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Isolated post-challenge hyperglycaemia predicts increased cardiovascular mortality
Atherosclerosis 225 (2012) 194e199
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Isolated post-challenge hyperglycaemia predicts increased cardiovascular mortality Guenther Silbernagel a, b, Harald Sourij c, Tanja B. Grammer d, Marcus E. Kleber a, d, Bríain ó Hartaigh e, f, Bernhard R. Winkelmann g, Bernhard O. Boehm h, Winfried März d, i, j, * a
LURIC Study Nonprofit LLC, Freiburg, Germany Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, Eberhard-Karls-University Tübingen, Tübingen, Germany c Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria d Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany e Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, United Kingdom f School of Sport and Exercise Sciences, University of Birmingham, Birmingham, United Kingdom g Cardiology Group Frankfurt-Sachsenhausen, Frankfurt, Germany h Division of Endocrinology and Diabetes, Department of Internal Medicine, Ulm University, Ulm, Germany i Synlab Services GmbH, Mannheim, Germany j Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 May 2012 Received in revised form 9 August 2012 Accepted 9 August 2012 Available online 27 August 2012
Objective: The American Diabetes Association (ADA) has revised the criteria for the diagnosis of diabetes in 2010. Glycated haemoglobin at a cut-point of 6.5% has been included in the diagnostic algorithm. We aimed to investigate whether there is still the need to perform oral glucose tolerance tests (OGTT). Methods: We studied 2002 people referred for angiography who did not have a history of diabetes. OGTT were performed in all 1772 subjects with fasting glucose <126 mg/dl. Participants were prospectively followed for all-cause and cardiovascular mortality over a mean duration (standard deviation) of 7.7 2.0 years. Results: Using the ADA 2010 criteria 618 individuals were categorised as having new-onset type 2 diabetes. Among these, 167 had isolated post-challenge hyperglycaemia. A total of 346 participants died during follow-up. Cardiovascular death occurred in 202 cases. Those with elevated fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5% had increased all-cause (hazard ratio [HR]: 1.63, 95% confidence interval [95%CI]: 1.28e2.08, p < 0.001) and cardiovascular mortality (HR: 1.66, 95%CI: 1.21 e2.29, p ¼ 0.002) compared to subjects without diabetes according to the ADA 2010 definition. Isolated elevation of post-challenge glucose independently predicted increased cardiovascular mortality (HR: 1.57, 95%CI: 1.02e2.43, p ¼ 0.041). All-cause and cardiovascular mortality were not significantly different between subjects with increased fasting glucose and/or glycated haemoglobin and those with isolated elevation of post-challenge glucose. Conclusions: Performing OGTT will identify a high risk group for cardiovascular mortality undetected by fasting glucose or glycated haemoglobin. Ó 2012 Published by Elsevier Ireland Ltd.
Keywords: All-cause mortality Cardiovascular mortality Diabetes classification Glycated haemoglobin Oral glucose tolerance test Post-challenge hyperglycaemia Type 2 diabetes
1. Introduction
Abbreviations: ADA, American Diabetes Association; LURIC, LUdwigshafen RIsk and Cardiovascular health; OGTT, oral glucose tolerance tests. * Corresponding author. Synlab Services GmbH, Synlab Academy, GottliebDaimler-Straße 25, D-68165 Mannheim, Germany. Tel.: þ49 621 43179432; fax: þ49 621 43179433. E-mail address: [email protected] (W. März). 0021-9150/$ e see front matter Ó 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.atherosclerosis.2012.08.008
Diabetes mellitus is a well-established cardiovascular risk factor [1e3]. The American Diabetes Association (ADA) in the past has recommended the use of fasting and post-challenge glucose for the diagnosis of diabetes [4]. In 2010, glycated haemoglobin at a threshold of 6.5% was introduced as an additional diagnostic criterion [5]. Glycated haemoglobin, a stable measure of average blood glucose [6,7], is a determinant of microvascular disease [8].
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However, several studies including the Hoorn Study, the CHARM program, and the EPIC-Norfolk Study have demonstrated that glycated haemoglobin is also associated with macrovascular complications [9e11]. Moreover, recent evidence from the ARIC and LUdwigshafen RIsk and Cardiovascular health (LURIC) studies have highlighted that glycated haemoglobin is a superior measure compared to fasting glucose for predicting cardiovascular endpoints [12,13]. Further data from the LURIC cohort have proposed that individuals with isolated elevation of glycated haemoglobin 6.5% are at greater risk of dying from cardiovascular causes [14]. Since glycated haemoglobin appears to be a feasible tool for diagnosing diabetes [15] and for estimating prognosis [9e14] the following question arises: Do we still need to perform oral glucose tolerance tests (OGTT)? Undoubtedly, numerous investigations such as the DECODE Study, the Euro Heart Survey, the AusDiab Study, the ADDITION-Leicester Study, and an Austrian collective have all confirmed that post-challenge hyperglycaemia is associated with an adverse outcome in subjects with fasting glucose <126 mg/dl [16e22]. Nevertheless, it is unclear whether OGTT will improve cardiovascular risk stratification in persons with both, fasting glucose <126 mg/dl and glycated haemoglobin <6.5%. Notably, a considerable amount of individuals exhibiting postchallenge hyperglycaemia 200 mg/dl will be categorised diabetic due to a concomitant elevation of glycated haemoglobin 6.5% [23,24]. Based on the previously mentioned novel guidelines, we sought to investigate whether isolated elevation of post-challenge glucose 200 mg/dl is predictive of increased all-cause and cardiovascular mortality. We report on data from the LURIC study. This large prospective clinical trial was planned to serve as a resource for analysing clinical, biochemical, and genetic predictors of hard cardiovascular outcomes and death from any other causes [25].
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having diabetes [5]. OGTT were performed in all 1772 subjects with fasting glucose <126 mg/dl. Hypertension was diagnosed if the systolic and/or diastolic blood pressure exceeded 140 and/or 90 mm Hg or if there was a history of hypertension, also evident through the use of antihypertensive drugs [25]. Coronary artery disease was diagnosed if coronary angiography revealed stenosis of one or more vessels 50%. The severity of coronary artery disease was quantified with the Friesinger score which was broken down to quartiles (group 1: score 0e1, group 2: score 2e4, group 3: score 5e8, group 4: score 9e15) [26]. Maximum luminal narrowing was estimated by visual analysis as described previously [25]. Cerebrovascular disease was defined clinically by documented history of a previous cerebrovascular disease event (transient ischaemic attack, prolonged ischaemic neurological deficit, cerebral infarction with or without a remaining neurological deficit) and/or by documented carotid plaques (50% luminal obstruction) [25]. Peripheral vascular disease was defined by a history of intermittent claudication, angiographic documentation of atherosclerotic luminal obstruction of the peripheral arteries and/or a history of a peripheral arterial intervention for atherosclerotic disease (angioplasty and/or surgery) [25]. Comorbidity was assessed using the Charlson comorbidity index. This is a weighted score that takes into account the number and the seriousness of comorbid disease. We formed 3 groups (group 0: 0 score points, group 1: 1 score point, and group 2: 2 or more score points) [27]. Physical activity was assessed using a questionnaire with a scoring system ranging from 1 “sedentary” (avoid walking or exertion) to 11 “regular heavy exercise”. The study participants were grouped into the following 3 categories of physical activity (below average: scores 1e3, average: scores 4e7, and above average: scores 8e11).
2. Methods 2.2. Follow-up 2.1. Study design, participants and clinical characterization A total of 3316 patients, who were referred for coronary angiography to Ludwigshafen Heart Center in South-West Germany, were recruited between July 1997 and January 2000 [25]. Inclusion criteria were: German ancestry, clinical stability except for acute coronary syndromes, and the availability of a coronary angiogram. The indications for angiography in individuals in clinically stable condition were chest pain and/or noninvasive test results consistent with myocardial ischaemia. Individuals suffering from any acute illness other than acute coronary syndromes, chronic noncardiac diseases, or malignancy within the five past years, and those unable to understand the purpose of the study were excluded. Subjects with a history of diabetes and 684 subjects with incomplete determination of the gluco-metabolic phenotype (missing OGTT despite fasting glucose <126 mg/d) were additionally ruled out resulting in a sample size of 2002 (60.4%) out of 3316 LURIC participants for the present study. Death certificates were not available for 11 individuals. Hence, the analytic sample for the calculations on cardiovascular mortality was 1991 subjects. 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 [25]. Diagnostic criteria for diabetes: According to ADA 2009 criteria subjects with increased fasting (126 mg/dl) and/or post-challenge (2 h after the 75 g glucose load 200 mg/dl) glucose are considered diabetic [4]. Using the ADA 2010 guidelines persons with elevated glycated haemoglobin (6.5%) are additionally categorised as
There was a follow-up for all-cause and cardiovascular mortality. The mean (standard deviation) duration of the followup was 7.7 2.0 years. Information on the vital status was obtained from local person registries. Using death certificates, two experienced clinicians independently classified the causes of death. Both were masked to any other data belonging to the study participants. In a case of disagreement or uncertainty concerning the coding of a specific cause of death, classification was confirmed by a principal investigator of the LURIC study (W. M.) who was also masked to any other data belonging to the study participants [25]. 2.3. Laboratory analyses The standard laboratory methods have been described [25]. Glucose was measured enzymatically on a Hitachi 717 analyzer (Roche, Mannheim, Germany). Glycated haemoglobin was measured with immunoassay (haemoglobin A1c UNIMATE 5; HoffmannLaRoche, Grenzach-Whylen, Germany). Lipoproteins were separated using a combined ultracentrifugationeprecipitation method and measured on a WAKO 30 R analyzer (WAKO Chemicals GmbH, Neuss, Germany). Triglycerides were quantified with an enzymatic colour assay on a Hitachi 717 analyzer (Roche). Creatinine was measured with the Jaffé method on a Hitachi 717 analyzer (Roche). 2.4. Statistical analysis Three groups were formed (category A: subjects without diabetes according to the ADA 2010 definition; category B: subjects
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with isolated increase of post-challenge glucose 200 mg/dl; category C: subjects with increased fasting glucose 126 mg/dl and/or increased glycated haemoglobin 6.5%). The baseline characteristics are reported as numbers and percentages in cases of categorical variables and as means with standard deviations or medians with inter-quartile ranges in cases of continuous variables. Comparisons across the three groups were made with the chi-square test and with analysis of variance for categorical and continuous data, respectively. Triglycerides and insulin (Shapiroe Wilk W test) were transformed logarithmically before being used in parametric statistical procedures. The Cox proportional
hazards model was used to perform survival analyses. Three hierarchical models of adjustment (model 1: unadjusted; model 2: adjusted for sex and age; model 3: also adjusted for body mass index, systolic blood pressure, diastolic blood pressure, smoking, glomerular filtration rate, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol) were employed. In addition, adjusted survival curves based on Cox model 3 were plotted for the association between the diagnostic criteria of diabetes and cardiovascular mortality. All statistical tests were 2-sided and p values < 0.05 were considered significant. The SPSS 15.0 statistical package (SPSS Inc., Chicago, USA) was used.
Table 1 Baseline characteristics according to diagnostic criteria of diabetes.
Number Male sex Age, years Body mass index, kg/m2 Waist circumference, cmb Fasting glucose, mg/dl Glucose 2 h, mg/dlc Glycated haemoglobin, % Systemic hypertension Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Blood lipid level Total cholesterol, mg/dl LDL cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glomerular filtration rate, ml/min/1.73 m2 Smoking Never Former smoker Current smoker Coronary artery disease (50% stenosis) Friesinger score 0e1 2e4 5e8 9e15 NYHA functional class 1 2 3 4 Peripheral vascular disease Cerebrovascular disease Charlson comorbidity indexe Group 0 Group 1 Group 2 Physical activityf Below average Average Above average Medication use b-Blocker ACE inhibitor Calcium antagonist Diuretic Statin Acetyl salicylic acid
Pa
No diabetes ADA 2010 criteria
Post-challenge glucose 200 mg/dl only
Fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5%
1384 1012 (73.1) 60.6 10.8 27.1 3.8 97 12 98 10 125 33 5.7 0.4 920 (66.5) 139 23 81 11
167 119 (71.3) 65.3 9.8 27.1 3.5 99 11 103 11 234 37 5.8 0.4 129 (77.2) 141 25 80 11
451 336 (74.5) 63.7 (9.3) 28.5 4.2 102 11 126 28 172 63 6.9 0.9 362 (80.3) 143 22 82 11
196 38 120 35 40 11 137 (103e190) 84 17
189 42 116 34 37 11 149 (107e195) 83 19
193 39 116 33 37 10 156 (121e220) 79 18
501 597 286 869
(36.2) (43.1) (20.7) (62.8)
64 (38.3) 83 (49.7) 20 (12.0) 116 (69.5)
137 213 101 330
368 303 436 277
(26.6) (21.9) (31.5) (20.0)
23 46 56 42
(13.8) (27.5) (33.5) (25.1)
71 (15.7) 106 (23.5) 163 (36.1) 111 (24.6)
768 (55.5) 397 (28.7) 189 (13.7) 30 (2.2) 82 (5.9) 89 (6.4)
81 (48.5) 53 (31.7) 28 (16.8) 5 (3.0) 10 (6.0) 16 (9.6)
218 (48.3) 150 (33.3) 73 (16.2) 10 (2.2) 39 (8.6) 33 (7.3)
439 (35.1) 473 (37.8) 340 (27.2)
50 (32.3) 49 (31.6) 56 (36.1)
92 (23.0) 158 (39.5) 150 (37.5)
77 (5.7) 960 (70.8) 319 (23.5)
13 (7.9) 121 (73.8) 30 (18.3)
37 (8.3) 318 (71.3) 91 (20.4)
0.100 0.096 <0.001 <0.001d <0.001 0.012 e e e <0.001 <0.001 e e e e 0.161 e e e e 0.122 0.291 <0.001 e e e 0.129 e e e
889 667 180 250 656 983
108 (64.7) 93 (55.7) 27 (16.2) 52 (31.1) 83 (49.7) 116 (69.5)
283 (62.7) 243 (53.9) 79 (17.5) 157 (34.8) 226 (50.1) 324 (71.8)
0.832 0.036 0.046 <0.001 0.558 0.843
(64.2) (48.2) (13.0) (18.1) (47.4) (71.0)
(30.4) (47.2) (22.4) (73.2)
0.701 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.067 0.095
Values are means standard deviations or medians (25the75th percentiles) in cases of continuous variables and numbers (percentages) in cases of categorical data. a For differences across the three groups calculated with chi-square test and analysis of variance for categorical and continuous data, respectively. b Number: 1363/165/445. c Number: 1384/167/221. d Analysis of variance of logarithmically transformed values. e Number: 1252/155/400. f Number: 1356/164/446.
G. Silbernagel et al. / Atherosclerosis 225 (2012) 194e199 Table 2 Cause of death according to diagnostic criteria of diabetes.
Death from any cause Cardiovascular death Fatal infection Fatal cancer Other cause of death
No diabetes ADA 2010 criteria
Post-challenge glucose 200 mg/dl only
Fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5%
194 (14.0)
41 (24.6)
111 (24.6)
111 (8.1)
26 (15.7)
65 (14.5)
15 (1.1) 30 (2.2) 32 (2.3)
3 (1.8) 3 (1.8) 8 (4.8)
7 (1.6) 19 (4.3) 16 (3.6)
Values are numbers (percentages); data on cause of death available for 1378/166/ 447 subjects.
197
subjects without type 2 diabetes (Table 3). After multivariate adjustment, this association remained significant for those with increased fasting glucose and/or glycated haemoglobin (Table 3). The risk of death from any cause was not different between subjects with isolated elevation of post-challenge glucose and persons with increased fasting glucose and/or glycated haemoglobin (p ¼ 0.860, model 1). In agreement, subjects with isolated elevation of postchallenge glucose and persons with increased fasting glucose and/or glycated haemoglobin were more likely to die from cardiovascular diseases as shown in crude and adjusted models (Table 3, Fig. 1). The risk of cardiovascular death was not different between subjects with isolated elevation of post-challenge glucose and persons with increased fasting glucose and/or glycated haemoglobin (p ¼ 0.873, model 1). 4. Discussion
3. Results 3.1. Baseline characteristics according to diagnostic criteria of diabetes According to the ADA 2010 criteria a total of 618 subjects were categorised as having type 2 diabetes. Participant characteristics for those without type 2 diabetes, for those with isolated postchallenge hyperglycaemia, and for those with increased fasting plasma glucose and/or glycated haemoglobin are reported in Table 1. Persons without diabetes according to the ADA 2010 criteria and subjects with isolated post-challenge hyperglycaemia did not differ in body mass index (p ¼ 0.956) and glomerular filtration rate (p ¼ 0.424). However, age (p < 0.001), high density lipoprotein cholesterol (p < 0.001), and proportion of subjects with hypertension (p ¼ 0.003) were significantly different between individuals without diabetes and those with isolated postchallenge hyperglycaemia. 3.2. Mortality according to diagnostic criteria of diabetes Prevalent causes of death for subjects without type 2 diabetes, for those with isolated post-challenge hyperglycaemia, and for those with increased fasting plasma glucose and/or glycated haemoglobin are shown in Table 2. Univariate Cox regression analyses revealed that subjects with isolated post-challenge hyperglycaemia as well as subjects with increased fasting glucose and/or glycated haemoglobin had increased all-cause mortality compared to
This study in people undergoing coronary angiography indicates that subjects with fasting glucose <126 mg/dl and glycated haemoglobin <6.5% but with post-challenge glucose 200 mg/dl have increased cardiovascular mortality compared to subjects without type 2 diabetes according to the ADA 2010 criteria [5]. Moreover, the increase in the risk of death from any cause and from cardiovascular diseases is not different between subjects with isolated post-challenge hyperglycaemia and subjects with elevated fasting glucose and/or glycated haemoglobin. How are LURIC participants with isolated elevation of postchallenge glucose 200 mg/dl clinically and metabolically characterized? Of note, these individuals did not differ from participants without diabetes according to the ADA 2010 criteria in terms of body mass index and glomerular filtration rate. However, people with isolated increase of post-challenge glucose were older, had lower levels of high density lipoprotein cholesterol, and were more likely to suffer from hypertension compared to those without diabetes according to the ADA 2010 criteria. Hence, LURIC participants with isolated post-challenge hyperglycaemia a priori had an unfavourable cardiovascular risk factor profile. Nevertheless, the association of isolated elevation of post-challenge glucose with increased cardiovascular mortality remained significant after multivariate adjustment. Statistical significance was lost for the relationship between isolated post-challenge hyperglycaemia and increased all-cause mortality when we adjusted for important cardiovascular risk factors. This is most probably due to the relatively low number of individuals in the subgroup identified as diabetic with OGTT only.
Table 3 Mortality according to diagnostic criteria of diabetes. Model 1a
All-cause mortality No diabetes ADA 2010 criteria Post-challenge glucose 200 mg/dl only Fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5% Cardiovascular mortalityd No diabetes ADA 2010 criteria Post-challenge glucose 200 mg/dl only Fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5%
Model 2b
Model 3c
HR
P
HR
P
HR
P
1.0 reference 1.86 (1.33e2.60) 1.92 (1.52e2.42)
<0.001 <0.001
1.0 reference 1.44 (1.03e2.02) 1.66 (1.31e2.10)
0.035 <0.001
1.0 reference 1.37 (0.97e1.92) 1.63 (1.28e2.08)
0.075 <0.001
1.0 reference 2.04 (1.33e3.13) 1.97 (1.45e2.68)
0.001 <0.001
1.0 reference 1.59 (1.04e2.45) 1.71 (1.26e2.32)
0.034 0.001
1.0 reference 1.57 (1.02e2.43) 1.66 (1.21e2.29)
0.041 0.002
HR hazard ratio (calculated with Cox proportional hazards model). a Unadjusted. b Adjusted for sex and age. c Adjusted for sex, age, body mass index, systolic blood pressure, diastolic blood pressure, smoking, glomerular filtration rate, triglycerides, LDL cholesterol, and HDL cholesterol. d Data available for 1991 subjects.
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Although the predictive value of post-challenge hyperglycaemia for cardiovascular mortality has been demonstrated in subjects with non-diabetic fasting glucose [16e22], such a relationship has not been shown for subjects with both, non-diabetic fasting glucose and non-diabetic glycated haemoglobin, so far. Thus, our results extend previous studies suggesting that post-challenge hyperglycaemia represents an independent cardiovascular risk factor [16e22,28]. Yet, there is paucity of data demonstrating that hard cardiovascular endpoints can be reduced by treating post-challenge hyperglycaemia [29]. Only the Stop-NIDDM Trial, a randomised prospective study comparing acarbose therapy with placebo, confirmed that a significant amount of cardiovascular events could be prevented by interventions targeting elevated post-challenge glucose levels [30]. Long-term interventional studies will be needed to further support the concept of a causal relationship between post-challenge hyperglycaemia and cardiovascular complications [29]. The main disadvantage of OGTT is that they are time-consuming and, unfortunately, often neglected in clinical practice. This was also observed in the LURIC cohort considering that OGTT were not performed in all participants without a previous diagnosis of diabetes mainly due to lack of manpower or time. Therefore, another important future scientific goal could be to investigate whether fasting measurements could provide the same prognostic information as OGTT. All participants of the LURIC study were referred for coronary angiography. Hence, our conclusions are confined to people at intermediate to high cardiovascular risk. Moreover, fasting and post-challenge glucose and glycated haemoglobin were measured once only. Consequently, the criteria for the diagnosis of diabetes could not be confirmed as recommend by the ADA in the absence of unequivocal hyperglycemia [5]. With regard to the strengths of the LURIC study we want to emphasize the detailed clinical and metabolic characterization of the participants including coronary angiography. Furthermore, we point out the long duration and the completeness of the follow-up with a large number of particularly cardiovascular events.
To sum up, the LURIC data suggest that post-challenge glucose levels 200 mg/dl identify a high risk group for cardiovascular mortality undetected by fasting glucose or glycated haemoglobin using the cut points recommended by the ADA. Performing OGTT may, therefore, be warranted to achieve optimal cardiovascular risk stratification in people without known diabetes. Contributions B.O.B., B.R.W., and W.M. designed the study. G.S., M.E.K., B.H., and W.M. performed the statistical analysis. B.O.B, G.S., and W.M. wrote the manuscript. H.S. and T.B.G. contributed to the interpretation of the results and reviewed/edited the manuscript. All authors have read and approved the manuscript as submitted. Funding sources LURIC was supported by the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and 7th of Framework Program (integrated project Atheroremo, Grant Agreement number 201668) of the European Union. B.O.B. received grants form the DFG GrK 1041 and the Centre of Excellence “Metabolic Diseases” Baden-Wuerttemberg. Disclosure The authors have no conflict of interest to declare. Acknowledgements The authors thank the participants of the LURIC study, 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. References
1,00
Cumulative survival
0,98 0,96 0,94 A
0,92 0,90
B C
0,88 0,86 0
1
2
3
4
5
6
7
8
9
10
Survival time, years Fig. 1. Adjusted survival curves (model 3) for cardiovascular mortality according to diagnostic criteria of diabetes: A) subjects without type 2 diabetes according to the ADA 2010 criteria, B) subjects with isolated elevation of post-challenge glucose 200 mg/dl, and C) subjects with increase of fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5%.
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and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation 2007;116:151e7. Webb DR, Gray LJ, Khunti K, et al. Screening for diabetes using an oral glucose tolerance test within a western multi-ethnic population identifies modifiable cardiovascular risk: the ADDITION-Leicester study. Diabetologia 2011;54:2237e46. Sourij H, Saely CH, Schmid F, et al. Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients. Eur Heart J 2010;31:1583e90. Kramer CK, Araneta MR, Barrett-Connor E. A1C and diabetes diagnosis: the Rancho Bernardo study. Diabetes Care 2010;33:101e3. Boronat M, Saavedra P, López-Ríos L, Riaño M, Wägner AM, Nóvoa FJ. Differences in cardiovascular risk profile of diabetic subjects discordantly classified by diagnostic criteria based on glycated hemoglobin and oral glucose tolerance test. Diabetes Care 2010;33:2671e3. Winkelmann BR, Marz W, Boehm BO, et al; LURIC Study Group (Ludwigshafen Risk and Cardiovascular Health). Rationale and design of the LURIC study e a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2000;2(1 Suppl. 1):S1e73. Friesinger GC, Page EE, Ross RS. Prognostic significance of coronary arteriography. Trans Assoc Am Physicians 1970;83:78e92. de Groot V, Beckerman H, Lankhorst GJ, Bouter LM. How to measure comorbidity: a critical review of available methods. J Clin Epidemiol 2003;56:221e9. Rizza S, Cardellini M, Martelli E, et al. Occult impaired glucose regulation in patients with atherosclerosis is associated to the number of affected vascular districts and inflammation. Atherosclerosis 2010;212:316e20. Standl E, Schnell O, Ceriello A. Postprandial hyperglycemia and glycemic variability: should we care? Diabetes Care 2011;34(Suppl. 2):S120e7. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003;290:486e94.
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Isolated post-challenge hyperglycaemia predicts increased cardiovascular mortality Guenther Silbernagel a, b, Harald Sourij c, Tanja B. Grammer d, Marcus E. Kleber a, d, Bríain ó Hartaigh e, f, Bernhard R. Winkelmann g, Bernhard O. Boehm h, Winfried März d, i, j, * a
LURIC Study Nonprofit LLC, Freiburg, Germany Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, Eberhard-Karls-University Tübingen, Tübingen, Germany c Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria d Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany e Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, United Kingdom f School of Sport and Exercise Sciences, University of Birmingham, Birmingham, United Kingdom g Cardiology Group Frankfurt-Sachsenhausen, Frankfurt, Germany h Division of Endocrinology and Diabetes, Department of Internal Medicine, Ulm University, Ulm, Germany i Synlab Services GmbH, Mannheim, Germany j Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 May 2012 Received in revised form 9 August 2012 Accepted 9 August 2012 Available online 27 August 2012
Objective: The American Diabetes Association (ADA) has revised the criteria for the diagnosis of diabetes in 2010. Glycated haemoglobin at a cut-point of 6.5% has been included in the diagnostic algorithm. We aimed to investigate whether there is still the need to perform oral glucose tolerance tests (OGTT). Methods: We studied 2002 people referred for angiography who did not have a history of diabetes. OGTT were performed in all 1772 subjects with fasting glucose <126 mg/dl. Participants were prospectively followed for all-cause and cardiovascular mortality over a mean duration (standard deviation) of 7.7 2.0 years. Results: Using the ADA 2010 criteria 618 individuals were categorised as having new-onset type 2 diabetes. Among these, 167 had isolated post-challenge hyperglycaemia. A total of 346 participants died during follow-up. Cardiovascular death occurred in 202 cases. Those with elevated fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5% had increased all-cause (hazard ratio [HR]: 1.63, 95% confidence interval [95%CI]: 1.28e2.08, p < 0.001) and cardiovascular mortality (HR: 1.66, 95%CI: 1.21 e2.29, p ¼ 0.002) compared to subjects without diabetes according to the ADA 2010 definition. Isolated elevation of post-challenge glucose independently predicted increased cardiovascular mortality (HR: 1.57, 95%CI: 1.02e2.43, p ¼ 0.041). All-cause and cardiovascular mortality were not significantly different between subjects with increased fasting glucose and/or glycated haemoglobin and those with isolated elevation of post-challenge glucose. Conclusions: Performing OGTT will identify a high risk group for cardiovascular mortality undetected by fasting glucose or glycated haemoglobin. Ó 2012 Published by Elsevier Ireland Ltd.
Keywords: All-cause mortality Cardiovascular mortality Diabetes classification Glycated haemoglobin Oral glucose tolerance test Post-challenge hyperglycaemia Type 2 diabetes
1. Introduction
Abbreviations: ADA, American Diabetes Association; LURIC, LUdwigshafen RIsk and Cardiovascular health; OGTT, oral glucose tolerance tests. * Corresponding author. Synlab Services GmbH, Synlab Academy, GottliebDaimler-Straße 25, D-68165 Mannheim, Germany. Tel.: þ49 621 43179432; fax: þ49 621 43179433. E-mail address: [email protected] (W. März). 0021-9150/$ e see front matter Ó 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.atherosclerosis.2012.08.008
Diabetes mellitus is a well-established cardiovascular risk factor [1e3]. The American Diabetes Association (ADA) in the past has recommended the use of fasting and post-challenge glucose for the diagnosis of diabetes [4]. In 2010, glycated haemoglobin at a threshold of 6.5% was introduced as an additional diagnostic criterion [5]. Glycated haemoglobin, a stable measure of average blood glucose [6,7], is a determinant of microvascular disease [8].
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However, several studies including the Hoorn Study, the CHARM program, and the EPIC-Norfolk Study have demonstrated that glycated haemoglobin is also associated with macrovascular complications [9e11]. Moreover, recent evidence from the ARIC and LUdwigshafen RIsk and Cardiovascular health (LURIC) studies have highlighted that glycated haemoglobin is a superior measure compared to fasting glucose for predicting cardiovascular endpoints [12,13]. Further data from the LURIC cohort have proposed that individuals with isolated elevation of glycated haemoglobin 6.5% are at greater risk of dying from cardiovascular causes [14]. Since glycated haemoglobin appears to be a feasible tool for diagnosing diabetes [15] and for estimating prognosis [9e14] the following question arises: Do we still need to perform oral glucose tolerance tests (OGTT)? Undoubtedly, numerous investigations such as the DECODE Study, the Euro Heart Survey, the AusDiab Study, the ADDITION-Leicester Study, and an Austrian collective have all confirmed that post-challenge hyperglycaemia is associated with an adverse outcome in subjects with fasting glucose <126 mg/dl [16e22]. Nevertheless, it is unclear whether OGTT will improve cardiovascular risk stratification in persons with both, fasting glucose <126 mg/dl and glycated haemoglobin <6.5%. Notably, a considerable amount of individuals exhibiting postchallenge hyperglycaemia 200 mg/dl will be categorised diabetic due to a concomitant elevation of glycated haemoglobin 6.5% [23,24]. Based on the previously mentioned novel guidelines, we sought to investigate whether isolated elevation of post-challenge glucose 200 mg/dl is predictive of increased all-cause and cardiovascular mortality. We report on data from the LURIC study. This large prospective clinical trial was planned to serve as a resource for analysing clinical, biochemical, and genetic predictors of hard cardiovascular outcomes and death from any other causes [25].
195
having diabetes [5]. OGTT were performed in all 1772 subjects with fasting glucose <126 mg/dl. Hypertension was diagnosed if the systolic and/or diastolic blood pressure exceeded 140 and/or 90 mm Hg or if there was a history of hypertension, also evident through the use of antihypertensive drugs [25]. Coronary artery disease was diagnosed if coronary angiography revealed stenosis of one or more vessels 50%. The severity of coronary artery disease was quantified with the Friesinger score which was broken down to quartiles (group 1: score 0e1, group 2: score 2e4, group 3: score 5e8, group 4: score 9e15) [26]. Maximum luminal narrowing was estimated by visual analysis as described previously [25]. Cerebrovascular disease was defined clinically by documented history of a previous cerebrovascular disease event (transient ischaemic attack, prolonged ischaemic neurological deficit, cerebral infarction with or without a remaining neurological deficit) and/or by documented carotid plaques (50% luminal obstruction) [25]. Peripheral vascular disease was defined by a history of intermittent claudication, angiographic documentation of atherosclerotic luminal obstruction of the peripheral arteries and/or a history of a peripheral arterial intervention for atherosclerotic disease (angioplasty and/or surgery) [25]. Comorbidity was assessed using the Charlson comorbidity index. This is a weighted score that takes into account the number and the seriousness of comorbid disease. We formed 3 groups (group 0: 0 score points, group 1: 1 score point, and group 2: 2 or more score points) [27]. Physical activity was assessed using a questionnaire with a scoring system ranging from 1 “sedentary” (avoid walking or exertion) to 11 “regular heavy exercise”. The study participants were grouped into the following 3 categories of physical activity (below average: scores 1e3, average: scores 4e7, and above average: scores 8e11).
2. Methods 2.2. Follow-up 2.1. Study design, participants and clinical characterization A total of 3316 patients, who were referred for coronary angiography to Ludwigshafen Heart Center in South-West Germany, were recruited between July 1997 and January 2000 [25]. Inclusion criteria were: German ancestry, clinical stability except for acute coronary syndromes, and the availability of a coronary angiogram. The indications for angiography in individuals in clinically stable condition were chest pain and/or noninvasive test results consistent with myocardial ischaemia. Individuals suffering from any acute illness other than acute coronary syndromes, chronic noncardiac diseases, or malignancy within the five past years, and those unable to understand the purpose of the study were excluded. Subjects with a history of diabetes and 684 subjects with incomplete determination of the gluco-metabolic phenotype (missing OGTT despite fasting glucose <126 mg/d) were additionally ruled out resulting in a sample size of 2002 (60.4%) out of 3316 LURIC participants for the present study. Death certificates were not available for 11 individuals. Hence, the analytic sample for the calculations on cardiovascular mortality was 1991 subjects. 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 [25]. Diagnostic criteria for diabetes: According to ADA 2009 criteria subjects with increased fasting (126 mg/dl) and/or post-challenge (2 h after the 75 g glucose load 200 mg/dl) glucose are considered diabetic [4]. Using the ADA 2010 guidelines persons with elevated glycated haemoglobin (6.5%) are additionally categorised as
There was a follow-up for all-cause and cardiovascular mortality. The mean (standard deviation) duration of the followup was 7.7 2.0 years. Information on the vital status was obtained from local person registries. Using death certificates, two experienced clinicians independently classified the causes of death. Both were masked to any other data belonging to the study participants. In a case of disagreement or uncertainty concerning the coding of a specific cause of death, classification was confirmed by a principal investigator of the LURIC study (W. M.) who was also masked to any other data belonging to the study participants [25]. 2.3. Laboratory analyses The standard laboratory methods have been described [25]. Glucose was measured enzymatically on a Hitachi 717 analyzer (Roche, Mannheim, Germany). Glycated haemoglobin was measured with immunoassay (haemoglobin A1c UNIMATE 5; HoffmannLaRoche, Grenzach-Whylen, Germany). Lipoproteins were separated using a combined ultracentrifugationeprecipitation method and measured on a WAKO 30 R analyzer (WAKO Chemicals GmbH, Neuss, Germany). Triglycerides were quantified with an enzymatic colour assay on a Hitachi 717 analyzer (Roche). Creatinine was measured with the Jaffé method on a Hitachi 717 analyzer (Roche). 2.4. Statistical analysis Three groups were formed (category A: subjects without diabetes according to the ADA 2010 definition; category B: subjects
196
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with isolated increase of post-challenge glucose 200 mg/dl; category C: subjects with increased fasting glucose 126 mg/dl and/or increased glycated haemoglobin 6.5%). The baseline characteristics are reported as numbers and percentages in cases of categorical variables and as means with standard deviations or medians with inter-quartile ranges in cases of continuous variables. Comparisons across the three groups were made with the chi-square test and with analysis of variance for categorical and continuous data, respectively. Triglycerides and insulin (Shapiroe Wilk W test) were transformed logarithmically before being used in parametric statistical procedures. The Cox proportional
hazards model was used to perform survival analyses. Three hierarchical models of adjustment (model 1: unadjusted; model 2: adjusted for sex and age; model 3: also adjusted for body mass index, systolic blood pressure, diastolic blood pressure, smoking, glomerular filtration rate, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol) were employed. In addition, adjusted survival curves based on Cox model 3 were plotted for the association between the diagnostic criteria of diabetes and cardiovascular mortality. All statistical tests were 2-sided and p values < 0.05 were considered significant. The SPSS 15.0 statistical package (SPSS Inc., Chicago, USA) was used.
Table 1 Baseline characteristics according to diagnostic criteria of diabetes.
Number Male sex Age, years Body mass index, kg/m2 Waist circumference, cmb Fasting glucose, mg/dl Glucose 2 h, mg/dlc Glycated haemoglobin, % Systemic hypertension Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Blood lipid level Total cholesterol, mg/dl LDL cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glomerular filtration rate, ml/min/1.73 m2 Smoking Never Former smoker Current smoker Coronary artery disease (50% stenosis) Friesinger score 0e1 2e4 5e8 9e15 NYHA functional class 1 2 3 4 Peripheral vascular disease Cerebrovascular disease Charlson comorbidity indexe Group 0 Group 1 Group 2 Physical activityf Below average Average Above average Medication use b-Blocker ACE inhibitor Calcium antagonist Diuretic Statin Acetyl salicylic acid
Pa
No diabetes ADA 2010 criteria
Post-challenge glucose 200 mg/dl only
Fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5%
1384 1012 (73.1) 60.6 10.8 27.1 3.8 97 12 98 10 125 33 5.7 0.4 920 (66.5) 139 23 81 11
167 119 (71.3) 65.3 9.8 27.1 3.5 99 11 103 11 234 37 5.8 0.4 129 (77.2) 141 25 80 11
451 336 (74.5) 63.7 (9.3) 28.5 4.2 102 11 126 28 172 63 6.9 0.9 362 (80.3) 143 22 82 11
196 38 120 35 40 11 137 (103e190) 84 17
189 42 116 34 37 11 149 (107e195) 83 19
193 39 116 33 37 10 156 (121e220) 79 18
501 597 286 869
(36.2) (43.1) (20.7) (62.8)
64 (38.3) 83 (49.7) 20 (12.0) 116 (69.5)
137 213 101 330
368 303 436 277
(26.6) (21.9) (31.5) (20.0)
23 46 56 42
(13.8) (27.5) (33.5) (25.1)
71 (15.7) 106 (23.5) 163 (36.1) 111 (24.6)
768 (55.5) 397 (28.7) 189 (13.7) 30 (2.2) 82 (5.9) 89 (6.4)
81 (48.5) 53 (31.7) 28 (16.8) 5 (3.0) 10 (6.0) 16 (9.6)
218 (48.3) 150 (33.3) 73 (16.2) 10 (2.2) 39 (8.6) 33 (7.3)
439 (35.1) 473 (37.8) 340 (27.2)
50 (32.3) 49 (31.6) 56 (36.1)
92 (23.0) 158 (39.5) 150 (37.5)
77 (5.7) 960 (70.8) 319 (23.5)
13 (7.9) 121 (73.8) 30 (18.3)
37 (8.3) 318 (71.3) 91 (20.4)
0.100 0.096 <0.001 <0.001d <0.001 0.012 e e e <0.001 <0.001 e e e e 0.161 e e e e 0.122 0.291 <0.001 e e e 0.129 e e e
889 667 180 250 656 983
108 (64.7) 93 (55.7) 27 (16.2) 52 (31.1) 83 (49.7) 116 (69.5)
283 (62.7) 243 (53.9) 79 (17.5) 157 (34.8) 226 (50.1) 324 (71.8)
0.832 0.036 0.046 <0.001 0.558 0.843
(64.2) (48.2) (13.0) (18.1) (47.4) (71.0)
(30.4) (47.2) (22.4) (73.2)
0.701 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.067 0.095
Values are means standard deviations or medians (25the75th percentiles) in cases of continuous variables and numbers (percentages) in cases of categorical data. a For differences across the three groups calculated with chi-square test and analysis of variance for categorical and continuous data, respectively. b Number: 1363/165/445. c Number: 1384/167/221. d Analysis of variance of logarithmically transformed values. e Number: 1252/155/400. f Number: 1356/164/446.
G. Silbernagel et al. / Atherosclerosis 225 (2012) 194e199 Table 2 Cause of death according to diagnostic criteria of diabetes.
Death from any cause Cardiovascular death Fatal infection Fatal cancer Other cause of death
No diabetes ADA 2010 criteria
Post-challenge glucose 200 mg/dl only
Fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5%
194 (14.0)
41 (24.6)
111 (24.6)
111 (8.1)
26 (15.7)
65 (14.5)
15 (1.1) 30 (2.2) 32 (2.3)
3 (1.8) 3 (1.8) 8 (4.8)
7 (1.6) 19 (4.3) 16 (3.6)
Values are numbers (percentages); data on cause of death available for 1378/166/ 447 subjects.
197
subjects without type 2 diabetes (Table 3). After multivariate adjustment, this association remained significant for those with increased fasting glucose and/or glycated haemoglobin (Table 3). The risk of death from any cause was not different between subjects with isolated elevation of post-challenge glucose and persons with increased fasting glucose and/or glycated haemoglobin (p ¼ 0.860, model 1). In agreement, subjects with isolated elevation of postchallenge glucose and persons with increased fasting glucose and/or glycated haemoglobin were more likely to die from cardiovascular diseases as shown in crude and adjusted models (Table 3, Fig. 1). The risk of cardiovascular death was not different between subjects with isolated elevation of post-challenge glucose and persons with increased fasting glucose and/or glycated haemoglobin (p ¼ 0.873, model 1). 4. Discussion
3. Results 3.1. Baseline characteristics according to diagnostic criteria of diabetes According to the ADA 2010 criteria a total of 618 subjects were categorised as having type 2 diabetes. Participant characteristics for those without type 2 diabetes, for those with isolated postchallenge hyperglycaemia, and for those with increased fasting plasma glucose and/or glycated haemoglobin are reported in Table 1. Persons without diabetes according to the ADA 2010 criteria and subjects with isolated post-challenge hyperglycaemia did not differ in body mass index (p ¼ 0.956) and glomerular filtration rate (p ¼ 0.424). However, age (p < 0.001), high density lipoprotein cholesterol (p < 0.001), and proportion of subjects with hypertension (p ¼ 0.003) were significantly different between individuals without diabetes and those with isolated postchallenge hyperglycaemia. 3.2. Mortality according to diagnostic criteria of diabetes Prevalent causes of death for subjects without type 2 diabetes, for those with isolated post-challenge hyperglycaemia, and for those with increased fasting plasma glucose and/or glycated haemoglobin are shown in Table 2. Univariate Cox regression analyses revealed that subjects with isolated post-challenge hyperglycaemia as well as subjects with increased fasting glucose and/or glycated haemoglobin had increased all-cause mortality compared to
This study in people undergoing coronary angiography indicates that subjects with fasting glucose <126 mg/dl and glycated haemoglobin <6.5% but with post-challenge glucose 200 mg/dl have increased cardiovascular mortality compared to subjects without type 2 diabetes according to the ADA 2010 criteria [5]. Moreover, the increase in the risk of death from any cause and from cardiovascular diseases is not different between subjects with isolated post-challenge hyperglycaemia and subjects with elevated fasting glucose and/or glycated haemoglobin. How are LURIC participants with isolated elevation of postchallenge glucose 200 mg/dl clinically and metabolically characterized? Of note, these individuals did not differ from participants without diabetes according to the ADA 2010 criteria in terms of body mass index and glomerular filtration rate. However, people with isolated increase of post-challenge glucose were older, had lower levels of high density lipoprotein cholesterol, and were more likely to suffer from hypertension compared to those without diabetes according to the ADA 2010 criteria. Hence, LURIC participants with isolated post-challenge hyperglycaemia a priori had an unfavourable cardiovascular risk factor profile. Nevertheless, the association of isolated elevation of post-challenge glucose with increased cardiovascular mortality remained significant after multivariate adjustment. Statistical significance was lost for the relationship between isolated post-challenge hyperglycaemia and increased all-cause mortality when we adjusted for important cardiovascular risk factors. This is most probably due to the relatively low number of individuals in the subgroup identified as diabetic with OGTT only.
Table 3 Mortality according to diagnostic criteria of diabetes. Model 1a
All-cause mortality No diabetes ADA 2010 criteria Post-challenge glucose 200 mg/dl only Fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5% Cardiovascular mortalityd No diabetes ADA 2010 criteria Post-challenge glucose 200 mg/dl only Fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5%
Model 2b
Model 3c
HR
P
HR
P
HR
P
1.0 reference 1.86 (1.33e2.60) 1.92 (1.52e2.42)
<0.001 <0.001
1.0 reference 1.44 (1.03e2.02) 1.66 (1.31e2.10)
0.035 <0.001
1.0 reference 1.37 (0.97e1.92) 1.63 (1.28e2.08)
0.075 <0.001
1.0 reference 2.04 (1.33e3.13) 1.97 (1.45e2.68)
0.001 <0.001
1.0 reference 1.59 (1.04e2.45) 1.71 (1.26e2.32)
0.034 0.001
1.0 reference 1.57 (1.02e2.43) 1.66 (1.21e2.29)
0.041 0.002
HR hazard ratio (calculated with Cox proportional hazards model). a Unadjusted. b Adjusted for sex and age. c Adjusted for sex, age, body mass index, systolic blood pressure, diastolic blood pressure, smoking, glomerular filtration rate, triglycerides, LDL cholesterol, and HDL cholesterol. d Data available for 1991 subjects.
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G. Silbernagel et al. / Atherosclerosis 225 (2012) 194e199
Although the predictive value of post-challenge hyperglycaemia for cardiovascular mortality has been demonstrated in subjects with non-diabetic fasting glucose [16e22], such a relationship has not been shown for subjects with both, non-diabetic fasting glucose and non-diabetic glycated haemoglobin, so far. Thus, our results extend previous studies suggesting that post-challenge hyperglycaemia represents an independent cardiovascular risk factor [16e22,28]. Yet, there is paucity of data demonstrating that hard cardiovascular endpoints can be reduced by treating post-challenge hyperglycaemia [29]. Only the Stop-NIDDM Trial, a randomised prospective study comparing acarbose therapy with placebo, confirmed that a significant amount of cardiovascular events could be prevented by interventions targeting elevated post-challenge glucose levels [30]. Long-term interventional studies will be needed to further support the concept of a causal relationship between post-challenge hyperglycaemia and cardiovascular complications [29]. The main disadvantage of OGTT is that they are time-consuming and, unfortunately, often neglected in clinical practice. This was also observed in the LURIC cohort considering that OGTT were not performed in all participants without a previous diagnosis of diabetes mainly due to lack of manpower or time. Therefore, another important future scientific goal could be to investigate whether fasting measurements could provide the same prognostic information as OGTT. All participants of the LURIC study were referred for coronary angiography. Hence, our conclusions are confined to people at intermediate to high cardiovascular risk. Moreover, fasting and post-challenge glucose and glycated haemoglobin were measured once only. Consequently, the criteria for the diagnosis of diabetes could not be confirmed as recommend by the ADA in the absence of unequivocal hyperglycemia [5]. With regard to the strengths of the LURIC study we want to emphasize the detailed clinical and metabolic characterization of the participants including coronary angiography. Furthermore, we point out the long duration and the completeness of the follow-up with a large number of particularly cardiovascular events.
To sum up, the LURIC data suggest that post-challenge glucose levels 200 mg/dl identify a high risk group for cardiovascular mortality undetected by fasting glucose or glycated haemoglobin using the cut points recommended by the ADA. Performing OGTT may, therefore, be warranted to achieve optimal cardiovascular risk stratification in people without known diabetes. Contributions B.O.B., B.R.W., and W.M. designed the study. G.S., M.E.K., B.H., and W.M. performed the statistical analysis. B.O.B, G.S., and W.M. wrote the manuscript. H.S. and T.B.G. contributed to the interpretation of the results and reviewed/edited the manuscript. All authors have read and approved the manuscript as submitted. Funding sources LURIC was supported by the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and 7th of Framework Program (integrated project Atheroremo, Grant Agreement number 201668) of the European Union. B.O.B. received grants form the DFG GrK 1041 and the Centre of Excellence “Metabolic Diseases” Baden-Wuerttemberg. Disclosure The authors have no conflict of interest to declare. Acknowledgements The authors thank the participants of the LURIC study, 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. References
1,00
Cumulative survival
0,98 0,96 0,94 A
0,92 0,90
B C
0,88 0,86 0
1
2
3
4
5
6
7
8
9
10
Survival time, years Fig. 1. Adjusted survival curves (model 3) for cardiovascular mortality according to diagnostic criteria of diabetes: A) subjects without type 2 diabetes according to the ADA 2010 criteria, B) subjects with isolated elevation of post-challenge glucose 200 mg/dl, and C) subjects with increase of fasting glucose 126 mg/dl and/or glycated haemoglobin 6.5%.
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