Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with diabetes, for which 65% of deaths are attributable to heart disease or stroke. Hyperglycemia is encountered in up to 50% of all ST elevation myocardial infarcted (STEMI) patients, whereas previously diagnosed DM is present in only 20% to 25% of STEMI patients. (1) When admission glucose level exceeds 200 mg/dL, mortality is similar in non-DM and DM subjects with MI. Admission glucose has been identified as a major independent predictor of both in-hospital congestive heart failure and mortality in STEMI (1). In the HEART2D Study treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event (2).   Recently the glucose variability has been highlighted (3).  Recent analyses delving into glucose variability in diabetic patients’ post-myocardial infarction have sparked intrigue. Despite efforts to target intraday glucose variability as opposed to basal glucose levels, the anticipated reduction in cardiovascular outcomes remains elusive (4,5). These findings underscore the complexity of glycemic management in high-risk populations and underscore the imperative for multifaceted approaches addressing not only glucose levels but also variability (6,7). The pervasive threat of coronary artery disease (CAD) looms large, particularly in the context of diabetes mellitus. As the leading cause of mortality in industrialized nations, CAD poses a formidable challenge exacerbated by the heightened risk conferred by diabetes (8,9). The intricate interplay between metabolic derangements, endothelial dysfunction, and atherosclerosis underscores the need for targeted interventions aimed at stemming the tide of cardiovascular morbidity and mortality in diabetic populations (15,16). The grim prognosis associated with diabetes-related cardiovascular complications casts a shadow over patient outcomes. With diabetic individuals facing a markedly elevated risk of cardiovascular disease, the resultant decline in life expectancy underscores the urgency of proactive management strategies (1,2).  The convergence of traditional cardiovascular risk factors and diabetes-related pathophysiological mechanisms underscores the need for a holistic approach encompassing lifestyle modification, pharmacotherapy, and vigilant risk factor management (20,21). A1c hemoglobin serves as a cornerstone in the assessment of long-term glycemic control, offering valuable insights into diabetes management. While acute coronary syndromes may transiently influence A1c levels, its utility as a prognostic marker in high-risk cardiovascular cohorts remains undisputed (22). Leveraging A1c hemoglobin as a predictive tool holds promise for refining risk stratification algorithms and tailoring therapeutic interventions to mitigate adverse outcomes in vulnerable patient populations (23,24). Efforts to unravel the prevalence of undiagnosed diabetes mellitus and prediabetes in STEMI patients represent a crucial frontier in cardiovascular research (226,25). By shedding light on the prevalence and impact of undiagnosed dysglycemia in this high-risk cohort, these endeavors hold promise for informing targeted screening and intervention strategies aimed at mitigating the burden of diabetes-related cardiovascular complications. Embracing a proactive approach to diabetes screening and management is paramount in stemming the tide of cardiovascular morbidity and mortality in at-risk populations (28,29). Diabetes mellitus is linked to increased mortality rates in patients with acute MI (AMI) during both in-hospital and long-term follow-up. This is the case for the entire range of ACS. (30). In that study, patients with ACS who had diabetes had a higher risk of both death and re-infarction at 30 days than those without diabetes. The rates of mortality or reinfarction at 6 months remained higher in the diabetic group, regardless of whether they reported STEMI or NSTEMI. (31,32,33,34). High blood glucose levels are prevalent in patients who have been admitted for ACS/AMI and are linked to an elevated risk of mortality in both diabetic and non-diabetic patients. (35,36,37,38).  In patients without a medical history of diabetes, admission hyperglycemia is an even more potent predictor of mortality. (39). The previous research has established a correlation between diabetes and ACS. However, the objective of our study is to ascertain the prevalence of undiagnosed diabetes in patients with ACS and to compare the 30-day mortality rate of patients with undiagnosed diabetes to that of normal-glycemic and known diabetic patients. (40).   The aim of this study is to determine the frequency of undiagnosed diabetes mellitus and prediabetes in STEMI patients

This cross-sectional study was conducted in the Coronary Care Unit of Azadi Teaching Hospital, focusing on the relationship between glycemic indices and cardiovascular risk among non-diabetic individuals. The study spanned from April 2023 to July 2023.

Study Population

A cohort of 51 non-diabetic patients, aged between 31 and 91 years, was selected from the Duhok Governorate. The cohort included 44 males and 7 females.

Data Collection

A pre-tested questionnaire was used to gather demographic information (name, gender) and medical history (diabetes mellitus, hypertension, smoking habits, hyperlipidemia). Additionally, serum levels of fasting blood glucose (FBS), glycosylated hemoglobin (HbA1c), fasting total serum cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL), and serum triglycerides were recorded.

Diagnostic Criteria

Cardiovascular events like ST-elevation myocardial infarction (STEMI) and unstable angina were diagnosed using criteria from the European Society of Cardiology (ESC) and the American College of Cardiology (ACC).

Stratification by HbA1c Levels

Patients were stratified into three groups based on HbA1c levels: Group 1 (<5.7), Group 2 (5.7-6.4), and Group 3 (≥6.5), following the guidelines of the American Diabetes Association.

Diagnosis of Undiagnosed Diabetes Mellitus

Undiagnosed diabetes mellitus was identified in individuals with elevated fasting and random glucose levels and an HbA1c level above 6.5%.

Risk Factors Assessment

Blood pressure (systolic and diastolic) was measured to evaluate cardiovascular risk. This assessment highlighted the interaction between glycemic indices, traditional risk factors, and cardiovascular outcomes.

Sample Collection and Analysis

Venous blood was collected from each subject, with 1 ml added to EDTA tubes for the immunofluorescence technique (i-chroma II) and 4 ml transferred to sterile gel tubes. After clotting and centrifugation, the sera were stored at -30ºC for analysis of serum glucose, cholesterol, and HDL-C levels.

Statistical Analysis

Data were analyzed using SPSS. A paired Student's t-test assessed differences in serum analytes among groups. The Chi-square test evaluated associations between risk factors, with statistical significance set at p < 0.05.

The baseline characteristics of the patients show that a majority are aged ≥50 years (78.4%), predominantly male (86.3%), and a significant portion are smokers (64.7%). About one-third have a history of hypertension (35.3%), while very few have a history of coronary heart disease (3.9%). Approximately one-third have a family history of diabetes (33.3%), and over half are hypertensive (56.9%). Most patients have normal fasting blood sugar levels (74.5%), with a significant portion being pre-diabetic based on HbA1c levels (31.4%) and a majority being non-diabetic (52.9%). A small proportion have high total cholesterol (21.6%), while a notable portion have high triglyceride levels (64.7%). Additionally, a considerable number of male patients have low HDL levels (47.1%), with a smaller fraction of female patients having low HDL levels (13.7%).

Table 1: Baseline characteristics of patients

Table 2 illustrates the gender distribution within different HbA1c categories, showing that a majority of the patients are male across all groups. Among diabetic patients, 75.0% are male and 25.0% are female. In the pre-diabetic group, 87.5% are male and 12.5% are female, while in the non-diabetic group, 88.9% are male and 11.1% are female. Overall, males constitute 86.3% of the total patient population, with females making up 13.7%.

Table 2: Distribution of study groups according to gender

P value =0.59

Table 3 highlights the distribution of study groups according to fasting blood sugar (FBS) levels within different HbA1c categories. Among patients with hyperglycemia (≥12), 37.5% are diabetic, 18.8% are pre-diabetic, and 25.9% are non-diabetic, comprising 25.5% of the total population. In contrast, the majority of patients with normoglycemia (<129) are non-diabetic (74.1%), followed by pre-diabetic (81.3%) and diabetic (62.5%), making up 74.5% of the total population.

Table 3: Distribution of study groups according to FBS:

P value =0.6

Table 4 shows the distribution of study groups according to total cholesterol levels within different HbA1c categories. Among patients with hypercholesterolemia (≥200), 50.0% are diabetic, 18.8% are pre-diabetic, and 14.8% are non-diabetic, representing 21.6% of the total population. Conversely, among those with normal cholesterol levels (<200), 50.0% are diabetic, 81.3% are pre-diabetic, and 85.2% are non-diabetic, making up 78.4% of the total population. This suggests that a higher percentage of pre-diabetic and non-diabetic patients maintain normal cholesterol levels, whereas hypercholesterolemia is more evenly distributed among the diabetic group.

Table 4: Distribution of study groups according to total cholesterol

P value=0.09

Table 5 presents the distribution of study groups according to HDL levels for both females and males within different HbA1c categories. For females with low HDL (<50), all diabetic (100%), pre-diabetic (100%), and 50% of non-diabetic patients fall into this category. Conversely, none of the diabetic or pre-diabetic females have normal HDL (≥50), but 50% of non-diabetic females do. For males with low HDL (<40), 66.7% of diabetic, 69.2% of pre-diabetic, and 47.8% of non-diabetic patients are included. Among those with normal HDL (≥40), 33.3% of diabetic, 30.8% of pre-diabetic, and 52.2% of non-diabetic males fall into this category. T

Table 5: Distribution of study groups according to HDL for female

P value=0.4

The distribution of study groups according to smoking status within different HbA1c categories reveals that among smokers, 75.0% are diabetic, 56.3% are pre-diabetic, and 66.7% are non-diabetic, making up 64.7% of the total population. Among non-smokers, 25.0% are diabetic, 43.8% are pre-diabetic, and 33.3% are non-diabetic, comprising 35.3% of the total population. This indicates that smoking is more prevalent among diabetic and non-diabetic patients compared to pre-diabetic patients, while non-smoking is more common among pre-diabetic patients.

Table 6: Distribution of study groups according to smoking.

P value=0.63

Table 7 shows the distribution of study groups according to hypertension history within different HbA1c categories. Among those with a positive history of hypertension, 50.0% are diabetic, 31.3% are pre-diabetic, and 33.3% are non-diabetic, comprising 35.3% of the total population. For those with a negative history of hypertension, 50.0% are diabetic, 68.8% are pre-diabetic, and 66.7% are non-diabetic, making up 64.7% of the total population. This indicates that a positive history of hypertension is equally common among diabetic patients but less common among pre-diabetic and non-diabetic patients. Conversely, a negative history of hypertension is more prevalent among pre-diabetic and non-diabetic patients, highlighting that the majority of the patient population (64.7%) does not have a history of hypertension.

Table 7: Distribution of study groups according to Hypertension

P value=0.6

Table 8 presents the distribution of study groups according to family history of coronary heart disease (CHD) within different HbA1c categories. Among those with a positive family history of CHD, none are diabetic (0%), 6.3% are pre-diabetic, and 3.7% are non-diabetic, representing 3.9% of the total population. In contrast, among those with a negative family history of CHD, 100% of diabetic, 93.8% of pre-diabetic, and 96.3% of non-diabetic patients fall into this category, comprising 96.1% of the total population. This data indicates that a family history of CHD is quite rare among the patients, with the vast majority (96.1%) having no such history.

Table 8: Distribution of study groups according to family HX of CHD

P value=0.7

The distribution of study groups according to family history of diabetes mellitus (DM) within different HbA1c categories reveals significant differences. Among those with a positive family history of DM, 87.5% are diabetic, 18.8% are pre-diabetic, and 25.9% are non-diabetic, comprising 33.3% of the total population. Conversely, among those with a negative family history of DM, 12.5% are diabetic, 81.3% are pre-diabetic, and 74.1% are non-diabetic, making up 66.7% of the total population. This data indicates that a positive family history of DM is strongly associated with diabetes, as a high percentage of diabetic patients have a family history of DM. The P value of 0.002 suggests that this association is statistically significant.

Table 9: Distribution of study groups according to family history of DM 

P value =0.002

Table 10 shows the distribution of study groups according to current blood pressure within different HbA1c categories. Among hypertensive patients (≥140/90), 75.0% are diabetic, 56.3% are pre-diabetic, and 51.9% are non-diabetic, making up 56.9% of the total population. In contrast, among non-hypertensive patients (<140/90), 25.0% are diabetic, 43.8% are pre-diabetic, and 48.1% are non-diabetic, comprising 43.1% of the total population. This indicates that a higher percentage of diabetic and pre-diabetic patients have hypertension compared to non-diabetic patients, suggesting a correlation between higher blood pressure and increased HbA1c levels. Overall, hypertensive individuals represent a slight majority (56.9%) of the total patient population.

Table 10: Distribution of study groups according to current blood pressure:

P value =0.5

According to the findings of the current investigation, having elevated HbA1c levels at the time of admission was a significant risk factor for STEMI. Researchers Selvin E. et al. and Khaw KT. et al. demonstrated that an elevated HbA1c is linked to an increased risk of cardiovascular disease in patients who have diabetes as well as those who do not have diabetes (31,32). An relationship between increased HbA1c and mortality after myocardial infarction was discovered by Malmberg et al., with a relative risk (95% CI) of 1.07 (1.01-1.21) (33). However, Timmer et al. and Cao et al. did not confirm this association, with 1.63 (0.99-2.79) and 1.08 (0.31-3.23) respectively. With due respect (34,35).  There was a clear association between rising HbA1c levels and unfavorable baseline features, such as a higher cardiovascular risk profile, which helped to explain a portion of the bad outcome of acute coronary syndrome for example.  Non-diabetic patients had a higher link between hyperglycemia and increased in-hospital mortality than diabetic patients did, according to a systematic evaluation of several studies that were conducted on acute myocardial infarction (AMI) (44,45,46,47). The majority of our non-diabetic patients, specifically 8 out of 51 (15.7%), and 16 out of 50 (31.4%), had HbA1c levels that were between 5.7 and 6.4%, and 27 out of 51 (59.2%) had HbA1c levels that were less than 5.7.  There was a significant link between HbA1c and cardiovascular risk factors, according to the findings of a study that was carried out on Asian Indians who had normal glucose tolerance (NGT). The HbA1c levels of NGT participants with three or more metabolic abnormalities were found to be the highest. Furthermore, it was discovered that a HbA1c cut off point of > 6.5% had the highest accuracy in predicting both metabolic syndrome and coronary artery disease (336,37). An elevated glucose level is not only a marker of glucose dysregulation, but it is also a symptom of stress and individuals who are at a higher risk of developing diabetes. Stress hyperglycemia is a medical condition that frequently occurs in patients who have been admitted to intensive care units and have acute coronary syndromes.  Within the scope of our research, 15.7% of the entire sample was identified as new cases of diabetes. According to the findings of a recent cohort study, increased HbA1c levels can be predictive for cardiovascular disease and death in patients who do not have diabetes mellitus. This is the case regardless of the patient's fasting glucose levels (38).  In addition to the effect of insulin resistance that is linked with ACS, excess glucose may be directly deleterious during the condition, which provides a target for treatment. Amplification of inflammation, suppression of immunity, and the promotion of oxidative stress are some of the molecular mechanisms that are responsible for this deleterious effect. Other mechanisms include the non-enzymatic glycation of platelet glycoproteins, which is accompanied by rapid changes in aggregability (39). In point of fact, a number of studies have demonstrated that hypoglycemic patients with hyperglycemia who had not been diagnosed with diabetes before had a higher risk of cardiovascular mortality and morbidity than patients who were diagnosed with diabetes or subjects who were not hypoglycemic (41). Furthermore, the complex mechanisms that are responsible for the negative connection between overt diabetes mellitus and cardiovascular fate are also responsible for a portion of the association that exists between long-term aberrations in glucose control and outcome (41).

Multivariate logistic regression analysis in this study showed that in STEMI patients without known diabetes mellitus, both short- and long-term abnormalities in glucose control assessed by FBS and HbA1c respectively; are associated with poor outcome. HbA1c may be used to assess cardiovascular risk in a nondiabetic population with STEMI.

Recommendation

1. Glucose level should be a part of the initial laboratory evaluation in all patients with suspected or confirmed acute coronary syndrome.

1. In patients admitted to an ICU with acute myocardial infarction, glucose levels should be monitored closely. It is reasonable to consider intensive glucose control in patients with significant hyperglycemia (plasma glucose >180 mg/dL), regardless of prior diabetes history. Although efforts to optimize glucose control may also be considered in patients with milder degrees of hyperglycemia, the data regarding a benefit from this approach are not yet definitive, and regardless of diabetes status. The precise goal of treatment has not yet been defined. Until further data are available, approximation of normoglycemia appears to be a reasonable goal (suggested range for plasma glucose 90 to 140 mg/dl) ,as long as hypoglycemia is avoided.

1. Acute myocardial infarcted patients with hyperglycemia but without prior history of diabetes should have further evaluation (preferably before hospital discharge) to determine the severity of their metabolic derangements. This evaluation may include fasting glucose and HbA1C assessment and, in some cases, a post discharge oral glucose tolerance test and follow up.

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