence, the sensitivity of these tests to select subjects with disturbance of glucose metabolism is not optimal.

Our data support that the use of glycated hemoglobin at a cut point of ≥6.5% as an additional criterion for the diagnosis of diabetes may improve cardiovascular risk stratification in subjects referred for coronary angiography. Future studies should attempt to answer the question whether measurement of glycated hemoglobin will obviate the need for oral glucose tolerance testing.

B.O.B. has received grants from the Deutsche Forschungsgemeinschaft (GrK 1041) and the Centre of Excellence “Metabolic Diseases” Baden-Wuerttemberg. The LURIC study has received funding through the 6th Framework Program (integrated project Bloodomics, Grant LSHM-CT-2004-503485) and the 7th Framework Program (integrated project Atheroremo, Grant 201668) of the European Union.

No potential conflicts of interest relevant to this article were reported.

G.S. performed the statistical analysis and wrote the manuscript. M.E.K. performed the statistical analysis. T.B.G. contributed to the interpretation of results and reviewed the manuscript. B.R.W. designed the study. B.O.B. and W.M. designed the study and wrote the manuscript. All authors have read and approved the manuscript as submitted and take responsibility for the content of the article.

Parts of this study were presented in abstract form at the 79th Congress of the European Atherosclerosis Society, Gothenburg, Sweden, 26–29 June 2011.

The authors are grateful to the participants of the LURIC study; without their collaboration, this article would not have been written. The authors also thank the LURIC study team either temporarily or permanently involved in patient recruitment and sample and data handling, the laboratory staff at the Ludwigshafen General Hospital, and the Universities of Freiburg and Ulm.