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Does glycated hemoglobin have clinical significance in ischemic stroke patients?
Clinical Neurology and Neurosurgery 112 (2010) 98–102
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Does glycated hemoglobin have clinical significance in ischemic stroke patients? Sung Hyuk Heo a,b , Seung-Hoon Lee a,c,∗ , Beom Joon Kim a,c , Bong Su Kang c , Byung Woo Yoon a,c,∗∗ a
Clinical Research Center for Stroke, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea Department of Neurology, Kyung Hee University Medical Center, Seoul, Republic of Korea c Department of Neurology, Seoul National University Hospital, #28 Yeongeon-dong, Jongno-gu, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 8 January 2009 Received in revised form 10 August 2009 Accepted 24 August 2009 Available online 18 September 2009 Keywords: Hemoglobin A1c Diabetes Ischemic stroke
a b s t r a c t Objectives: It has been suggested that patients with an elevated hemoglobin A1c (HbA1c) level have an increased risk of cardiovascular disease regardless of the presence of diabetes. However, an association between HbA1c and stroke has not yet been determined. In this study, our purpose was to examine whether HbA1c was independently associated with various types of cerebral vascular lesions in stroke patients. Methods: A consecutive series of acute ischemic stroke patients were included for this analysis from October, 2002, to March, 2006. HbA1c was examined on admission, and MR imaging was performed for analysis of large artery diseases (LADs) and small artery diseases (SADs). Symptomatic or asymptomatic LAD was diagnosed by MR angiography, and SAD was classified as leukoaraiosis, microbleeds, or old lacunar infarctions. Results: A total of 639 stroke patients were analyzed (diabetics, n = 247; non-diabetics, n = 392). There was no relationship between the level of HbA1c and any type of cerebrovascular lesion in the nondiabetic patients. In contrast, HbA1c showed a significant negative association with symptomatic LAD and leukoaraiosis in the diabetic patients using univariate analysis (p = 0.01 and p < 0.05, respectively). These associations did not remain significant, however, after adjustment for age and hypertension. This was, in part, because the HbA1c level in our diabetic population decreased gradually with age (p = 0.03). Conclusions: Our results indicate that HbA1c is not associated with risk for various types of cerebrovascular lesions in ischemic stroke patients. The negative association between age and HbA1c in diabetic patients should be further investigated. © 2009 Elsevier B.V. All rights reserved.
1. Introduction It is well known that diabetes may contribute to an increased risk for cardiovascular and cerebrovascular disease including stroke [1,2]. However, the findings from meta-analyses of the effects of hyperglycemia on stroke are contradictory. While a meta-analysis focusing on prospective cohort studies found that people with chronic hyperglycemia had an increased risk of microvascular complications, such as retinopathy, as well as myocardial infarction and stroke [3], another two meta-analyses and recent randomized controlled trials such as ACCORD, ADVANCE, and VADT found
∗ Corresponding author at: Department of Neurology, Seoul National University Hospital, #28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Republic of Korea. Tel.: +82 2 2072 1014; fax: +82 2 3672 7553. ∗∗ Corresponding author at: Department of Neurology, Seoul National University Hospital, #28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Republic of Korea. Tel.: +82 2 2072 2875; fax: +82 2 744 1785. E-mail addresses: [email protected] (S.-H. Lee), [email protected] (B.W. Yoon). 0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2009.08.024
that lowering blood glucose did not significantly reduce the pooled incidence of stroke [4–8]. The HbA1c level reflects long-term glycemic control and is a more accurate and stable measure than fasting blood glucose levels; therefore, it is widely used in clinical practice to assess control of diabetes [9]. Observational analyses of data from the United Kingdom Prospective Diabetes Study (UKPDS) suggested HbA1c is positively associated with stroke risk [10], and a cohort study revealed that elevated HbA1c could be an independent risk factor for ischemic stroke in people with and without diabetes [11]. Furthermore, it was reported that HbA1c was independently associated with cerebral microbleeds in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [12]. The relationship between cerebral microbleeds and diabetes, however, has been unclear [13]. We wondered whether glycated hemoglobin might influence microbleeds in only a specific disease group, such as CADASIL, or if it might be related to general ischemic stroke. In the present study, we examined whether HbA1c had any clinical significance associated with ischemic stroke and whether it could be an independent risk factor of vascular lesions in the brain.
S.H. Heo et al. / Clinical Neurology and Neurosurgery 112 (2010) 98–102
2. Subjects and methods 2.1. Subjects From October, 2002, to March, 2006, we first collected 849 consecutive ischemic stroke patients who visited the department in our hospital (less than 7 days after onset). We excluded patients whose stroke mechanism was cardioembolism (n = 170) or other determined etiologies (n = 10). HbA1c was examined on admission, and patients were excluded if they did not have laboratory data for HbA1c (n = 30). Therefore, the final study population consisted of a total of 639 patients. This study was approved by an independent ethics committee in Seoul National University Hospital (H-0802-035-234). 2.2. Clinical information We collected clinical information regarding the following vascular risk factors: age, sex, hypertension, diabetes mellitus, dyslipidemia, and smoking. Hypertension was defined as follows: patients with known hypertension and/or taking antihypertensive medication, or de novo hypertension with systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg at discharge (mean hospitalization period: 14.9 ± 10.7 days). We classified diabetes as alleged diabetic subjects with or without medication and subjects with fasting glucose (FG) ≥ 7.0 mmol/L (126 mg/dl) or with 2-h postprandial serum glucose ≥11.1 mmol/L (200 mg/dl) after achieving stable medical and neurological condition [14]. Dyslipidemia was determined as prior diagnosis with hypercholesterolemia or newly diagnosis with level of fasting serum low-density lipoprotein (LDL) cholesterol based on National Cholesterol Education Program Adult Treatment Panel III guidelines [15]. Cigarette smoking status was classified as habitual smokers and non-habitual smokers. 2.3. Image analysis MR was performed with a 1.5-T superconducting magnet system [Signa; GE Medical Systems, Milwaukee, WI, USA] under the following conditions: axial T2-weighted spin-echo [repetition time (TR)/echo time (TE) 2500–4500/80–112 ms; slice thickness 5 mm; interslice gap 0–2 mm], fluid-attenuated inversion recovery (FLAIR; TR/TE = 8000–9500/90–120 ms; slice thickness 5 mm; interslice gap 0–2 mm), axial T2-weighted gradient echo sequence (TR/TE = 200–500/15 ms; slice thickness 5 mm; interslice gap 0–2 mm), and three-dimensional time of flight MR angiography (flight of view = 220 mm; TR/TE = 30–45/5–8; flip angle = 20–25). MRA imaging was performed for analysis of LAD and SAD. Symptomatic or asymptomatic LAD (extracranial and intracranial arterial stenosis of 50% or more) was assessed by MR angiography in the proximal internal carotid artery (ICA) and vertebral artery (VA) for extracranial stenosis and in proximal portions of the middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), basilar artery (BA), and distal ICA for intracranial stenosis, in consideration of the sensitivity and specificity of MR angiography. SAD was classified as advanced leukoaraiosis, cerebral microbleeds, or old lacunar infarctions. Imaging analysis was performed independently by two experienced neurologists (BJK and BSK) operating by consensus and without any knowledge of clinical information. Old lacunar infarctions and cerebral microbleeds were assessed as in our previous study [16,17]. Briefly, cerebral microbleeds were observed as homogeneous round hypointense lesions with a diameter ≤5 mm on gradient echo MRI; old lacunar infarctions were defined as a focal lesion of ≥3 mm in diameter with signal intensity corresponding to liquor (i.e., hyperintense on T2-weighted images and hypointense on FLAIR images). A score
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of 2 or more in Fazekas’ white matter rating scale according to the following criteria (0 = absence, 1 = punctuate foci, 2 = beginning confluence of foci, or 3 = large confluent areas) was classified as advanced leukoaraiosis [18]. 2.4. Statistical analysis Baseline demographic and laboratory data were expressed as mean ± standard deviation for continuous variables and as frequencies for categorical variables by t-test and 2 -test. Univariate and multivariate logistic regression analyses were also used to determine the association of HbA1c and large or small artery disease. The predictive model was based on demographic and major clinical vascular risk factor variables, which included age, sex, hypertension, dyslipidemia, and smoking. In all tests, a p-value < 0.05 was considered significant. All statistical analyses were conducted using the SPSS 13.0 package for Windows (SPSS Inc., Chicago, IL, USA). 3. Results Of the 639 subjects included in this study, 438 were male (68.5%) and the mean age of the patients was 64.9 ± 11.1 years. There were 448 patients with hypertension (70.1%), 247 with diabetes (38.7%), 300 with dyslipidemia (46.9%), and 259 with a smoking history (40.5%). We divided subjects into two groups depending on the presence of diabetes (Table 1). Previous stroke history, increased FG and HbA1c level, dyslipidemia, and reduced high density lipoprotein (HDL) level were more common in the diabetes group. There were no differences in stroke subtype or in the existence of leukoaraiosis, cerebral microbleeds, or old lacunes. There was no relationship between HbA1c and LAD in the non-diabetic patients (Table 2). Unexpectedly, in the patients with diabetes, HbA1c showed a significant negative association with symptomatic LAD (p = 0.01). There was also no relationship between HbA1c and any of the SAD subtypes in the non-diabetic patients. In contrast, a negative association between HbA1c and Table 1 Demographic findings of patients. Diabetics (n = 247)
Non-diabetics (n = 392)
p-Value
Sex (male/female) Age TIA history Old stroke history BMI Hypertension Fasting blood glucose HbA1c
173/74 65.6 ± 9.8 6 (2.4%) 70 (28.3%) 24.1 ± 3.0 179 (72.5%) 154.1 ± 59.9 7.93 ± 1.61
265/127 64.4 ± 11.8 18 (4.6%) 71 (18.1%) 24.1 ± 3.3 269 (68.6%) 101.8 ± 21.0 5.64 ± 0.45
0.541 0.150* 0.202 0.003 0.972 0.329 <0.001* <0.001*
Dyslipidemia LDL HDL TG
185 (74.9%) 117.7 ± 39.9 40.3 ± 10.4 149.8 ± 96.8
115 (29.3%) 112.6 ± 31.1 44.2 ± 12.5 123.1 ± 66.6
<0.001 0.091* <0.001* <0.001*
Smoking
96 (38.9%)
163 (41.6%)
0.509
Stroke subtype LAD SVO UD
88 (35.6%) 97 (39.3%) 62 (25.1%)
135 (34.4%) 163 (41.6%) 94 (24.0%)
Cerebral microbleeds Advanced leukoaraiosisa Old lacunes
67 (27.1%) 74 (30.0%) 69 (28.4%)
126 (32.8%) 136 (35.2%) 105 (27.2%)
0.844
0.184 0.225 0.784
TIA, transient ischemic attack; BMI, body mass index; HbA1c, hemoglobin A1c; LDL, low density lipoprotein; HDL, high density lipoprotein; TG, triglyceride; LAA, large artery atherosclerosis; SVO, small vessel occlusion; UD, stroke of undetermined aetiology. Pearson’s 2 test and *Student t-tests were used. a Advanced leukoaraiosis means Fazekas score ≥2.
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Table 2 The influence of HbA1c on large artery disease, leukoaraiosis, cerebral microbleeds, and old lacunes. HbA1c (non-diabetes)
p-Value
HbA1c (diabetes)
p-Value
LAD No symptomatic LAD Symptomatic LAD No asymptomatic LAD Asymptomatic LAD LAD(−) LAD(+)
5.62 5.68 5.63 5.67 5.64 5.64
Leukoaraiosis None to minimal (Fazekas score ≤1) Moderate to severe (Fazekas score ≥ 2)
5.63 ± 0.45 5.65 ± 0.46
0.700
8.09 ± 1.64 7.64 ± 1.48
0.043
Cerebral microbleeds CMB = 0 CMB(s) ≥ 1
5.64 ± 0.43 5.63 ± 0.50
0.765
8.04 ± 1.51 7.75 ± 1.82
0.201
Old lacunes No old lacune Old lacune(s) ≥ 1
5.64 ± 0.45 5.65 ± 0.46
0.844
8.06 ± 1.63 7.69 ± 1.52
0.114
± ± ± ± ± ±
0.45 0.45 0.43 0.49 0.43 0.46
8.21 7.65 8.10 7.78 8.35 7.77
0.215 0.566 0.979
± ± ± ± ± ±
1.78 1.38 1.74 1.47 1.91 1.46
0.008 0.129 0.014
LAD, large artery disease; CMB, cerebral microbleed.
leukoaraiosis was seen in the diabetic patients (p = 0.04), and the same trend was seen for microbleeds and old lacunes using an independent t-test (p = 0.20 and 0.11, respectively). Still, HbA1c was not related to symptomatic LAD or leukoaraiosis after adjusting for age and hypertension (Table 3). The same results were seen after adjusting for all variables (age, sex, hypertension, dyslipidemia, and smoking). Age (relative risk (RR) = 1.03, p = 0.04) was only related with symptomatic LAD, and age (RR = 1.07, p < 0.01) and hypertension (RR = 2.84, p = 0.01) were related with advanced leukoaraiosis, suggesting SAD in multivariate analysis. 4. Discussion We found that HbA1c was not independently associated with any of the examined types of cerebrovascular lesions in ischemic stroke patients with and without diabetes. In our study, age was the most important risk factor for LAD; while male gender, hypertension, and dyslipidemia showed tendencies towards a relationship with LAD. In addition, age and hypertension were significantly related with a risk of leukoaraiosis. These results were similar to previous studies demonstrating differences in risk factor profiles between ischemic stroke subtypes. These studies revealed that LAD was associated with male gender, smoking, and raised cholesterol; while SVD was associated with hypertension [19,20].
It is widely accepted that diabetes increases microvascular and macrovascular complications including stroke, particularly in the type 2 diabetic population [21]. In the Framingham Study, the incidence of nonhemorrhagic stroke was found to be between 2.5 and 3.5 times higher among diabetic subjects compared to nondiabetics [22]. It has also been shown that diabetes increases both lacunar and non-lacunar strokes [23]. In addition, HbA1c may be useful in determining risk for incident cardiovascular events [3,11,24–26]. Some prospective studies concluded that HbA1c could be an independent risk factor for stroke in people with and without diabetes. However, many studies showed that this association was diminished and lost statistical significance after adjustment for traditional cardiovascular risk factors, while diabetes itself remained a strong independent risk factor [5–8,24,25]. In addition, recent ADVANCE trial revealed that the decrease in HbA1c was only related to the reduction of microvascular events such as nephropathy and this influenced total outcome of events, it may be asked whether the relationship between HbA1c and various cerebral SAD exists [5]. In our study population, the results suggested that age was only important for development of LAD, and HbA1c was not related. We also found that a chronic hyperglycemic state did not influence the incidence of SAD subtypes. Therefore, the previously reported association between HbA1c and cerebral microbleeds in CADASIL cannot be generalized to the ischemic stroke population [12].
Table 3 Univariate and multivariate relative risks for symptomatic LAD and advanced leukoaraiosis in diabetes patients. Risk factor
Univariate
Multivariate (age and hypertension)a
Multivariate (all variables)b RR
RR
95% CI
p-Value
RR
Sx LAD Age Hypertension HbA1c Male sex Dyslipidemia Smoking
95% CI
1.036 2.045 0.798 1.145 1.629 0.936
1.009–1.064 1.155–3.620 0.676–0.943 0.664–1.973 0.911–2.914 0.561–1.561
0.009 0.014 0.008 0.627 0.100 0.800
1.027 1.651 0.847
0.998–1.056 0.910–2.995 0.712–1.007
0.065 0.099 0.060
1.031 1.632 0.859 1.450 1.600 0.984
1.002–1.061 0.893–2.983 0.720–2.846 0.739–2.846 0.872–2.938 0.530–1.827
0.038 0.112 0.093 0.280 0.129 0.959
Advanced LA Age Hypertension HbA1c Male sex Dyslipidemia Smoking
1.081 3.774 0.823 0.778 2.110 0.608
1.046–1.118 1.754–8.118 0.679–0.996 0.433–1.398 1.046–4.256 0.341–1.084
<0.001 0.001 0.046 0.400 0.037 0.092
1.073 2.967 0.929
1.037–1.110 1.336–6.588 0.756–1.142
<0.001 0.008 0.485
1.075 2.835 0.953 1.446 1.982 0.732
1.038–1.114 1.267–6.341 0.775–1.172 0.683–3.059 0.934–4.203 0.359–1.495
<0.001 0.011 0.648 0.470 0.075 0.392
RR, relative risk; CI, confidence interval; Sx LAD, symptomatic large artery disease; LA, leukoaraiosis. a Adjusted for age and hypertension. b Adjusted for all variables (age, sex, hypertension, dyslipidemia, and smoking).
p-Value
95% CI
p-Value
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Fig. 1. The age-related patterns of HbA1c level (A, p = 0.033) and hypertension proportion (B, p = 0.028) in diabetic patients.
The strength of our study was that multiple indices of small vessel disease were employed to evaluate cerebral SAD. We classified SAD into leukoaraiosis, cerebral microbleeds and old lacunes, which may reflect various aspects of SAD. Leukoaraiosis is known to be mainly caused by stenosis or occlusion of small vessels with sudden or chronic ischemia leading to incomplete white matter infarction [27]. Disturbed autoregulation in diseased small vessels and subsequent fluctuations in blood flow in response to changes in systemic blood pressure have some influence on leukoaraiosis. Microbleeds indicate previous extravasation of blood, signifying bleeding-prone cerebral microangiopathy [28,29]. Old lacunes indicate small vessel obstruction caused by arteriolosclerosis with hyaline deposition and microatheromatosis [30]. Previous studies regarding cerebral microvasculopathy largely used lacunar infarction, which only explains a portion of SAD [20,30]. Therefore, interpretation is complicated because some studies divide patients into those with single lacunar infarction and those with multiple lacunar infarctions regardless of the presence of leukoaraiosis. The relationship between diabetes and all SAD subtypes is still controversial. A cross-sectional population-based study revealed that type 2 diabetes was associated with deep white matter lesions (p = 0.02) [31], but in the Framingham Study, diabetes was not related to white matter hyperintensity volume [32]. The same was found for microbleeds [12,13,29]. For old lacunes, both positive and negative results have been reported regarding the association with diabetes [20,33]. Although only some of these reports included HbA1c data, these had also controversial results [12,13,29,31,33]. We can now speculate why HbA1c levels in patients with diabetes had a significant negative association with symptomatic LAD and a tendency toward a negative association with all of the SAD subtypes in univariate analysis. It is widely accepted that age and hypertension are the two most important risk factors for LAD and SAD [19,20,34]. Interestingly, we found that the HbA1c level in the diabetic population decreased gradually with age (p = 0.03, Fig. 1A), as the proportion of patients with hypertension increased (p = 0.03, Fig. 1B). Therefore, in our diabetic patients, those with higher HbA1c levels were younger and more frequently hypertensive. As a result, the relationship of HbA1c level with LAD and SAD was insignificant in multivariate analyses. There have been some reports about the relationship between age and HbA1c level. In normal subjects, HbA1c level was found to increase with age [35,36], but in diabetic patients, there was a negative correlation or no relationship [37,38]. This might be caused by age-related nutritional, hygienic, and economic factors or simply the natural course of diabetes itself. In addition, uncontrolled
diabetes particularly increased the risk of stroke among younger patients [39]. It was also reported that diabetes increased the risk of stroke more than 10-fold in the stroke population younger than 55 years old [40]. With respect to hypertension, our results agreed with previous studies reporting that the overall prevalence of hypertension gradually increased with age in the Korean population [41]. There were several limitations of our study. First, we obtained all of the in-hospital data retrospectively. Nevertheless, as was seen in recent prospective study, HbA1c could predict diabetes, but not cardiovascular disease [42]. Second, we did not carry out oral glucose tolerance tests and did not include impaired glucose tolerance in our data. Third, we did not record the duration and medication of diabetes and used a single baseline measurement of HbA1c. We therefore cannot evaluate the effects of changes in this parameter over time. However, HbA1c values have been found to reliably categorize glycemic status in nondiabetic subjects over a period of at least four to six years [43]. Finally, we only analyzed acute stroke patients classified into large artery atherosclerosis, small artery occlusion, and stroke of undetermined etiology by TOAST classification and did not compare with a normal control group. In summary, our study suggests that baseline HbA1c is not an independent risk factor for symptomatic LAD or any vascular lesions suggesting SAD. This may be the result of an age-related decrease in HbA1c levels and increase in the prevalence of hypertension. Therefore, established cardiovascular risk factors instead of hyperglycemia itself may be more important for the development of ischemic stroke. Competing interests None. Acknowledgements This study was supported by grants of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A060171). References [1] Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 1991;151:1141–7.
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[22] Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241:2035–8. [23] Ohira T, Shahar E, Chambless LE, Rosamond WD, Mosley Jr TH, Folsom AR. Risk factors for ischemic stroke subtypes: the Atherosclerosis Risk in Communities study. Stroke 2006;37:2493–8. [24] Blake GJ, Pradhan AD, Manson JE, Williams GR, Buring J, Ridker PM, et al. Hemoglobin A1c level and future cardiovascular events among women. Arch Intern Med 2004;164:757–61. [25] Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004;141:413–20. [26] Myint PK, Sinha S, Wareham NJ, Bingham SA, Luben RN, Welch AA, et al. Glycated hemoglobin and risk of stroke in people without known diabetes in the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study: a threshold relationship? Stroke 2007;38:271–5. [27] Pantoni L. Pathophysiology of age-related cerebral white matter changes. Cerebrovasc Dis 2002;13(Suppl. 2):7–10. [28] Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. Am J Neuroradiol 1999;20:637–42. [29] Jeerakathil T, Wolf PA, Beiser A, Hald JK, Au R, Kase CS, et al. Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham Study. Stroke 2004;35:1831–5. [30] Boiten J, Lodder J, Kessels F. Two clinically distinct lacunar infarct entities? A hypothesis. Stroke 1993;24:652–6. [31] Manschot SM, Brands AM, van der Grond J, Kessels RP, Algra A, Kappelle LJ, et al. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 2006;55:1106–13. [32] Jeerakathil T, Wolf PA, Beiser A, Massaro J, Seshadri S, D’Agostino RB, et al. Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study. Stroke 2004;35:1857–61. [33] Saitoh T, Daimon M, Eguchi H, Hosoya T, Kawanami T, Kurita K, et al. Type 2 diabetes is not a risk factor for asymptomatic ischemic brain lesion—the Funagata study. Intern Med 2002;41:351–6. [34] Jackson C, Sudlow C. Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke 2005;36:891–901. [35] Nuttall FQ. Effect of age on the percentage of hemoglobin A1c and the percentage of total glycohemoglobin in non-diabetic persons. J Lab Clin Med 1999;134:451–3. [36] Vallee Polneau S, Lasserre V, Fonfrede M, Delattre J, Benazeth S. A different approach to analyzing age-related HbA1c values in non-diabetic subjects. Clin Chem Lab Med 2004;42:423–8. [37] Van Wersch JW, Westerhuis LW, Venekamp WJ. HbA1C and serum fructosamine in diabetic patients: relationship to age, clotting and fibrinolysis parameters and urinary microalbumin excretion. Clin Chim Acta 1991;201:99–104. [38] Wiener K, Roberts NB. Age does not influence levels of HbA1c in normal subject. QJM 1999;92:169–73. [39] Jorgensen H, Nakayama H, Raaschou HO, Olsen TS. Stroke in patients with diabetes. The Copenhagen Stroke Study. Stroke 1994;25:1977–84. [40] You RX, McNeil JJ, O’Malley HM, Davis SM, Thrift AG, Donnan GA. Risk factors for stroke due to cerebral infarction in young adults. Stroke 1997;28:1913–8. [41] Jo I, Ahn Y, Lee J, Shin KR, Lee HK, Shin C. Prevalence, awareness, treatment, control and risk factors of hypertension in Korea: the Ansan study. J Hypertens 2001;19:1523–32. [42] Pradhan AD, Rifai N, Buring JE, Ridker PM. Hemoglobin A1c predicts diabetes but not cardiovascular disease in nondiabetic women. Am J Med 2007;120:720–7. [43] Meigs JB, Nathan DM, Cupples LA, Wilson PW, Singer DE. Tracking of glycated hemoglobin in the original cohort of the Framingham Heart Study. J Clin Epidemiol 1996;49:411–7.
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Does glycated hemoglobin have clinical significance in ischemic stroke patients? Sung Hyuk Heo a,b , Seung-Hoon Lee a,c,∗ , Beom Joon Kim a,c , Bong Su Kang c , Byung Woo Yoon a,c,∗∗ a
Clinical Research Center for Stroke, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea Department of Neurology, Kyung Hee University Medical Center, Seoul, Republic of Korea c Department of Neurology, Seoul National University Hospital, #28 Yeongeon-dong, Jongno-gu, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 8 January 2009 Received in revised form 10 August 2009 Accepted 24 August 2009 Available online 18 September 2009 Keywords: Hemoglobin A1c Diabetes Ischemic stroke
a b s t r a c t Objectives: It has been suggested that patients with an elevated hemoglobin A1c (HbA1c) level have an increased risk of cardiovascular disease regardless of the presence of diabetes. However, an association between HbA1c and stroke has not yet been determined. In this study, our purpose was to examine whether HbA1c was independently associated with various types of cerebral vascular lesions in stroke patients. Methods: A consecutive series of acute ischemic stroke patients were included for this analysis from October, 2002, to March, 2006. HbA1c was examined on admission, and MR imaging was performed for analysis of large artery diseases (LADs) and small artery diseases (SADs). Symptomatic or asymptomatic LAD was diagnosed by MR angiography, and SAD was classified as leukoaraiosis, microbleeds, or old lacunar infarctions. Results: A total of 639 stroke patients were analyzed (diabetics, n = 247; non-diabetics, n = 392). There was no relationship between the level of HbA1c and any type of cerebrovascular lesion in the nondiabetic patients. In contrast, HbA1c showed a significant negative association with symptomatic LAD and leukoaraiosis in the diabetic patients using univariate analysis (p = 0.01 and p < 0.05, respectively). These associations did not remain significant, however, after adjustment for age and hypertension. This was, in part, because the HbA1c level in our diabetic population decreased gradually with age (p = 0.03). Conclusions: Our results indicate that HbA1c is not associated with risk for various types of cerebrovascular lesions in ischemic stroke patients. The negative association between age and HbA1c in diabetic patients should be further investigated. © 2009 Elsevier B.V. All rights reserved.
1. Introduction It is well known that diabetes may contribute to an increased risk for cardiovascular and cerebrovascular disease including stroke [1,2]. However, the findings from meta-analyses of the effects of hyperglycemia on stroke are contradictory. While a meta-analysis focusing on prospective cohort studies found that people with chronic hyperglycemia had an increased risk of microvascular complications, such as retinopathy, as well as myocardial infarction and stroke [3], another two meta-analyses and recent randomized controlled trials such as ACCORD, ADVANCE, and VADT found
∗ Corresponding author at: Department of Neurology, Seoul National University Hospital, #28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Republic of Korea. Tel.: +82 2 2072 1014; fax: +82 2 3672 7553. ∗∗ Corresponding author at: Department of Neurology, Seoul National University Hospital, #28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Republic of Korea. Tel.: +82 2 2072 2875; fax: +82 2 744 1785. E-mail addresses: [email protected] (S.-H. Lee), [email protected] (B.W. Yoon). 0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2009.08.024
that lowering blood glucose did not significantly reduce the pooled incidence of stroke [4–8]. The HbA1c level reflects long-term glycemic control and is a more accurate and stable measure than fasting blood glucose levels; therefore, it is widely used in clinical practice to assess control of diabetes [9]. Observational analyses of data from the United Kingdom Prospective Diabetes Study (UKPDS) suggested HbA1c is positively associated with stroke risk [10], and a cohort study revealed that elevated HbA1c could be an independent risk factor for ischemic stroke in people with and without diabetes [11]. Furthermore, it was reported that HbA1c was independently associated with cerebral microbleeds in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [12]. The relationship between cerebral microbleeds and diabetes, however, has been unclear [13]. We wondered whether glycated hemoglobin might influence microbleeds in only a specific disease group, such as CADASIL, or if it might be related to general ischemic stroke. In the present study, we examined whether HbA1c had any clinical significance associated with ischemic stroke and whether it could be an independent risk factor of vascular lesions in the brain.
S.H. Heo et al. / Clinical Neurology and Neurosurgery 112 (2010) 98–102
2. Subjects and methods 2.1. Subjects From October, 2002, to March, 2006, we first collected 849 consecutive ischemic stroke patients who visited the department in our hospital (less than 7 days after onset). We excluded patients whose stroke mechanism was cardioembolism (n = 170) or other determined etiologies (n = 10). HbA1c was examined on admission, and patients were excluded if they did not have laboratory data for HbA1c (n = 30). Therefore, the final study population consisted of a total of 639 patients. This study was approved by an independent ethics committee in Seoul National University Hospital (H-0802-035-234). 2.2. Clinical information We collected clinical information regarding the following vascular risk factors: age, sex, hypertension, diabetes mellitus, dyslipidemia, and smoking. Hypertension was defined as follows: patients with known hypertension and/or taking antihypertensive medication, or de novo hypertension with systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg at discharge (mean hospitalization period: 14.9 ± 10.7 days). We classified diabetes as alleged diabetic subjects with or without medication and subjects with fasting glucose (FG) ≥ 7.0 mmol/L (126 mg/dl) or with 2-h postprandial serum glucose ≥11.1 mmol/L (200 mg/dl) after achieving stable medical and neurological condition [14]. Dyslipidemia was determined as prior diagnosis with hypercholesterolemia or newly diagnosis with level of fasting serum low-density lipoprotein (LDL) cholesterol based on National Cholesterol Education Program Adult Treatment Panel III guidelines [15]. Cigarette smoking status was classified as habitual smokers and non-habitual smokers. 2.3. Image analysis MR was performed with a 1.5-T superconducting magnet system [Signa; GE Medical Systems, Milwaukee, WI, USA] under the following conditions: axial T2-weighted spin-echo [repetition time (TR)/echo time (TE) 2500–4500/80–112 ms; slice thickness 5 mm; interslice gap 0–2 mm], fluid-attenuated inversion recovery (FLAIR; TR/TE = 8000–9500/90–120 ms; slice thickness 5 mm; interslice gap 0–2 mm), axial T2-weighted gradient echo sequence (TR/TE = 200–500/15 ms; slice thickness 5 mm; interslice gap 0–2 mm), and three-dimensional time of flight MR angiography (flight of view = 220 mm; TR/TE = 30–45/5–8; flip angle = 20–25). MRA imaging was performed for analysis of LAD and SAD. Symptomatic or asymptomatic LAD (extracranial and intracranial arterial stenosis of 50% or more) was assessed by MR angiography in the proximal internal carotid artery (ICA) and vertebral artery (VA) for extracranial stenosis and in proximal portions of the middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), basilar artery (BA), and distal ICA for intracranial stenosis, in consideration of the sensitivity and specificity of MR angiography. SAD was classified as advanced leukoaraiosis, cerebral microbleeds, or old lacunar infarctions. Imaging analysis was performed independently by two experienced neurologists (BJK and BSK) operating by consensus and without any knowledge of clinical information. Old lacunar infarctions and cerebral microbleeds were assessed as in our previous study [16,17]. Briefly, cerebral microbleeds were observed as homogeneous round hypointense lesions with a diameter ≤5 mm on gradient echo MRI; old lacunar infarctions were defined as a focal lesion of ≥3 mm in diameter with signal intensity corresponding to liquor (i.e., hyperintense on T2-weighted images and hypointense on FLAIR images). A score
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of 2 or more in Fazekas’ white matter rating scale according to the following criteria (0 = absence, 1 = punctuate foci, 2 = beginning confluence of foci, or 3 = large confluent areas) was classified as advanced leukoaraiosis [18]. 2.4. Statistical analysis Baseline demographic and laboratory data were expressed as mean ± standard deviation for continuous variables and as frequencies for categorical variables by t-test and 2 -test. Univariate and multivariate logistic regression analyses were also used to determine the association of HbA1c and large or small artery disease. The predictive model was based on demographic and major clinical vascular risk factor variables, which included age, sex, hypertension, dyslipidemia, and smoking. In all tests, a p-value < 0.05 was considered significant. All statistical analyses were conducted using the SPSS 13.0 package for Windows (SPSS Inc., Chicago, IL, USA). 3. Results Of the 639 subjects included in this study, 438 were male (68.5%) and the mean age of the patients was 64.9 ± 11.1 years. There were 448 patients with hypertension (70.1%), 247 with diabetes (38.7%), 300 with dyslipidemia (46.9%), and 259 with a smoking history (40.5%). We divided subjects into two groups depending on the presence of diabetes (Table 1). Previous stroke history, increased FG and HbA1c level, dyslipidemia, and reduced high density lipoprotein (HDL) level were more common in the diabetes group. There were no differences in stroke subtype or in the existence of leukoaraiosis, cerebral microbleeds, or old lacunes. There was no relationship between HbA1c and LAD in the non-diabetic patients (Table 2). Unexpectedly, in the patients with diabetes, HbA1c showed a significant negative association with symptomatic LAD (p = 0.01). There was also no relationship between HbA1c and any of the SAD subtypes in the non-diabetic patients. In contrast, a negative association between HbA1c and Table 1 Demographic findings of patients. Diabetics (n = 247)
Non-diabetics (n = 392)
p-Value
Sex (male/female) Age TIA history Old stroke history BMI Hypertension Fasting blood glucose HbA1c
173/74 65.6 ± 9.8 6 (2.4%) 70 (28.3%) 24.1 ± 3.0 179 (72.5%) 154.1 ± 59.9 7.93 ± 1.61
265/127 64.4 ± 11.8 18 (4.6%) 71 (18.1%) 24.1 ± 3.3 269 (68.6%) 101.8 ± 21.0 5.64 ± 0.45
0.541 0.150* 0.202 0.003 0.972 0.329 <0.001* <0.001*
Dyslipidemia LDL HDL TG
185 (74.9%) 117.7 ± 39.9 40.3 ± 10.4 149.8 ± 96.8
115 (29.3%) 112.6 ± 31.1 44.2 ± 12.5 123.1 ± 66.6
<0.001 0.091* <0.001* <0.001*
Smoking
96 (38.9%)
163 (41.6%)
0.509
Stroke subtype LAD SVO UD
88 (35.6%) 97 (39.3%) 62 (25.1%)
135 (34.4%) 163 (41.6%) 94 (24.0%)
Cerebral microbleeds Advanced leukoaraiosisa Old lacunes
67 (27.1%) 74 (30.0%) 69 (28.4%)
126 (32.8%) 136 (35.2%) 105 (27.2%)
0.844
0.184 0.225 0.784
TIA, transient ischemic attack; BMI, body mass index; HbA1c, hemoglobin A1c; LDL, low density lipoprotein; HDL, high density lipoprotein; TG, triglyceride; LAA, large artery atherosclerosis; SVO, small vessel occlusion; UD, stroke of undetermined aetiology. Pearson’s 2 test and *Student t-tests were used. a Advanced leukoaraiosis means Fazekas score ≥2.
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Table 2 The influence of HbA1c on large artery disease, leukoaraiosis, cerebral microbleeds, and old lacunes. HbA1c (non-diabetes)
p-Value
HbA1c (diabetes)
p-Value
LAD No symptomatic LAD Symptomatic LAD No asymptomatic LAD Asymptomatic LAD LAD(−) LAD(+)
5.62 5.68 5.63 5.67 5.64 5.64
Leukoaraiosis None to minimal (Fazekas score ≤1) Moderate to severe (Fazekas score ≥ 2)
5.63 ± 0.45 5.65 ± 0.46
0.700
8.09 ± 1.64 7.64 ± 1.48
0.043
Cerebral microbleeds CMB = 0 CMB(s) ≥ 1
5.64 ± 0.43 5.63 ± 0.50
0.765
8.04 ± 1.51 7.75 ± 1.82
0.201
Old lacunes No old lacune Old lacune(s) ≥ 1
5.64 ± 0.45 5.65 ± 0.46
0.844
8.06 ± 1.63 7.69 ± 1.52
0.114
± ± ± ± ± ±
0.45 0.45 0.43 0.49 0.43 0.46
8.21 7.65 8.10 7.78 8.35 7.77
0.215 0.566 0.979
± ± ± ± ± ±
1.78 1.38 1.74 1.47 1.91 1.46
0.008 0.129 0.014
LAD, large artery disease; CMB, cerebral microbleed.
leukoaraiosis was seen in the diabetic patients (p = 0.04), and the same trend was seen for microbleeds and old lacunes using an independent t-test (p = 0.20 and 0.11, respectively). Still, HbA1c was not related to symptomatic LAD or leukoaraiosis after adjusting for age and hypertension (Table 3). The same results were seen after adjusting for all variables (age, sex, hypertension, dyslipidemia, and smoking). Age (relative risk (RR) = 1.03, p = 0.04) was only related with symptomatic LAD, and age (RR = 1.07, p < 0.01) and hypertension (RR = 2.84, p = 0.01) were related with advanced leukoaraiosis, suggesting SAD in multivariate analysis. 4. Discussion We found that HbA1c was not independently associated with any of the examined types of cerebrovascular lesions in ischemic stroke patients with and without diabetes. In our study, age was the most important risk factor for LAD; while male gender, hypertension, and dyslipidemia showed tendencies towards a relationship with LAD. In addition, age and hypertension were significantly related with a risk of leukoaraiosis. These results were similar to previous studies demonstrating differences in risk factor profiles between ischemic stroke subtypes. These studies revealed that LAD was associated with male gender, smoking, and raised cholesterol; while SVD was associated with hypertension [19,20].
It is widely accepted that diabetes increases microvascular and macrovascular complications including stroke, particularly in the type 2 diabetic population [21]. In the Framingham Study, the incidence of nonhemorrhagic stroke was found to be between 2.5 and 3.5 times higher among diabetic subjects compared to nondiabetics [22]. It has also been shown that diabetes increases both lacunar and non-lacunar strokes [23]. In addition, HbA1c may be useful in determining risk for incident cardiovascular events [3,11,24–26]. Some prospective studies concluded that HbA1c could be an independent risk factor for stroke in people with and without diabetes. However, many studies showed that this association was diminished and lost statistical significance after adjustment for traditional cardiovascular risk factors, while diabetes itself remained a strong independent risk factor [5–8,24,25]. In addition, recent ADVANCE trial revealed that the decrease in HbA1c was only related to the reduction of microvascular events such as nephropathy and this influenced total outcome of events, it may be asked whether the relationship between HbA1c and various cerebral SAD exists [5]. In our study population, the results suggested that age was only important for development of LAD, and HbA1c was not related. We also found that a chronic hyperglycemic state did not influence the incidence of SAD subtypes. Therefore, the previously reported association between HbA1c and cerebral microbleeds in CADASIL cannot be generalized to the ischemic stroke population [12].
Table 3 Univariate and multivariate relative risks for symptomatic LAD and advanced leukoaraiosis in diabetes patients. Risk factor
Univariate
Multivariate (age and hypertension)a
Multivariate (all variables)b RR
RR
95% CI
p-Value
RR
Sx LAD Age Hypertension HbA1c Male sex Dyslipidemia Smoking
95% CI
1.036 2.045 0.798 1.145 1.629 0.936
1.009–1.064 1.155–3.620 0.676–0.943 0.664–1.973 0.911–2.914 0.561–1.561
0.009 0.014 0.008 0.627 0.100 0.800
1.027 1.651 0.847
0.998–1.056 0.910–2.995 0.712–1.007
0.065 0.099 0.060
1.031 1.632 0.859 1.450 1.600 0.984
1.002–1.061 0.893–2.983 0.720–2.846 0.739–2.846 0.872–2.938 0.530–1.827
0.038 0.112 0.093 0.280 0.129 0.959
Advanced LA Age Hypertension HbA1c Male sex Dyslipidemia Smoking
1.081 3.774 0.823 0.778 2.110 0.608
1.046–1.118 1.754–8.118 0.679–0.996 0.433–1.398 1.046–4.256 0.341–1.084
<0.001 0.001 0.046 0.400 0.037 0.092
1.073 2.967 0.929
1.037–1.110 1.336–6.588 0.756–1.142
<0.001 0.008 0.485
1.075 2.835 0.953 1.446 1.982 0.732
1.038–1.114 1.267–6.341 0.775–1.172 0.683–3.059 0.934–4.203 0.359–1.495
<0.001 0.011 0.648 0.470 0.075 0.392
RR, relative risk; CI, confidence interval; Sx LAD, symptomatic large artery disease; LA, leukoaraiosis. a Adjusted for age and hypertension. b Adjusted for all variables (age, sex, hypertension, dyslipidemia, and smoking).
p-Value
95% CI
p-Value
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Fig. 1. The age-related patterns of HbA1c level (A, p = 0.033) and hypertension proportion (B, p = 0.028) in diabetic patients.
The strength of our study was that multiple indices of small vessel disease were employed to evaluate cerebral SAD. We classified SAD into leukoaraiosis, cerebral microbleeds and old lacunes, which may reflect various aspects of SAD. Leukoaraiosis is known to be mainly caused by stenosis or occlusion of small vessels with sudden or chronic ischemia leading to incomplete white matter infarction [27]. Disturbed autoregulation in diseased small vessels and subsequent fluctuations in blood flow in response to changes in systemic blood pressure have some influence on leukoaraiosis. Microbleeds indicate previous extravasation of blood, signifying bleeding-prone cerebral microangiopathy [28,29]. Old lacunes indicate small vessel obstruction caused by arteriolosclerosis with hyaline deposition and microatheromatosis [30]. Previous studies regarding cerebral microvasculopathy largely used lacunar infarction, which only explains a portion of SAD [20,30]. Therefore, interpretation is complicated because some studies divide patients into those with single lacunar infarction and those with multiple lacunar infarctions regardless of the presence of leukoaraiosis. The relationship between diabetes and all SAD subtypes is still controversial. A cross-sectional population-based study revealed that type 2 diabetes was associated with deep white matter lesions (p = 0.02) [31], but in the Framingham Study, diabetes was not related to white matter hyperintensity volume [32]. The same was found for microbleeds [12,13,29]. For old lacunes, both positive and negative results have been reported regarding the association with diabetes [20,33]. Although only some of these reports included HbA1c data, these had also controversial results [12,13,29,31,33]. We can now speculate why HbA1c levels in patients with diabetes had a significant negative association with symptomatic LAD and a tendency toward a negative association with all of the SAD subtypes in univariate analysis. It is widely accepted that age and hypertension are the two most important risk factors for LAD and SAD [19,20,34]. Interestingly, we found that the HbA1c level in the diabetic population decreased gradually with age (p = 0.03, Fig. 1A), as the proportion of patients with hypertension increased (p = 0.03, Fig. 1B). Therefore, in our diabetic patients, those with higher HbA1c levels were younger and more frequently hypertensive. As a result, the relationship of HbA1c level with LAD and SAD was insignificant in multivariate analyses. There have been some reports about the relationship between age and HbA1c level. In normal subjects, HbA1c level was found to increase with age [35,36], but in diabetic patients, there was a negative correlation or no relationship [37,38]. This might be caused by age-related nutritional, hygienic, and economic factors or simply the natural course of diabetes itself. In addition, uncontrolled
diabetes particularly increased the risk of stroke among younger patients [39]. It was also reported that diabetes increased the risk of stroke more than 10-fold in the stroke population younger than 55 years old [40]. With respect to hypertension, our results agreed with previous studies reporting that the overall prevalence of hypertension gradually increased with age in the Korean population [41]. There were several limitations of our study. First, we obtained all of the in-hospital data retrospectively. Nevertheless, as was seen in recent prospective study, HbA1c could predict diabetes, but not cardiovascular disease [42]. Second, we did not carry out oral glucose tolerance tests and did not include impaired glucose tolerance in our data. Third, we did not record the duration and medication of diabetes and used a single baseline measurement of HbA1c. We therefore cannot evaluate the effects of changes in this parameter over time. However, HbA1c values have been found to reliably categorize glycemic status in nondiabetic subjects over a period of at least four to six years [43]. Finally, we only analyzed acute stroke patients classified into large artery atherosclerosis, small artery occlusion, and stroke of undetermined etiology by TOAST classification and did not compare with a normal control group. In summary, our study suggests that baseline HbA1c is not an independent risk factor for symptomatic LAD or any vascular lesions suggesting SAD. This may be the result of an age-related decrease in HbA1c levels and increase in the prevalence of hypertension. Therefore, established cardiovascular risk factors instead of hyperglycemia itself may be more important for the development of ischemic stroke. Competing interests None. Acknowledgements This study was supported by grants of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A060171). References [1] Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 1991;151:1141–7.
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