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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 844-850

Severity of atherosclerotic coronary artery disease in relation to glycated hemoglobin level in diabetic patients


1 Department of Cardiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Cardiology, Police Academy Hospital, Cairo, Egypt
3 Department of Cardiology, Electricity Hospital, Cairo, Egypt

Date of Submission16-Oct-2017
Date of Acceptance19-Jan-2018
Date of Web Publication17-Oct-2019

Correspondence Address:
Bayoumi M Bayoumi
8th Gameat El Dewal El Arabia Street, El Mohandseen, Giza 12411
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_726_17

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  Abstract 

Objective
The aim of this work was to assess the relationship between the level of glycated hemoglobin (HbA1c) and the severity of coronary artery disease (CAD) among diabetic patients and perform a comparison with nondiabetic patients.
Background
Diabetes mellitus and coronary heart disease are closely associated and generally coexist. The severity CAD is directly related to the quality of glucose control in diabetic patients.
Patients and methods
This study included 150 patients referred to coronary angiography. In addition to the routine evaluation, assessment of HbA1c level, transthoracic echocardiogram, and coronary angiography were performed and the Gensini score (GS) was calculated. Diabetic patients were classified as controlled and uncontrolled on the basis of the cut-off point of HbA1c value of 7%. Nondiabetic patients were classified as low-risk and high-risk groups.
Results
Among the patients, 64.7% had diabetes mellitus and 54.7% were hypertensive. Also, 74.23% of the patients in the diabetic group had HbA1c greater than or equal to 7 mg%, with a mean HbA1c of 9.7 ± 2.2. The mean GS was 41 ± 31.3. There was a significant positive correlation between the level of HbA1c and fasting plasma glucose (r = 0.454, P = 0.000), waist–height ratio (r = 0.19, P = 0.045), regional wall motion score index (r = 0.23, P = 0.019), and GS (r = 0.312, P = 0.049) (in the diabetic group). Also, in the nondiabetic group, there was a significant correlation between HbA1c, GS (r = 0.448, P = 0.032), fasting plasma glucose (r = 0.470, P = 0.000), and weight (r = 0.264, P = 0.046).
Conclusion
HbA1c level is a useful biomarker and has prognostic value to predict the severity of CAD among diabetic and nondiabetic patients.

Keywords: angiography, atherosclerosis, coronary artery disease, diabetes mellitus, Gensini score, glycated hemoglobin


How to cite this article:
Kamal AM, Mostafa AA, Bayoumi BM. Severity of atherosclerotic coronary artery disease in relation to glycated hemoglobin level in diabetic patients. Menoufia Med J 2019;32:844-50

How to cite this URL:
Kamal AM, Mostafa AA, Bayoumi BM. Severity of atherosclerotic coronary artery disease in relation to glycated hemoglobin level in diabetic patients. Menoufia Med J [serial online] 2019 [cited 2019 Nov 14];32:844-50. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/844/268837




  Introduction Top


Diabetes mellitus (DM) has long been recognized to be an independent risk factor for cardiovascular disease (CVD) [1]. The public health impact of CVD in patients with diabetes has reached epidemic proportions [1]. Despite recent improvements in medical management and coronary revascularization, a recent WHO report showed that CVD accounts for ∼75% of all hospital admissions and ∼80% of deaths in DM patients. In addition, DM patients undergoing percutaneous coronary intervention admitted with acute myocardial infarction (AMI) are more likely to develop stent restenosis, and also major adverse cardiovascular events, and have worse clinical outcomes compared with non-DM patients undergoing percutaneous coronary intervention [2].

Previously, glycated hemoglobin (HbA1c) has been suggested for the determination of glucose control in patients with DM, and recently, the American Diabetes Association has recommended the use of HbA1c in the diagnosis of DM [3]. Also, it has been reported that an elevated HbA1c level is a risk factor for macrovascular diseases [4] and indicates increased mortality risk in patients with coronary artery disease (CAD) [5]. There is also a significant correlation between HbA1c levels and the extent of CAD [6].

The incidence of cardiovascular disease among diabetic patients is 2–4 times higher than that in the nondiabetic population. Cardiovascular event is also the leading cause of mortality among diabetic patients. To prevent the occurrence of cardiovascular events, it is important to reduce mortality in diabetic patients. Inflammation caused by oxidative stress is the primary mechanism of the formation of atherosclerosis [7].

Advances in the management of acute coronary syndromes (ACS) have been associated with a reduction in mortality rates over the last two decades, and yet patients with DM continue to have a worse prognosis [8],[9]. This prognostic gap has been suggested to be partly mediated by the altered glycometabolic state found in diabetic patients [10]. Indeed, improved glycemic control in diabetic patients following AMI has been associated previously with reduced long-term mortality [11],[12].

Thus, guidelines for the management of ACS [13] highlight the importance of maintaining adequate glycemic control in diabetic patients both in hospital and following discharge. Hospital admission provides an important opportunity to assess and improve disease control in diabetic patients [14]. Nevertheless, recent studies have reported that in many diabetic patients admitted for ACS, glycemic control is not comprehensively evaluated in-hospital [15],[16].

HbA1c level is an accepted measurement of recent glycemic control, reflecting the average blood glucose concentration over the previous 2–3-month period, and is commonly used to monitor the adequacy of long-term antihyperglycemic treatment in diabetes [17].

Thus, in the present study, we examined the association between HbA1c levels and CAD in diabetic and nondiabetic patients undergoing coronary angiography to evaluate the role of HbA1c in predicting CAD and to correlate HbA1c levels with angiographic disease severity.


  Patients and Methods Top


The study included 150 patients referred to coronary angiography in Electricity Hospital within a period from March 2015 to November 2016. The study was approved by the ethical Committee of faculty of medicine Menoufia university and the patient gave an informed consent. Patients who were referred to coronary angiography as indicated clinically were included in the study. The patients were subjected to a complete assessment of medical history, with a special focus on the history of DM and medications received and history of other risk factors for CAD including hypertension and medications received, smoking status, and family history of CAD. A physical examination was performed by the treating physician, with a special focus on identifying patients with hypertension. The diagnosis of hypertension is made on the basis of the JNC Seventh Report on Detection, Evaluation and treatment of high blood pressure [18]. The criteria for hypertension diagnosis were defined as follows: systolic blood pressure greater than or equal to 140 mmHg and/or diastolic blood pressure greater than or equal to 90 mmHg and/or current use of antihypertensive medication. The presence of obesity was confirmed by measuring waist circumference and BMI. The diagnosis of obesity is made on the basis of the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults [19]. Blood samples were taken at the time of admission for HbA1c, serum creatinine, and fasting plasma glucose (FPG) levels in addition to routine measurements. Samples for FPG were obtained after an 8 h fast. HbA1c was assessed quantitatively using a MUTIGENT TMHbA1c assay and the results were reported as percentage of total hemoglobin. Exclusion criteria were as follows: patients with normal coronary angiography and patients with the following because of decreased level HbA1c: (a) shortened life span of red blood cells (hemolytic anemia, congenital spherocytosis, acute or chronic blood loss, sickle cell disease, hemoglobinopathies), (b) pregnancy, (c) ingestion of large amounts greater than 1 g/day of vitamin C or E, (d) after blood transfusion. Patient With the following disorders because of increased level of HbA1c: (a) alcohol, lead, opiate toxicity; (b) splenectomy; (c) uremia.

A transthoracic echocardiogram study was carried out for every patient to identify the estimated ejection fraction, regional wall motion abnormalities, cardiac chambers dimensions, and associated valvular lesions as per American Society of Echocardiography guidelines and recommendations. The regional wall motion score index (RWMSI) was calculated. The echocardiographic machines used were Philips iE33 xMATRIX and GE Vivid 7 (Jury Court, San Jose, CA 95112).

Coronary angiography was performed and then reviewed by two physicians to assess the Gensini score (GS). It is a scoring system that allocates a numerical value for the degree of stenosis in a coronary artery and a multiplication factor that depends on which coronary artery is involved and where the stenosis is located in the coronary artery. This scoring system has been used in several studies to establish a correlation between the severity of CAD and other factors. It grades narrowing of the lumen of the coronary artery and scores it as follows: 1 for 1–25% narrowing, 2 for 26–50% narrowing, 4 for 51–75% narrowing, 8 for 76–90% narrowing, 16 for 91–99% narrowing, and 32 for a completely occluded artery. The score is then multiplied by a factor according to the importance of the coronary artery as follows: left main stem lesion is 5, proximal leukocyte adhesion deficiency (LAD) and proximal Left circumflex artery (LCX) is 2.5, mid LAD lesion is 1.5, distal LAD, and mid and distal LCX and RCA lesions is 1. Any branch is 0.5 [20].

For DM, assessment of history was performed including duration of illness and medications received if present. Patients who were recently diagnosed to be diabetic on presentation were reported as being diabetic. The diagnosis of DM was made on the basis of the recent American Diabetes Association (ADA) recommendations for the diagnosis and classification of DM. The criteria used for diagnosis were as follows: FPG at or above 126 mg/dl (7.0 mmol/l) and/or HbA1c greater than or equal to 6.5%. If the two tests were concordant for the diagnosis of diabetes, additional testing was not needed. If the two tests were discordant, the test that was diagnostic of diabetes was repeated the next day to confirm the diagnosis. Diabetic patients were classified as controlled and uncontrolled on the basis of the cut-off point of HbA1c value of 7%, whereas nondiabetic patients were classified into low-risk (HbA1c<5.7) and high-risk (HbA1c≥5.7) groups for the development of DM [21].

All statistical analyses were carried out using SPSS for windows with statistical package version 15.0 (SPSS Inc., Chicago, Illinois, USA). Normally distributed continuous variables were represented as mean ± SD, or as the percentage of the sample. Fisher's exact test was used to determine differences in patient characteristics. Comparison between diabetic and nondiabetic groups was performed using a two-tailed unpaired Student's t- test for continuous variables and Pearson's χ2-test for categorical variables. Correlations between variables were determined using the Pearson correlation coefficient. A P value less than 0.05 was considered significant for all tests.


  Results Top


A total of 150 patients referred to coronary angiography within a period of 1 year were included in this study. The majority of patients in the studied group were men; 64.7% had DM and the majority was being treated with oral hypoglycemic agents (35%). Most of the patients had BMI of 29.2 ± 3. The most common reason for performing coronary angiography was unstable angina pectoris (45.3% of the cases). The GS ranged from 1 to 125, with a mean of 34.7 ± 29.3. Baseline characteristics of the study participants are shown in [Figure 1], along with their laboratory, echo, and angiographic results [Table 1]. Both diabetic and nondiabetic groups had comparable sex distribution, prevalence of obesity, and clinical presentation. However, the diabetic group was older and had higher prevalence of hypertension. The majority of diabetic patients (74.23%) had poorly controlled DM, suggested by HbA1C more than 7%. The mean HbA1c measured in diabetic patients was 8.8 ± 2.3, ranging from 5.4 to 16.5. Diabetic patients also had high levels of FPG at presentation for coronary angiography, with mean 154 ± 49.3 [Table 2]. They also had lower high-density lipoprotein (HDL) cholesterol and lower creatinine clearance (crcl). Diabetic patients had higher RWMSI in comparison with nondiabetic patients. The GS was found to be significantly higher in the diabetic group. According to a recent ADA recommendation, which defines the HbA1c level of 7% as a cut-off point of controlled diabetes, diabetic patients were further classified into controlled (n = 25, representing 25.77% of diabetic patients) and uncontrolled (n = 72, representing 74.23%) groups. There were no significant differences between controlled and uncontrolled diabetic patients in clinical, demographic, and laboratory data. FPG and HbA1c were the only parameters that differed significantly between the two groups [Table 3].
Figure 1: Prevalence of conventional risk factors in all study participants.

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Table 1: Baseline clinical characteristics, echo, and angiographic characteristics of all study participants

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Table 2: Demographic, clinical characteristics, laboratory findings, echo, and angiographic characteristics of the diabetic and nondiabetic groups

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Table 3: Demographic, clinical characteristics, and laboratory findings among controlled and uncontrolled diabetic groups

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Among the diabetic participants, it was found that the level of HbA1c was correlated positively with FPG (r = 0.454, P = 0.000), waist–height ratio (r = 0.19, P = 0.045), triglycerides level (r = 0.21, P = 0.038), RWMSI (r = 0.23, P = 0.019), and GS (r = 0.312, P = 0.049) and correlated negatively with left ventricular ejection fraction (LVEF) (r = −0.28, P = 0.005). It was found that GS was correlated positively with RWMSI (r = 0.378, P = 0.000) and correlated negatively with LVEF (r = −0.337, P = 0.001).

Nondiabetic participants were classified into low-risk and high-risk groups for development of DM according to recent ADA standards for care of DM. Patients with HbA1c values 5.7–6.4% were considered a high-risk group (n = 32 representing 60.3% of the nondiabetic patients), whereas patients with an HbA1c value below 5.7% were considered to be at low risk for development of diabetes. It was found that although both high-risk and low-risk groups had comparable age, sex distributions and BMI, the high-risk group had lower LVEF, but higher RWMSI and GS. Also, there was no significant difference between the high-risk and low-risk groups in laboratory tests, except for FPG, HbA1c, and HDL [Table 4]. It was found that the level of HbA1c was correlated positively with the GS (r = 0.448, P = 0.032), FPG (r = 0.470, P = 0.000), weight (r = 0.264, P = 0.046), and crcl and correlated negatively with HDL (r = −0.289, P = 0.0036) and creatinine (r = −0.324, P = 0.018). It was found that GS was correlated positively with FPG (r = 0.271, P = 0.040) and correlated negatively with RWMSI (r = −0.528, P = 0.000) and LVEF (r = −0.526, P = 0.000).
Table 4: Demographic, clinical characteristics, and laboratory findings among high-risk and low-risk nondiabetic patients

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  Discussion Top


In this study, we examined the correlation between glycemic control among patients referred to coronary angiography and the severity of CAD by means of the GS.

The studied group included 150 patients referred to coronary angiography as indicated clinically over a period of 1 year. We excluded patients who had normal coronary angiography, hemolytic anemia, postblood transfusion, pregnancy, and uremia. Diabetic patients represented 64.6% of the entire group. Both diabetic and nondiabetic patients had comparable sex distribution, obesity parameters, clinical presentations, and laboratory results, except for the levels of HbA1c and FPG.

We found that the level of HbA1c is correlated positively with the severity of CAD in diabetic and nondiabetic patients. The level of HbA1c was correlated positively with the GS among the diabetic and nondiabetic patients.

The UK Prospective Diabetes Study [22] showed a 25% relative risk reduction of microvascular complications with intensive blood glucose control, but no significant effect of lowering blood glucose on cardiovascular complications. A 16% reduction (which was not statistically significant) in the risk of combined fatal or nonfatal myocardial infarction and sudden death was observed [23]. The ADA, in its position statement on glycemic control, stated that lowering HbA1c may be associated with a reduction in microvascular and neuropathic complications of DM and possibly macrovascular complications [24].

Khaw et al. [25] have also reported on the association between HbA1c levels and major cardiovascular events and mortality. They reported that increasing levels of HbA1c are associated with all-cause and cardiovascular mortality. An increase of 1% in HbA1c was associated with a 28% increase in the risk of death, independent of traditional cardiovascular risk factors. Interestingly, the association between increasing HbA1c levels and death persisted (hazard ratio 1.46) after individuals with DM and those with a HbA1c level above 7% were excluded from the analysis, suggesting a role of HbA1c assessment in risk stratification and prediction among individuals without DM. This was further supported by the results of a meta-analysis of prospective cohorts by Santos-Oliveira et al. [26]. In our study, we did not follow-up patients to trace the incidence of cardiovascular mortality, but all patients referred to coronary angiography had an ACS, that is, cardiovascular event.

In the Ravipati et al. [27] study, coronary angiography was performed for 152 men and 163 women with DM (mean age: 55 ± 8 years) because of chest pain. The mean HbA1c level was 6.66 ± 0.58% in 132 patients with 0-vessel CAD, 8.00 ± 0.84% in 40 patients with 1-vessel CAD, 8.83 ± 1.45% in 76 patients with 2-vessel CAD, and 10.40 ± 2.28% in 67 patients with 3-vessel or 4-vessel CAD. There was a significant increasing trend of HbA1c levels with increasing number of vessels with CAD (P < 0.0001). In our study, we performed a more detailed assessment of the CAD using the GS. The increasing number of diseased vessel does not reflect the severity of the lesions and in turn does not reflect the atherosclerotic burden. Moreover, patients without CAD represented 42% of the studied group, but in our study, we did not include patients with normal coronary angiograms.

In the Saleem et al. [28] study, 110 consecutive patients admitted to hospital with AMI were studied. Seventy-eight (70.9%) patients had DM and 73 (93.58%) had HbA1c greater than 7%. Coronary angiography was carried out in 87 (79.1%) patients and the severity of disease was assessed using the GS. The mean GS was 53.36 ± 36.94 and the mean HbA1c was 8.4 ± 2.39%. There was a significant association between the GS and DM (P = 0.003) and between the GS and hypertension (P = 0.018). HbA1c (r = 0.427, P = 0.001) and duration of DM (r = 0.362, P = 0.004) had a positive linear correlation with the GS. Multiple regression analysis showed HbA1c to be an independent factor that influenced the GS (P = 0.021). In our study, we included a larger number of patients and the clinical presentations for coronary angiography were variable (not just AMI). The coronary angiography was performed for the entire studied group (not just 79.1%). We also reclassified the studied group into controlled and uncontrolled diabetics and high-risk and low-risk nondiabetics (on the basis of the HbA1c level) to determine whether there are statistical differences among the subgroups. In our study, we used different parameters of obesity including waist circumference, BMI, and waist–height ratio to identify correlations with the HbA1c level; also, RWMSI and crcl were used as study variables.

The GS was significantly higher in the diabetic group (P = 0.007) than the nondiabetic group. However, we found a significant correlation between the HbA1c level and the GS in the diabetic group (r = 0.312, P = 0.049) and a significant correlation between the HbA1c level and the GS in the nondiabetic group. Our study included a larger number of diabetic patients than that of Saleem et al. [28] (97 vs. 78 patients), and this might have influenced our conflicting results. Our results in diabetic patients may support the opposing theory that HbA1c represents diabetic control only in the preceding 3 months and in turn does not influence the severity of CAD. Proper medical treatment by antidiabetic medications in this short period might influence the level of HbA1c, but does not affect the long-term ongoing atherosclerotic process among diabetic patients. However, further studies including a larger number of patients may yield different results. In the Eeg-Olofsson et al. [29] study, it was proposed that follow-up of patients with estimation of the mean HbA1c over years may provide a more significant correlation with the severity of CAD. The inclusion of nondiabetic patients in our study was important as several studies reported that there is a significant correlation between the level of HbA1c and future cardiovascular morbidity in nondiabetics within normal ranges below the diagnostic level of DM.


  Conclusion Top


HbA1c level is a useful biomarker and has prognostic value to predict the severity of CAD among diabetic and nondiabetic patients as well as to predict future cardiovascular events. The GS may be used as a detailed scoring system to assess the severity of CAD.

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Conflicts of interest

There are no conflicts of interest.



 
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