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. 2023 Nov 24;102(47):e36114. doi: 10.1097/MD.0000000000036114

Risk factors for acute ischemic stroke in patients with type 2 diabetes mellitus

Jingfeng Liu a,*, Xing Li b, Ji Qu b
PMCID: PMC10681607  PMID: 38013286

Abstract

To investigate the risk factors for acute ischemic stroke (AIS) in patients with type 2 diabetes mellitus (T2DM) patients. a total of 120 T2DM patients who met the inclusion and exclusion criteria, from between January 2021 to June 2022, were randomly selected and divided into T2DM and T2DM + AIS groups based on the presence or absence of a history of AIS. Blood samples were collected by fasting, 24 hours after admission, and levels of serum uric acid (UA), serum homocysteine (Hcy), serum creatinine (SCR), blood urea nitrogen (BUN), fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), serum total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein (hs-CRP), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured. Multivariate logistic regression analysis was performed for the significantly associated indicators to analyze the risk factors for AIS, and finally ROC curve analysis was carried out to explore the predictive value of the above risk factors for AIS in T2DM patients. the levels of FBG, Hcy, Hs-CRP and Lp-PLA2 were significantly higher in the T2DM + AIS group than those in T2DM group (P < .05). Multivariate logistic regression analysis revealed that hs-CRP and Lp-PLA2 were independent risk factors for the development of AIS in patients with T2DM with an OR of 2.85 (95% CI: 1.26–6.43, P = .012) and 3.64 (95% CI: 1.63–8.12, P = .002), respectively. ROC curve analysis showed that plasma hs-CRP and Lp-PLA2 showed good performance to predict AIS occurrence in T2DM patients (AUC = 0.749, 95% CI: 0.663, 0.835; and 0.791, 95% CI: 0.712, 0.870), with a sensitivity of 58.1% and 83.9%, and a specificity of 84.5% and 60.3%, respectively. The optimal concentration cutoff points of hs-CRP and Lp-PLA2 were 3.38 mg/L and 204.2 ng/mL. our findings suggested that plasma hs-CRP and Lp-PLA2 were independent risk factors for developing AIS in T2DM patients. Hs-CRP and Lp-PLA2 are potential biomarker for risk for AIS in patients with T2DM.

Keywords: acute ischemic stroke, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, type 2 diabetes mellitus

1. Introduction

Ischemic stroke (IS), one of the major causes of mortality and adult disability worldwide, comprised more than 80% of stroke cases.[1] Patients with type 2 diabetes mellitus (T2DM) have a notably higher risk to occur an ischemic stroke than those without T2DM,[1] and T2DM is a recognized risk factor ischemic stroke beyond conventional risk factors,[2] such as blood pressure, smoking habits, hypertension, and hyperlipidemia.[3] Controlling diabetes is extremely critical to reduce the risk and severity of the first-time stroke, as diabetic patients with optimal glycemic control suffering from recurrent stroke at a much lower risk.[4] Inflammation plays an important role in the development of atherosclerosis and IS.[5] Elevated inflammation could increase stroke risk and is an important contributor to poor stroke outcome in patients with diabetes.[4] C-reactive protein (CRP), a homopentameric acute-phase inflammatory protein,[6] is considered as an indicator of inflammation and atherosclerosis. A high-level CRP determined by high-sensitivity CRP (hs-CRP), has been suggested as a risk factor for occurrence and poor functional outcome of IS.[7–9]

Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase, is a calcium-independent phospholipase A2 secreted by leukocytes.[10] Lp-PLA2 is a proinflammatory enzyme that act as a risk factor for atherosclerosis, which is the most common cause of stroke.[11] Moreover, some studies have indicated that both Lp-PLA2 level and activity were higher in T2DM patients than those in individuals without diabetes[12] and that an elevated Lp-PLA2 mass is associated with poor control of diabetic patients.[13] We aimed to evaluate the risk factors associated with inflammation for acute ischemic stroke (AIS) in patients with T2DM, in order to provide the basis for the prevention and treatment of stroke in patients with diabetes.

2. Materials and methods

2.1. Study populations

A total of 120 patients with T2DM, who attended in Beijing Hepingli Hospital between January 2021 to June 2022, were enrolled in this study, and were divided into AIS + T2DM group (n = 62) and T2DM group (n = 58) based on the presence or absence of a history of acute ischemic stroke (AIS). The diagnosis of T2DM was according to the criteria in the 2010 American Diabetes Association Classification: FPG ≥ 7.0 mmol/l or 2 hours post glucose load ≥ 11.1 mmol/L, or HbA1c level of ≥ 6.5%; under diabetes medication.[14] Exclusion criteria included brain surgery, AIS caused by surgery or trauma, hemorrhagic stroke, cancerous diseases, autoimmune diseases and serious infection. Diagnostic criteria for AIS included[15,16]: Presenting with acute onset; Clinical signs or symptoms persisted for more than a few hours; Symptoms of complete or focal neurological impairment existed; Confirmed by computed tomography scan or magnetic resonance imaging after admitted to hospital within 48 hours from onset.

Treatments included: All T2DM patients received basic hypoglycemic treatment, according to Guidelines for the Prevention and Control of Type 2 Diabetes in China (2017 Edition). Treatments of patients with AIS were based on the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke 2018.

This study was approved by Ethics Committee of Beijing Hepingli Hospital (No. 2020-2-2241). Written informed consents were obtained from all participates before the study began. All the procedures in this study were performed in accordance with Declaration of Helsinki Ethical Principles.

2.2. Biochemical measurements

Patients’ venous blood samples were obtained from the antecubital vein after fasting for at least 10 hours within the first 24 hours of admission, and were centrifuged at 1,000 g for 10 minutes to obtain serum and plasma. Serum total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, UA and Hcy levels were measured by using the AU5800 automated biochemical analyzer (Beckman Coulter, CA, USA) combined with corresponding kits. FBG level was determined by glucose oxidase method. The high-performance liquid chromatography was used to measure HbA1C level. SCr and BUN levels were measured on a VITROS 5600 Integrated System (Ortho-Clinical Diagnostics) using corresponding kits following the manufacturer instructions. The quantitative measurement of Lp-PLA2 in plasma was detected using an enzyme-linked immunosorbent assay (ELISA) kit (Abcam, USA), which has a detection range between 0.16 ng/mL and 10 ng/mL. The OD value at 450 nm was recorded by an enzyme analyzer. Plasma hs-CRP was measured by a latex turbidimetric immunoassay kit (Medical System Biotechnology Co., Ltd., Ningbo, China).

2.3. Statistical analysis

Statistical analysis was performed using SPSS20.0 (IBM, Chicago, IL, USA) and GraphPad Prism 9 (GraphPad Software, San Diego, CA, USA). Categorical variables were presented as the frequencies with percentages. Continuous variables with a gaussian distribution were expressed as the mean ± standard deviation (SD); skewed distributed continuous variables were presented as the median with interquartile range. Continuous variables were analyzed using the Student t test or Mann-Whitney U-test, as appropriate. Categorical data were analyzed by the Chi-square test or Fisher exact test to assess intergroup differences. Multivariate logistic regression analysis was conducted to investigate risk factors for AIS in T2DM patients, and the odds ratios (ORs) with 95% confidence intervals (CIs) were presented. The receiving-operating characteristic (ROC) curve analysis and the area under curve (AUC) were used to evaluate the diagnostic accuracy of hs-CRP and Lp-PLA2 on AIS in T2DM patients. The cutoff values for each risk factor in AIS diagnosis was determined using the Youden method, selecting the cut point at which Youden index (sensitivity + specificity - 1) is maximized. P value < .05 was considered to be statistically significant.

3. Results

3.1. Comparison of demographic data, clinical characteristics and biochemical features between T2DM group and T2DM + AIS group

The demographic data, clinical characteristics and biochemical features were summarized in Tables 1 and 2. Overall, There were no statistic differences in sex, age, body mass index, T2DM duration, SBP, DBP, the rate of smoking, drinking, hypertension, and coronary artery disease between T2DM group and T2DM + AIS group. Similarly, no statistical difference in the levels of HbA1c, triglyceride, TC, LDL-L, HDL-L, UA, SCr and BUN was found between 2 groups. However, the levels of FBG, Hcy, Hs-CRP and Lp-PLA2 were significantly higher in the T2DM + AIS group than those in T2DM group (P < .05).

Table 1.

Demographic and clinical characteristics between T2DM group and T2DM + AIS group.

T2DM, n = 58 AIS + T2DM, n = 62 P
Male, n (%) 31, 53.45% 32, 51.61% .841
Age, yr 62.83 ± 7.52 62.87 ± 8.02 .976
BMI, kg/m2 24.59 ± 2.07 24.50 ± 1.79 .797
T2DM duration, yr 13.94 ± 3.04 14.39 ± 3.09 .426
Hypertension, n (%) 34, 58.62% 41, 66.13% .396
SBP, mm Hg 139.3 ± 8.32 142.4 ± 13.04 .129
DBP, mm Hg 82.12 ± 7.77 84.69 ± 9.45 .107
Smoking, n (%) 30, 51.72% 31, 50.00% .850
Drinking, n (%) 25, 43.10% 32, 51.61% .351
Coronary artery disease, n (%) 34, 58.62% 34, 54.84% .676
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AIS = acute ischemic stroke, BMI = body mass index, T2DM = type 2 diabetes mellitus.

Table 2.

Biochemical criterion between T2DM group and T2DM + AIS group.

T2DM, n = 58 T2DM + AIS, n = 52 P
HbA1c, % 9.10 ± 0.95 9.25 ± 1.29 .456
FBG, mmol/L 5.77 ± 0.88 6.55 ± 1.38 .0003
TG, mmol/L 1.6 ± 0.28 1.66 ± 0.25 .244
TC, mmol/L 4.53 ± 0.53 4.62 ± 0.46 .312
LDL-C, mmol/L 2.6 ± 0.38 2.48 ± 0.37 .080
HDL-C, mmol/L 0.91 ± 0.09 0.93 ± 0.08 .265
UA, μmol/L 323.8 ± 40.0 327.9 ± 40.3 .489
SCr, μmol/L 79.00 (64.53, 95.48) 82.20 (68.80, 101.7) .505
Hcy, μmol/L 12.69 ± 3.37 15.15 ± 4.87 .002
BUN, mmol/L 6.26 ± 0.85 6.48 ± 0.73 .121
hs-CRP, mg/L 2.37 ± 1.01 3.57 ± 1.40 <.0001
Lp-PLA2, ng/mL 194.9 ± 47.1 252.6 ± 50.1 <.0001
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AIS = acute ischemic stroke, HDL-C = high-density lipoprotein cholesterol, hs-CRP = high-sensitivity CRP, LDL-C = low-density lipoprotein cholesterol, Lp-PLA2 = lipoprotein-associated phospholipase A2, T2DM = type 2 diabetes mellitus, TC = serum total cholesterol, TG = triglyceride.

3.2. Risk factor for acute ischemic stroke in T2DM patients

Based on the results of univariate analysis, we carried out multivariate logistic regression analysis to identify independent risk factors for AIS occurrence in T2DM. As shown in Table 3, hs-CRP and Lp-PLA2 were independent risk factors for the development of AIS in patients with T2DM with an OR of 2.85 (95% CI: 1.26–6.43, P = .012) and 3.64 (95% CI: 1.63–8.12, P = .002), respectively.

Table 3.

Multivariate analysis of biochemical criterion affecting recurrence of acute ischemic stroke in AIS + T2DM patients.

B S.E. Wals P Exp (B) 95%CI
hs-CRP 1.047 0.416 6.344 .012 2.848 1.261, 6.430
Lp-PLA2 1.291 0.410 9.906 .002 3.635 1.627, 8.121
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AIS = acute ischemic stroke, CIs = confidence intervals, hs-CRP = high-sensitivity CRP, Lp-PLA2 = lipoprotein-associated phospholipase A2, T2DM = type 2 diabetes mellitus.

3.3. Predictive value of risk factors for AIS onset in T2DM patients

ROC curve analysis was performed to assess the predictive value of hs-CRP and Lp-PLA2 in differentiating AIS onset from T2DM patients (Fig. 1). Plasma hs-CRP and Lp-PLA2 showed good performance to predict AIS occurrence in T2DM patients (AUC = 0.749, 95% CI: 0.663, 0.835; and 0.791, 95% CI: 0.712, 0.870), with a sensitivity of 58.1% and 83.9%, and a specificity of 84.5% and 60.3%, respectively. The optimal concentration cutoff points of hs-CRP and Lp-PLA2 were 3.38 mg/L and 204.2 ng/mL (Table 4).

Figure 1.

Figure 1.

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ROC (receiver operating characteristics) curve analysis for plasma hs-CRP and Lp-PLA2 to assess their diagnostic values for AIS in patients with T2DM. AIS = acute ischemic stroke, hs-CRP = high-sensitivity CRP, Lp-PLA2 = lipoprotein-associated phospholipase A2, ROC = receiving-operating characteristic, T2DM = type 2 diabetes mellitus.

Table 4.

ROC curve analysis of the diagnostic value of each risk factor.

Cutoff value AUC (95% CI) Sensitivity Specificity Youden index
hs-CRP 3.38 0.749 (0.663, 0.835) 0.581 0.845 0.425
Lp-PLA2 204.2 0.791 (0.712, 0.870) 0.839 0.603 0.442
Open in a new tab

AUC = area under curve, CIs = confidence intervals, hs-CRP = high-sensitivity CRP, Lp-PLA2 = lipoprotein-associated phospholipase A2, ROC = receiving-operating characteristic,

4. Discussion

Some studies demonstrated that T2DM could elevate the risk of developing AIS compared with patients without T2DM.[17,18] Thus, it is important to investigate the potential risk factors for AIS among T2DM patients. In the present study, we observed that FBG, Hcy, hs-CRP and Lp-PLA2 were significantly higher in the T2DM + AIS group than those in T2DM group. We also found that plasma hs-CRP and Lp-PLA2 were independent risk factors for developing AIS in T2DM patients. The ROC curve suggested that plasma hs-CRP and Lp-PLA2 levels had good diagnostic performance for AIS in T2DM patients.

Both hs-CRP and Lp-PLA2 are well-verified risk factors for stroke in general population. Hs-CRP was associated with increased risk of recurrent stroke and poor functional outcome.[19,20] Most previous studies had indicated that an increased hs-CRP level was related to an increased risk of ischemic strokes in general population.[8,21,22] A meta-analysis provided evidence that elevated levels of hs-CRP were associated with ischemic but not hemorrhagic stroke.[8] These findings suggested an essential relationship between hs-CRP level and ischemic stroke. However, there are very few studies focus on the risk of plasma hs-CRP levels and stroke in type 2 diabetic patients. For example, Anne Gedebjerg et al has reported that high (>3 mg/L) hs-CRP was associated with increased cardiovascular events risk (aHR 1.45, 95% CI: 1.07–1.96) and with even greater risk of all-cause mortality (2.47, 1.88–3.25) when compared with patients with low (<1 mg/L) hs-CRP.[23] Katarzyna Krzyzanowska et al also reported that T2DM patients with baseline CRP in the highest tertile (>6.0 mg/L) had a significantly increased hazard ratio for incident cardiovascular events compared with those with CRP in tertile 1 (≤2.0 mg/L; HR, 3.63, 95% CI: 1.59–8.28, P = .002).[24] These findings were partially in accordance with our findings that elevated plasma hs-CRP level was an independent risk factor for AIS in T2DM patients. The mechanism underlying the positive relationship between increased hs-CRP level and higher ischemic stroke risk is not yet established. It might be that atherosclerosis is the most common underlying cause of ischemic stroke, whereas a chronic inflammatory response is directly involved in the development of atherosclerosis.[25,26] Hs-CRP is a systemic inflammation marker, whose level is associated with the progression of atherosclerosis.

Plasma Lp-PLA2 concentration was independently associated with the development of AIS in patients with atrial fibrillation. Lp-PLA2 is a potential biomarker for stratifying AIS in patients with atrial fibrillation.[27] A meta-analysis reported that higher Lp-PLA2 level may be independently associated with an increased risk of coronary heart disease and IS in the general population.[28] High serum Lp-PLA2 level was the independent risk factor for AIS with the adjusted OR of 1.057 (95% CI:1.040–1.075, P = .001).[29] In addition, they found that the AUC was 0.892 (P < .05, 95% CI: 0.856–0.929), with the sensitivity and specificity of 74.5 and 86.7%, respectively, for the diagnosis of AIS using Lp-PLA2, and the cutoff value was 123.365 ng/mL. These findings suggested a potential relationship between Lp-PLA2 level and AIS. However, little attention was paid to the relationship between plasma Lp-PLA2 levels and AIS risk in type 2 diabetic patients. Only a few studies showed that Lp-PLA2 was significantly associated with risk and outcome of cardiovascular diseases in diabetic patients.[30,31] The present study for the first time to demonstrate that plasma Lp-PLA2 level was an independent risk factor for developing AIS in T2DM patients, and plasma Lp-PLA2 showed good performance to predict AIS occurrence in T2DM patients with AUC of 0.791 (95% CI: 0.712, 0.870), and a sensitivity and specificity of 83.9% and 60.3%, respectively. Mechanistically, the association between inflammation and T2DM has previously been well elucidated. Inflammatory biomarkers such as CRP, tumor necrosis factor α, IL-6 and inflammasome were found to be significantly higher in patients with T2DM than in healthy subjects. Lys-phosphatidylcholine generated by Lp-PLA2 hydrolysis of oxidized phospholipids and the accumulation of platelet-activating factor in adipose tissue could aggravate insulin resistance.[32,33] Insulin resistance is an independent risk factor for ischemic stroke and negatively influences the prognosis of patients with ischemic stroke,[34] thus high Lp-PLA2 level may be a promoter of ischemic stroke.

Some limitations of this study should be realized. Firstly, the present study was a single center trial, the sample size was relatively small, and the participants may not be representative of patients in other places of China. Thus, multicenter, large-sample studies will be needed to verify the findings of the present study. Secondly, the hs-CRP and Lp-PLA2 levels in AIS + T2DM patients were measured only after the onset of stroke, thus may be influenced by the disease itself. A prospective study will be needed to obtain pre-stroke hs-CRP Lp-PLA2 levels in all participants.

In conclusion, our findings suggested that plasma hs-CRP and Lp-PLA2 were independent risk factors for developing AIS in T2DM patients. Hs-CRP and Lp-PLA2 are potential biomarker for risk for AIS in patients with T2DM.

Author contributions

Conceptualization: Jingfeng Liu.

Data curation: Jingfeng Liu.

Formal analysis: Jingfeng Liu.

Investigation: Xing Li.

Methodology: Xing Li.

Resources: Xing Li, Ji Qu.

Software: Ji Qu.

Writing – original draft: Jingfeng Liu.

Writing – review & editing: Jingfeng Liu.

Abbreviations:

AIS
acute ischemic stroke
AUC
area under curve
CIs
confidence intervals
CRP
C-reactive protein
hs-CRP
high-sensitivity CRP
IS
ischemic stroke
Lp-PLA2
lipoprotein-associated phospholipase A2
ROC
receiving-operating characteristic
T2DM
type 2 diabetes mellitus
TC
serum total cholesterol
TG
triglyceride

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

The authors have no conflicts of interest to disclose.

How to cite this article: Liu J, Li X, Qu J. Risk factors for acute ischemic stroke in patients with type 2 diabetes mellitus. Medicine 2023;102:47(e36114).

Contributor Information

Xing Li, Email: lixhplh@sina.com.

Ji Qu, Email: qji1984@163.com.

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