|Year : 2015 | Volume
| Issue : 1 | Page : 29-33
Association between glycosylated hemoglobin and acute coronary syndrome in type 2 diabetes mellitus
Raju Hosuru Narayana1, Nithyananda Chowta Kallige1, Mangalore Venkatraya Prabhu1, Mukta Nithyananda Chowta2, Bhaskaran Unnikrishnan3
1 Department of Medicine, Kasturba Medical College, Manipal University, Mangalore, Karnataka, India
2 Department of Pharmacology, Kasturba Medical College, Manipal University, Mangalore, Karnataka, India
3 Department of Community Medicine, Kasturba Medical College, Manipal University, Mangalore, Karnataka, India
|Date of Web Publication||13-Apr-2015|
Nithyananda Chowta Kallige
Department of Medicine, Kasturba Medical College, Manipal University, Mangalore - 575 001, Karnataka
Source of Support: None, Conflict of Interest: None
Background and objective: Chronic hyperglycemia in type 2 diabetes increases the risk of microvascular events. However, the prognostic value of hemoglobin A1c (HbA1c) level in patients with coronary atherosclerotic disease has not been well characterized and remains controversial. This study was an attempt to know the association between HbA1c and acute coronary syndrome (ACS) in Indian type 2 diabetic patients. Materials and Methods: This study is a case-control study done at a tertiary care hospital. Cases were diabetic patients with ACS and controls were diabetic patients without any evidence of ACS. To eliminate confounding bias, matching was done between two groups for age, sex, duration of diabetes, presence of hypertension, smoking, and dyslipidemia. Patients belonging to either gender in age group of 40-80 years, with diagnosis of diabetes mellitus (as per American diabetic association (ADA) criteria) on treatment were selected. HbA1c was measured by immunological assay. Results: A total of 60 cases (Group A, diabetic patients with ACS) and 60 controls (Group B, diabetic patients without the evidence of ACS) were included in the study. Mean age of patients in group A is 64.22 ± 6.39 years and in group B is 64.48 ± 6.57 years. Duration of diabetes group in A is 9 ± 5.75 years and in group B is 9.2 ± 5.45 years. The association of HbA1c level with ACS was highly significant when analyzed by multiple regression analysis after adjusting for confounders (adjusted odds ratio (OR): 4.92, confidence interval (CI): 2.16-11.17, P = 0.0001).The difference in HbA1c level between the groups was highly significant in the whole groups (P < 0.0001) and when analyzed by categorizing the patients based on gender, presence of hypertension, dyslipidemia, and smoking. Conclusion: HbA1c level is strongly associated with risk of ACS. Occurrence of ACS was significantly more in patients with HbA1c level more than 7% when compared with patients with HbA1c level less than 7%.
Keywords: Acute coronary syndrome, diabetes mellitus, HbA1c
|How to cite this article:|
Narayana RH, Kallige NC, Prabhu MV, Chowta MN, Unnikrishnan B. Association between glycosylated hemoglobin and acute coronary syndrome in type 2 diabetes mellitus. Arch Med Health Sci 2015;3:29-33
|How to cite this URL:|
Narayana RH, Kallige NC, Prabhu MV, Chowta MN, Unnikrishnan B. Association between glycosylated hemoglobin and acute coronary syndrome in type 2 diabetes mellitus. Arch Med Health Sci [serial online] 2015 [cited 2022 May 19];3:29-33. Available from: https://www.amhsjournal.org/text.asp?2015/3/1/29/154938
| Introduction|| |
Chronic hyperglycemia in type 2 diabetes increases the risk of microvascular events. Though there is continuing uncertainty about its effect on macrovascular outcomes and death,  several studies have clearly demonstrated a link between type 2 diabetes and acute coronary syndromes (ACS). High prevalence of diabetes and undiagnosed diabetes or prediabetic states are seen in patients with stable or unstable coronary artery disease (CAD). 
This link can be attributed to hyperglycemia, insulin resistance, and a clustering of the risk factors for atherosclerosis. Potential mechanisms that could explain the relationship between diabetes mellitus and ACS include the following: decreased insulin sensitivity leading to impaired glucose used, increased levels of catecholamines leading to increased myocardial damage and infarct size, hyperglycemia-induced osmotic diuresis and volume depletion, enhanced platelet activation, and inflammatory-immune reactions with increased markers of inflammation. Fatty acids-mediated inhibition of glucose oxidation leads to myocardial cell death, injury of cardiomyocyte plasma membrane, calcium overload, and arrhythmias.  Several studies have shown prognostic role of hyperglycemia and diabetes in patients with ACS. Hyperglycemia at admission for ACS is associated with less favorable outcome. ,,,
Though acute hyperglycemia may be due to the preexisting diabetes mellitus, it may also occur as a part of stress response to the disease state. Hemoglobin A1c (HbA1c) is less influenced by acute stress. Therefore, HbA1c levels may provide insight into the relation between chronic glucose control and patient outcomes. Thus HbA1c level being a stable indicator of unstressed long-term glycemic control may be a more useful predictor in ACS. HbA1c level is an indicator of average blood glucose concentrations over the preceding 2-3 months, which is a convenient and well-known biomarker in clinical practice. It is now recommended as the preferred method for diagnosis and monitoring glycemic control in diabetes mellitus. Studies evaluating the association of HbA1c with ACS have reported discrepant results. Several studies showed higher crude mortality rate in patients with elevated HbA1c following adjustment for many cardiovascular risk factors. ,,
But many other studies failed to demonstrate HbA1c as the potent independent predictor of inhospital and long-term death in patients with ACS. The results of meta-analysis done by Liu et al. suggest that elevated HbA1c levels predict increased risk of short- and long-term mortality in patients hospitalized with CAD. After systematically reviewing previously published data and directly comparing the effect of HbA1c on outcomes in patients with and without recognized diabetes, they found that HbA1c levels had different prognostic effects based on patient's diabetes status. Elevated HbA1c was associated with a higher risk of mortality in patients without recognized diabetes even after adjusting for other known risk factors but had a neutral effect on mortality in patients with diabetes. Patients with elevated HbA1c but without known diabetes likely have diabetes that was neither diagnosed nor treated and other relevant cardiovascular risk factors such as hypertension and dyslipidemia that were also untreated before hospitalization, whereas those with diabetes are more likely to be treated with insulin and control the established risk factors.  Chan et al. suggested that HbA1c levels before admission are not associated with short-term cardiovascular outcome in diabetic patients subsequently admitted with ACS.  Thus, the prognostic value of HbA1c level in patients with coronary atherosclerotic disease has not been well characterized and remains controversial. Also there are not many studies in this regard in Indian population. This study was an attempt to know the association between HbA1c and ACS in Indian type 2 diabetic patients.
| Materials and Methods|| |
This study is a case-control study done at a tertiary care hospital. A total of 60 cases and 60 controls were included in the study. Cases were diabetic patients with ACS and controls were diabetic patients without any evidence of ACS. To eliminate confounding bias, matching was done between two groups for age, sex, duration of diabetes, presence of hypertension, smoking, and dyslipidemia. Patients belonging to either gender in age group of 40-80 years, with diagnosis of diabetes mellitus (as per American Diabetes Association (ADA) criteria) on treatment were selected. Patients with congenital or rheumatic heart disease were excluded from the study. The study was initiated after obtaining approval from institutional ethics committee and patients were enrolled into the study after their written informed consent. After screening, details of patients with regard to symptoms, duration of diabetes mellitus, medical history, and history of smoking were collected. All patients underwent thorough physical examination and the investigations done included fasting and postprandial blood glucose, HbA1c, troponins, Creatinine kinase-MB (CK-MB), Electrocardiogram (ECG), and echocardiography. ACS included the following diagnoses: unstable angina, non-ST elevation myocardial infarction (NSTEMI), and segment in ECG (ST) elevation myocardial infarction (STEMI). Symptoms of ACS included chest pain, shortness of breath, nausea, vomiting, palpitations, sweating, and anxiety. Diagnosis of ACS was based on at least two of the following: characteristic symptoms, electrocardiographic changes, and typical rise and fall in biochemical parameters (troponin, CK-MB). HbA1c was measured by High performance liquid chromatography (HPLC) method in a National Accreditation Board for Testing and Calibration Laboratories (NABL)-accredited laboratory.
Statistical analysis: Mean ± standard deviation was reported for continuous variables, and percentages (number) were reported for categorical variables. Continuous variables were compared using unpaired Student's t-test, and categorical variables were compared using chi-square tests. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each independent variable. All comparisons were two-tailed and P < 0.05 was considered statistically significant. The entire analysis was performed with Statistical Package for the Social Sciences (SPSS) version 11.5.
| Results|| |
A total of 60 cases (Group A, diabetic patients with ACS) and 60 controls (Group B, diabetic patients without the evidence of ACS) were included in the study. [Table 1] shows the comparison of baseline characteristics among two groups. Mean age of patients in group A was 64.22 ± 6.39 years and in group B was 64.48 ± 6.57 years. Duration of diabetes in group A was 9 ± 5.75 years and in group B was 9.2 ± 5.49 ± 5.75 5 years. HbA1c level was 8.43 ± 1.63% in group A and 7.15 ± 1.23% in group B. Distribution of patients between group A and B as per gender, smoking, hypertension, and dyslipidemia status was not significant (chi-square test, P > 0.05)
[Table 2] shows the comparison of HbA1c level between Group A and B among all patients as well as subgroup analysis. The difference in HbA1c level between the groups was highly significant in the whole groups (P < 0.0001) as well as when analyzed by categorizing the patients based on gender, presence of hypertension, dyslipidemia, and smoking.
|Table 2: Comparison of HbA1c level between Group A and B among all patients and in subgroups|
Click here to view
Comparison of HbA1c level among different age group category showed significant difference in age group 61-70 years and 71-80 years (P < 0.001, P = 0.026, respectively), but the difference was not significant in age group of 50-60 years (P = 0.09) [Table 2]. Mean difference in HbA1c level among patients with or without ACS progressively increased as the duration of diabetes increases.
When patients are categorized based on duration of diabetes mellitus, the differences in HbA1c level were statistically highly significant in all categories except in patients with duration of diabetes of 1-5 years (P = 0.08, [Table 2]). Mean difference in HbA1c level among patients with or without ACS progressively increased as the age advances.
[Table 3] shows the adjusted OR for association of HbA1c with ACS when analyzed by multiple regression analysis adjusting for confounders like age, gender, duration of diabetes mellitus, presence of dyslipidemia, hypertension, and smoking. HbA1c showed strong association with adjusted OR 4.92 (CI: 2.16-11.17, P = 0.0001).
|Table 3: Multivariate regression analysis showing adjusted OR for association between HbA1c and ACS|
Click here to view
| Discussion|| |
Many studies have clearly demonstrated the strong association of HbA1c with microvascular complications in type 2 diabetes mellitus. There are few studies in the western literature reporting the association of HbA1c with macrovascular complications like ACS. The present study was done to know the association of HbA1c level with ACS in Indian population. The results of our study showed that HbA1c level is significantly higher among diabetics with ACS when compared with diabetics without ACS even after matching for age, sex, duration of diabetes, hypertension, smoking, and dyslipidemia.
The cohort study done by Selvin and colleagues  on 7435 patients with type 2 diabetes mellitus has shown that 1% increase HbA1c was associated with 18% increase in the risk of coronary heart disease. In our study, mean HbA1c among diabetics with ACS was 8.43% and in diabetic patients without ACS was 7.15%. The difference was highly significant statistically. Subgroup analysis based on status of gender, smoking, dyslipidemia, and hypertension also showed similar results. The effect of these confounding variables was negligible as analyzed by calculation of OR, which did not show any statistical significance for all the variables in the study. The prospective population study done by Khaw and colleagues  on 10232 subjects has shown that after adjustment for systolic blood pressure, cholesterol level, body mass index, waist-to-hip ratio, smoking, and previous myocardial infarction or stroke, there was a 21% increase in cardiovascular events for every 1% increase in HbA1c level above 5%.
In contrast to our findings, Liu et al. suggested that elevated HbA1c was associated with a higher risk of mortality in patients without recognized diabetes but had a neutral effect on mortality in patients with diabetes. Chan et al. suggested that HbA1c levels before admission are not associated with short-term cardiovascular outcome in diabetic patients subsequently admitted with ACS. 
When analysis was done by categorizing the patients into different age group, the difference of HbA1c level among diabetic patients with and without ACS had not showed statistical significance for the age group 50-60 years (P = 0.09). The mean HbA1c level in this age group category was 7.6 ± 1.56% for diabetics with ACS and 6.83 ± 0.99% for diabetics without ACS. The HbA1c level in both the groups in this age category was near to normal range and higher in patients with ACS though statistically insignificant.
There are several biologically plausible mechanisms that might account for the finding that chronic hyperglycemia is associated with ACS. Hyperglycemic periods play a major role in the activation of oxidative stress and overproduction of mitochondrial superoxide, which trigger various metabolic pathways of glucose-mediated vascular damage. , Glucose can react with various proteins to form advanced glycation end products, which may contribute to long-term complications in diabetes, plaque formation, and atherosclerosis.  These effects are gradual and likely to be cumulative, occurring during decades of exposure to chronically elevated blood glucose levels. Elevated HbA1c level is likely the result of long-term insulin resistance. Metabolic disturbances associated with insulin resistance including hyperglycemia, dyslipidemia, hypercoagulability, and inflammation might play a major role in the adverse impact of elevated HbA1c on cardiovascular system.
Limitations of the present study is its cross-sectional design where we did not collect the follow up details to comment on the long-term outcomes and mortality associated with ACS in relation to HbA1c level. The number of patients in each group was also small to calculate cardiovascular risk with increase in percentage of HbA1c. Details regarding body mass index and anthropometric measurements were also not collected in our study. The strength of our study is matched control group for all confounding variables like duration of diabetes, age, sex, status of hypertension, dyslipidemia, and smoking.
| Conclusion|| |
HbA1c level is strongly associated with risk of ACS. Occurrence of ACS was significantly more in patients with HbA1c level more than 7% when compared with patients with HbA1c level less than 7%. Our finding supports the notion that diabetic patients with higher HbA1c level should be closely followed due to their higher risks of cardiovascular outcomes. HbA1c level is an independent predictor of CAD in patients with diabetes mellitus. Glycemic control may help to reduce cardiovascular events in type 2 diabetic patients. It is desirable to achieve target HbA1c level.
| References|| |
Zhang Y, Hu G, Yuan Z, Chen L. Glycosylated hemoglobin in relationship to cardiovascular outcomes and death in patients with type 2 diabetes: A systematic review and meta-analysis. PLoS One 2012;7:e42551.
De Caterina R, Madonna R, Sourij H, Wascher T. Glycaemic control in acute coronary syndromes:prognostic value and therapeutic options. Eur Heart J 2010;31:1557-64.
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004;88:787-835.
Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: A systematic overview. Lancet 2000;355:773-8.
Bolk J, van der Ploeg T, Cornel JH, Arnold AE, Sepers J, Umans VA. Impaired glucose metabolism predicts mortality after a myocardial infarction. Int J Cardiol 2001;79:207-14.
Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL, ICONS Investigators. Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol 2002;40:1748-54.
Foo K, Cooper J, Deaner A, Knight C, Suliman A, Ranjadayalan K, et al
. A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes. Heart 2003;89:512-6.
Cakmak M, Cakmak N, Cetemen S, Tanriverdi H, Enc Y, Teskin O, et al
. The value of admission glycosylated hemoglobin level in patients with acute myocardial infarction. Can J Cardiol 2008;24:375-8.
Hadjadj S, Coisne D, Mauco G, Ragot S, Duengler F, Sosner P, et al
. Prognostic value of admission plasma glucose and HbA in acute myocardial infarction. Diabet Med 2004;21:305-10.
Timmer JR, Hoekstra M, Nijsten MW, van der Horst IC, Ottervanger JP, Slingerland RJ, et al
. Prognostic value of admission glycosylated hemoglobin and glucose in nondiabetic patients with ST-segment-elevation myocardial infarction treated with percutaneous coronary intervention. Circulation 2011;124:704-11.
Liu Y, Yang YM, Zhu J, Tan HQ, Liang Y, Li JD. Prognostic significance of hemoglobin A1c level in patients hospitalized with coronary artery disease. A systematic review and meta-analysis. Cardiovasc Diabetol 2011;10:98.
Britton KA, Aggarwal V, Chen AY, Alexander KP, Amsterdam E, Fraulo E, et al
. No association between hemoglobin a1c and in-hospital mortality in patients with diabetes and acutemyocardial infarction. Am Heart J 2011;161:657-63.
Chan CY, Li R, Chan JY, Zhang Q, Chan CP, Dong M, et al
. The value of admission HbA(1c) level in diabetic patients with acute coronary syndrome. Clin Cardiol 2011;34:507-12.
Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Power NR, et al
. Meta-analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421-31.
Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A 1C
with cardiovascular disease and mortality in adults. Ann Intern Med 2004;141:413-20.
Brownlee M, Hirsch IB. Glycemic variability: A hemoglobin A1c-independent risk factor for diabetic complications. JAMA 2006;295:1707-8.
Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, et al
. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006;295:1681-7.
Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 2002;288:2579-88.
[Table 1], [Table 2], [Table 3]